%0 Journal Article %J Epigenetics %D 2024 %T Epigenome-wide association study of long-term psychosocial stress in older adults. %A Opsasnick, Lauren A %A Zhao, Wei %A Schmitz, Lauren L %A Ratliff, Scott M %A Faul, Jessica D %A Zhou, Xiang %A Needham, Belinda L %A Smith, Jennifer A %K DNA Methylation %K Epigenome %K Smoking %K Stress, Psychological %K Tobacco Smoking %X

Long-term psychosocial stress is strongly associated with negative physical and mental health outcomes, as well as adverse health behaviours; however, little is known about the role that stress plays on the epigenome. One proposed mechanism by which stress affects DNA methylation is through health behaviours. We conducted an epigenome-wide association study (EWAS) of cumulative psychosocial stress ( = 2,689) from the Health and Retirement Study (mean age = 70.4 years), assessing DNA methylation (Illumina Infinium HumanMethylationEPIC Beadchip) at 789,656 CpG sites. For identified CpG sites, we conducted a formal mediation analysis to examine whether smoking, alcohol use, physical activity, and body mass index (BMI) mediate the relationship between stress and DNA methylation. Nine CpG sites were associated with psychosocial stress (all  < 9E-07; FDR q < 0.10). Additionally, health behaviours and/or BMI mediated 9.4% to 21.8% of the relationship between stress and methylation at eight of the nine CpGs. Several of the identified CpGs were in or near genes associated with cardiometabolic traits, psychosocial disorders, inflammation, and smoking. These findings support our hypothesis that psychosocial stress is associated with DNA methylation across the epigenome. Furthermore, specific health behaviours mediate only a modest percentage of this relationship, providing evidence that other mechanisms may link stress and DNA methylation.

%B Epigenetics %V 19 %P 2323907 %G eng %N 1 %R 10.1080/15592294.2024.2323907 %0 Journal Article %J Genes %D 2022 %T Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium. %A Xu, Huichun %A Nguyen, Kevin %A Gaynor, Brady J %A Ling, Hua %A Zhao, Wei %A McArdle, Patrick F %A O'Connor, Timothy D %A Stine, O Colin %A Ryan, Kathleen A %A Lynch, Megan %A Smith, Jennifer A %A Jessica Faul %A Hu, Yao %A Haessler, Jeffrey W %A Fornage, Myriam %A Kooperberg, Charles %A Perry, James A %A Hong, Charles C %A Cole, John W %A Pugh, Elizabeth %A Doheny, Kimberly %A Sharon L R Kardia %A David R Weir %A Kittner, Steven J %A Mitchell, Braxton D %K Exome %K Gene Frequency %K Genome-Wide Association Study %K Ischemic stroke %K Stroke %X

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., < 4.7 × 10), including two common SNPs in that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples ( = 5613 cases) or UK Biobank ( = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.

%B Genes %V 14 %P 61 %G eng %N 1 %R 10.3390/genes14010061 %0 Journal Article %J Molecular Psychiatry %D 2022 %T Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. %A Lahti, Jari %A Tuominen, Samuli %A Yang, Qiong %A Pergola, Giulio %A Ahmad, Shahzad %A Amin, Najaf %A Armstrong, Nicola J %A Beiser, Alexa %A Bey, Katharina %A Bis, Joshua C %A Boerwinkle, Eric %A Bressler, Jan %A Campbell, Archie %A Campbell, Harry %A Chen, Qiang %A Corley, Janie %A Cox, Simon R %A Davies, Gail %A De Jager, Philip L %A Derks, Eske M %A Jessica Faul %A Fitzpatrick, Annette L %A Fohner, Alison E %A Ford, Ian %A Fornage, Myriam %A Gerring, Zachary %A Grabe, Hans J %A Grodstein, Francine %A Gudnason, Vilmundur %A Simonsick, Eleanor %A Holliday, Elizabeth G %A Joshi, Peter K %A Kajantie, Eero %A Kaprio, Jaakko %A Karell, Pauliina %A Kleineidam, Luca %A Knol, Maria J %A Kochan, Nicole A %A Kwok, John B %A Leber, Markus %A Lam, Max %A Lee, Teresa %A Li, Shuo %A Loukola, Anu %A Luck, Tobias %A Marioni, Riccardo E %A Mather, Karen A %A Medland, Sarah %A Mirza, Saira S %A Nalls, Mike A %A Nho, Kwangsik %A O'Donnell, Adrienne %A Oldmeadow, Christopher %A Painter, Jodie %A Pattie, Alison %A Reppermund, Simone %A Risacher, Shannon L %A Rose, Richard J %A Sadashivaiah, Vijay %A Scholz, Markus %A Satizabal, Claudia L %A Schofield, Peter W %A Schraut, Katharina E %A Scott, Rodney J %A Simino, Jeannette %A Smith, Albert V %A Smith, Jennifer A %A Stott, David J %A Surakka, Ida %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Trompet, Stella %A Turner, Stephen T %A van der Lee, Sven J %A Villringer, Arno %A Völker, Uwe %A Wilson, Robert S %A Wittfeld, Katharina %A Vuoksimaa, Eero %A Xia, Rui %A Yaffe, Kristine %A Yu, Lei %A Zare, Habil %A Zhao, Wei %A Ames, David %A Attia, John %A Bennett, David A %A Brodaty, Henry %A Chasman, Daniel I %A Goldman, Aaron L %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Sharon L R Kardia %A Lencz, Todd %A Loeffler, Markus %A Mattay, Venkata S %A Palotie, Aarno %A Psaty, Bruce M %A Ramirez, Alfredo %A Ridker, Paul M %A Riedel-Heller, Steffi G %A Sachdev, Perminder S %A Saykin, Andrew J %A Scherer, Martin %A Schofield, Peter R %A Sidney, Stephen %A Starr, John M %A Trollor, Julian %A Ulrich, William %A Wagner, Michael %A David R Weir %A Wilson, James F %A Wright, Margaret J %A Weinberger, Daniel R %A Debette, Stéphanie %A Eriksson, Johan G %A Mosley, Thomas H %A Launer, Lenore J %A van Duijn, Cornelia M %A Deary, Ian J %A Seshadri, Sudha %A Räikkönen, Katri %K Genome %K health outcomes %K Memory %K neurocognitive outcomes %K polygenic score %K Verbal Learning %X

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

%B Molecular Psychiatry %G eng %R 10.1038/s41380-022-01710-8 %0 Journal Article %J Genes %D 2022 %T The Interplay of Epigenetic, Genetic, and Traditional Risk Factors on Blood Pressure: Findings from the Health and Retirement Study. %A Zhang, Xinman %A Ammous, Farah %A Lin, Lisha %A Ratliff, Scott M %A Ware, Erin B %A Jessica Faul %A Zhao, Wei %A Sharon L R Kardia %A Smith, Jennifer A %K Blood pressure %K DNA Methylation %K genetic risk score %K Genetics %K interaction %K methylation risk score. %X

The epigenome likely interacts with traditional and genetic risk factors to influence blood pressure. We evaluated whether 13 previously reported DNA methylation sites (CpGs) are associated with systolic (SBP) or diastolic (DBP) blood pressure, both individually and aggregated into methylation risk scores (MRS), in 3070 participants (including 437 African ancestry (AA) and 2021 European ancestry (EA), mean age = 70.5 years) from the Health and Retirement Study. Nine CpGs were at least nominally associated with SBP and/or DBP after adjusting for traditional hypertension risk factors ( < 0.05). MRS was positively associated with SBP in the full sample (β = 1.7 mmHg per 1 standard deviation in MRS; = 2.7 × 10) and in EA (β = 1.6; = 0.001), and MRS with DBP in the full sample (β = 1.1; = 1.8 × 10), EA (β = 1.1; = 7.2 × 10), and AA (β = 1.4; = 0.03). The MRS and BP-genetic risk scores were independently associated with blood pressure in EA. The effects of both MRSs were weaker with increased age ( < 0.01), and the effect of MRS was higher among individuals with at least some college education ( = 0.02). In AA, increasing MRS was associated with higher SBP in females only ( = 0.01). Our work shows that MRS is a potential biomarker of blood pressure that may be modified by traditional hypertension risk factors.

%B Genes %V 13 %P 1959 %G eng %N 11 %R 10.3390/genes13111959 %0 Journal Article %J Epigenetics %D 2022 %T The Socioeconomic Gradient in Epigenetic Ageing Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study. %A Lauren L Schmitz %A Zhao, Wei %A Scott M Ratliff %A Goodwin, Julia %A Miao, Jiacheng %A Lu, Qiongshi %A Guo, Xiuqing %A Kent D Taylor %A Ding, Jingzhong %A Liu, Yongmei %A Morgan E. Levine %A Smith, Jennifer A %K DNA methylation age %K epigenetic clock %K polygenic score %K socioeconomic status %X

Epigenetic clocks have been widely used to predict disease risk in multiple tissues or cells. Their success as a measure of biological ageing has prompted research on the connection between epigenetic pathways of ageing and the socioeconomic gradient in health and mortality. However, studies examining social correlates of epigenetic ageing have yielded inconsistent results. We conducted a comprehensive, comparative analysis of associations between various dimensions of socioeconomic status (SES) (education, income, wealth, occupation, neighbourhood environment, and childhood SES) and eight epigenetic clocks in two well-powered US ageing studies: The Multi-Ethnic Study of Atherosclerosis (MESA) (n = 1,211) and the Health and Retirement Study (HRS) (n = 4,018). In both studies, we found robust associations between SES measures in adulthood and the GrimAge and DunedinPoAm clocks (Bonferroni-corrected -value < 0.01). In the HRS, significant associations with the Levine and Yang clocks were also evident. These associations were only partially mediated by smoking, alcohol consumption, and obesity, which suggests that differences in health behaviours alone cannot explain the SES gradient in epigenetic ageing in older adults. Further analyses revealed concurrent associations between polygenic risk for accelerated intrinsic epigenetic ageing, SES, and the Levine clock, indicating that genetic risk and social disadvantage may contribute additively to faster biological aging.

%B Epigenetics %V 17 %P 589-611 %G eng %N 6 %R 10.1080/15592294.2021.1939479 %0 Journal Article %J The Journals of Gerontology, Series A %D 2022 %T Trans-ethnic Meta-analysis of Interactions between Genetics and Early Life Socioeconomic Context on Memory Performance and Decline in Older Americans. %A Jessica Faul %A Kho, Minjung %A Zhao, Wei %A Rumfelt, Kalee E %A Yu, Miao %A Colter Mitchell %A Smith, Jennifer A %K Childhood SES %K Cognition %K Education %K Epidemiology %K Gene-Environment Interaction %K Genetics %K Memory %K Rare Variant %X

Later life cognitive function is influenced by genetics as well as early- and later-life socioeconomic context. However, few studies have examined the interaction between genetics and early childhood factors. Using gene-based tests (iSKAT/iSKAT-O), we examined whether common and/or rare exonic variants in 39 gene regions previously associated with cognitive performance, dementia, and related traits had an interaction with childhood socioeconomic context (parental education and financial strain) on memory performance or decline in European ancestry (EA, N=10,468) and African ancestry (AA, N=2,252) participants from the Health and Retirement Study. Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions with at least one childhood socioeconomic measure on memory performance and/or decline; however, all but one (father's education by SLC24A4 in AA) were not significant after multiple testing correction (FDR <0.05). In trans-ethnic meta-analysis, two genes interacted with childhood socioeconomic context (FDR <0.05): mother's education by MS4A4A on memory performance, and father's education by SLC24A4 on memory decline. Both interactions remained significant (p<0.05) after adjusting for respondent's own educational attainment, APOE ε4 status, lifestyle factors, BMI, and comorbidities. For both interactions in EA and AA, the genetic effect was stronger in participants with low parental education. Examination of common and rare variants in genes discovered through GWAS shows that childhood context may interact with key gene regions to jointly impact later life memory function and decline. Genetic effects may be more salient for those with lower childhood socioeconomic status.

%B The Journals of Gerontology, Series A %V 77 %P 2248-2256 %G eng %N 11 %R 10.1093/gerona/glab255 %0 Journal Article %J The American Journal of Human Genetics %D 2021 %T Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. %A Graff, Mariaelisa %A Justice, Anne E %A Young, Kristin L %A Marouli, Eirini %A Zhang, Xinruo %A Fine, Rebecca S %A Lim, Elise %A Buchanan, Victoria %A Rand, Kristin %A Feitosa, Mary F %A Wojczynski, Mary K %A Yanek, Lisa R %A Shao, Yaming %A Rohde, Rebecca %A Adeyemo, Adebowale A %A Aldrich, Melinda C %A Matthew A. Allison %A Ambrosone, Christine B %A Ambs, Stefan %A Amos, Christopher %A Donna K Arnett %A Atwood, Larry %A Bandera, Elisa V %A Traci M Bartz %A Becker, Diane M %A Berndt, Sonja I %A Bernstein, Leslie %A Bielak, Lawrence F %A Blot, William J %A Erwin P Bottinger %A Bowden, Donald W %A Bradfield, Jonathan P %A Brody, Jennifer A %A Broeckel, Ulrich %A Burke, Gregory %A Brian E Cade %A Cai, Qiuyin %A Caporaso, Neil %A Carlson, Chris %A John Carpten %A Casey, Graham %A Chanock, Stephen J %A Chen, Guanjie %A Chen, Minhui %A Chen, Yii-Der I %A Chen, Wei-Min %A Chesi, Alessandra %A Chiang, Charleston W K %A Chu, Lisa %A Coetzee, Gerry A %A Conti, David V %A Cooper, Richard S %A Cushman, Mary %A Ellen W Demerath %A Deming, Sandra L %A Dimitrov, Latchezar %A Ding, Jingzhong %A Diver, W Ryan %A Duan, Qing %A Michele K Evans %A Falusi, Adeyinka G %A Jessica Faul %A Myriam Fornage %A Caroline S Fox %A Freedman, Barry I %A Garcia, Melissa %A Gillanders, Elizabeth M %A Phyllis J Goodman %A Gottesman, Omri %A Grant, Struan F A %A Guo, Xiuqing %A Hakonarson, Hakon %A Haritunians, Talin %A Tamara B Harris %A Harris, Curtis C %A Henderson, Brian E %A Hennis, Anselm %A Dena G Hernandez %A Hirschhorn, Joel N %A McNeill, Lorna Haughton %A Howard, Timothy D %A Howard, Barbara %A Hsing, Ann W %A Hsu, Yu-Han H %A Hu, Jennifer J %A Huff, Chad D %A Huo, Dezheng %A Ingles, Sue A %A Irvin, Marguerite R %A John, Esther M %A Johnson, Karen C %A Jordan, Joanne M %A Kabagambe, Edmond K %A Kang, Sun J %A Sharon L R Kardia %A Keating, Brendan J %A Rick A Kittles %A Eric A Klein %A Kolb, Suzanne %A Kolonel, Laurence N %A Charles Kooperberg %A Kuller, Lewis %A Kutlar, Abdullah %A Leslie A Lange %A Langefeld, Carl D %A Loic Le Marchand %A Leonard, Hampton %A Lettre, Guillaume %A Levin, Albert M %A Li, Yun %A Li, Jin %A Liu, Yongmei %A Liu, Youfang %A Liu, Simin %A Kurt Lohman %A Lotay, Vaneet %A Lu, Yingchang %A Maixner, William %A JoAnn E Manson %A McKnight, Barbara %A Meng, Yan %A Monda, Keri L %A Monroe, Kris %A Moore, Jason H %A Thomas H Mosley %A Mudgal, Poorva %A Murphy, Adam B %A Nadukuru, Rajiv %A Michael A Nalls %A Nathanson, Katherine L %A Nayak, Uma %A N'Diaye, Amidou %A Nemesure, Barbara %A Neslund-Dudas, Christine %A Neuhouser, Marian L %A Nyante, Sarah %A Ochs-Balcom, Heather %A Ogundiran, Temidayo O %A Ogunniyi, Adesola %A Ojengbede, Oladosu %A Okut, Hayrettin %A Olopade, Olufunmilayo I %A Olshan, Andrew %A Padhukasahasram, Badri %A Palmer, Julie %A Palmer, Cameron D %A Palmer, Nicholette D %A George J Papanicolaou %A Patel, Sanjay R %A Pettaway, Curtis A %A Peyser, Patricia A %A Press, Michael F %A Rao, D C %A Rasmussen-Torvik, Laura J %A Redline, Susan %A Reiner, Alex P %A Rhie, Suhn K %A Rodriguez-Gil, Jorge L %A Charles N Rotimi %A Rotter, Jerome I %A Ruiz-Narvaez, Edward A %A Rybicki, Benjamin A %A Babatunde Salako %A Sale, Michele M %A Sanderson, Maureen %A Eric E Schadt %A Schreiner, Pamela J %A Schurmann, Claudia %A Schwartz, Ann G %A Daniel Shriner %A Signorello, Lisa B %A Andrew B Singleton %A David S Siscovick %A Smith, Jennifer A %A Smith, Shad %A Elizabeth K Speliotes %A Spitz, Margaret %A Stanford, Janet L %A Stevens, Victoria L %A Stram, Alex %A Strom, Sara S %A Sucheston, Lara %A Yan V Sun %A Tajuddin, Salman M %A Taylor, Herman %A Taylor, Kira %A Bamidele O Tayo %A Michael J Thun %A Tucker, Margaret A %A Vaidya, Dhananjay %A Van Den Berg, David J %A Vedantam, Sailaja %A Vitolins, Mara %A Wang, Zhaoming %A Erin B Ware %A Wassertheil-Smoller, Sylvia %A David R Weir %A Wiencke, John K %A Williams, Scott M %A L Keoki Williams %A Wilson, James G %A Witte, John S %A Wrensch, Margaret %A Wu, Xifeng %A Yao, Jie %A Zakai, Neil %A Zanetti, Krista %A Zemel, Babette S %A Zhao, Wei %A Jing Hua Zhao %A Zheng, Wei %A Zhi, Degui %A Zhou, Jie %A Zhu, Xiaofeng %A Ziegler, Regina G %A Zmuda, Joe %A Alan B Zonderman %A Psaty, Bruce M %A Ingrid B Borecki %A Cupples, L Adrienne %A Liu, Ching-Ti %A Christopher A Haiman %A Ruth J F Loos %A Ng, Maggie C Y %A Kari E North %K Africa %K African Americans %K Blacks %K Body Height %K Europe %K Female %K Genome-Wide Association Study %K Humans %K Male %K Polymorphism, Single Nucleotide %X

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

%B The American Journal of Human Genetics %V 108 %P 564-582 %G eng %N 4 %R 10.1016/j.ajhg.2021.02.011 %0 Journal Article %J Mol Psychiatry %D 2021 %T Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. %A de Las Fuentes, Lisa %A Yun Ju Sung %A Noordam, Raymond %A Thomas W Winkler %A Feitosa, Mary F %A Schwander, Karen %A Bentley, Amy R %A Brown, Michael R %A Guo, Xiuqing %A Alisa Manning %A Daniel I Chasman %A Aschard, Hugues %A Traci M Bartz %A Bielak, Lawrence F %A Campbell, Archie %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Hartwig, Fernando P %A Horimoto, A R V R %A Li, Changwei %A Li-Gao, Ruifang %A Liu, Yongmei %A Marten, Jonathan %A Musani, Solomon K %A Ntalla, Ioanna %A Rankinen, Tuomo %A Melissa Richard %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Bamidele O Tayo %A Vojinovic, Dina %A Warren, Helen R %A Xuan, Deng %A Alver, Maris %A Boissel, Mathilde %A Jin-Fang Chai %A Chen, Xu %A Christensen, Kaare %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Giorgia G Girotto %A Sarah E Harris %A He, Meian %A Hsu, Fang-Chi %A Kühnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Ilja M Nolte %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Rueedi, Rico %A Shu, Xiao-Ou %A Snieder, Harold %A Sofer, Tamar %A Takeuchi, Fumihiko %A Verweij, Niek %A Erin B Ware %A Weiss, Stefan %A Yanek, Lisa R %A Amin, Najaf %A Dan E Arking %A Donna K Arnett %A Bergmann, Sven %A Boerwinkle, Eric %A Brody, Jennifer A %A Broeckel, Ulrich %A Brumat, Marco %A Burke, Gregory %A Cabrera, Claudia P %A Canouil, Mickaël %A Chee, Miao Li %A Chen, Yii-Der Ida %A Cocca, Massimiliano %A Connell, John %A de Silva, H Janaka %A de Vries, Paul S %A Eiriksdottir, Gudny %A Jessica Faul %A Fisher, Virginia %A Forrester, Terrence %A Fox, Ervin F %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Tamara B Harris %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven %A Ikram, M Arfan %A Irvin, Marguerite R %A Kähönen, Mika %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Kraja, Aldi T %A Krieger, J E %A Langefeld, Carl D %A Li, Yize %A Liang, Jingjing %A David C Liewald %A Liu, Ching-Ti %A Liu, Jianjun %A Kurt Lohman %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Andres Metspalu %A Milaneschi, Yuri %A Lili Milani %A Dennis O Mook-Kanamori %A Michael A Nalls %A Nelson, Christopher P %A Norris, Jill M %A Jeff O'Connell %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Nancy L Pedersen %A Thomas T Perls %A Peters, Annette %A Petersmann, Astrid %A Peyser, Patricia A %A Polasek, Ozren %A David J Porteous %A Raffel, Leslie J %A Rice, Treva K %A Rotter, Jerome I %A Rudan, Igor %A Rueda-Ochoa, Oscar-Leonel %A Sabanayagam, Charumathi %A Babatunde Salako %A Schreiner, Pamela J %A Shikany, James M %A Stephen Sidney %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A John M Starr %A Strauch, Konstantin %A Swertz, Morris A %A Teumer, Alexander %A Tham, Yih Chung %A André G Uitterlinden %A Vaidya, Dhananjay %A van der Ende, M Yldau %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya-Xing %A Wei, Wen-Bin %A David R Weir %A Wen, Wanqing %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Alan B Zonderman %A Becker, Diane M %A Bowden, Donald W %A Ian J Deary %A Dörr, Marcus %A Tõnu Esko %A Freedman, Barry I %A Froguel, Philippe %A Paolo P. Gasparini %A Gieger, Christian %A Jost Bruno Jonas %A Kammerer, Candace M %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Patrik K E Magnusson %A Marques-Vidal, Pedro %A Brenda W J H Penninx %A Nilesh J Samani %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Cooper, Richard S %A Correa, Adolfo %A Michele K Evans %A Gudnason, Vilmundur %A Caroline Hayward %A Horta, Bernardo L %A Tanika N Kelly %A Stephen B Kritchevsky %A Levy, Daniel %A Walter R Palmas %A Pereira, A C %A Province, Michael M %A Psaty, Bruce M %A Ridker, Paul M %A Charles N Rotimi %A Tai, E Shyong %A van Dam, Rob M %A Cornelia M van Duijn %A Wong, Tien Yin %A Kenneth Rice %A Gauderman, W James %A Alanna C Morrison %A Kari E North %A Sharon L R Kardia %A Caulfield, Mark J %A Elliott, Paul %A Munroe, Patricia B %A Franks, Paul W %A Rao, Dabeeru C %A Myriam Fornage %K Blood pressure %K Epistasis, Genetic %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Polymorphism, Single Nucleotide %X

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

%B Mol Psychiatry %V 26 %P 2111-2125 %G eng %N 6 %R 10.1038/s41380-020-0719-3 %0 Journal Article %J Human Genetics and Genomics Advances %D 2021 %T Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. %A Sun, Daokun %A Melissa Richard %A Musani, Solomon K %A Yun Ju Sung %A Thomas W Winkler %A Schwander, Karen %A Jin-Fang Chai %A Guo, Xiuqing %A Kilpeläinen, Tuomas O %A Vojinovic, Dina %A Aschard, Hugues %A Traci M Bartz %A Bielak, Lawrence F %A Brown, Michael R %A Chitrala, Kumaraswamy %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Liu, Yongmei %A Alisa Manning %A Noordam, Raymond %A Smith, Albert V %A Sarah E Harris %A Kühnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Ilja M Nolte %A Rauramaa, Rainer %A van der Most, Peter J %A Wang, Rujia %A Erin B Ware %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Dan E Arking %A Donna K Arnett %A Barac, Ana %A Boerwinkle, Eric %A Broeckel, Ulrich %A Chakravarti, Aravinda %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A Davigulus, Martha L %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Vries, Paul S %A Delaney, Joseph A C %A Ana V Diez Roux %A Dörr, Marcus %A Jessica Faul %A Fretts, Amanda M %A Gallo, Linda C %A Hans-Jörgen Grabe %A Gu, C Charles %A Tamara B Harris %A Hartman, Catharina C A %A Heikkinen, Sami %A Ikram, M Arfan %A Isasi, Carmen %A Johnson, W Craig %A Jost Bruno Jonas %A Kaplan, Robert C %A Komulainen, Pirjo %A Krieger, Jose E %A Levy, Daniel %A Liu, Jianjun %A Kurt Lohman %A Luik, Annemarie I %A Martin, Lisa W %A Meitinger, Thomas %A Milaneschi, Yuri %A Jeff O'Connell %A Walter R Palmas %A Peters, Annette %A Peyser, Patricia A %A Pulkki-Raback, Laura %A Raffel, Leslie J %A Reiner, Alex P %A Kenneth Rice %A Robinson, Jennifer G %A Rosendaal, Frits R %A Schmidt, Carsten Oliver %A Schreiner, Pamela J %A Schwettmann, Lars %A Shikany, James M %A Shu, Xiao-Ou %A Stephen Sidney %A Sims, Mario %A Smith, Jennifer A %A Sotoodehnia, Nona %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent %A André G Uitterlinden %A Cornelia M van Duijn %A Waldenberger, Melanie %A Wee, Hwee-Lin %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Zeng, Donglin %A Zhao, Wei %A Zhu, Xiaofeng %A Alan B Zonderman %A Becker, Diane M %A Ian J Deary %A Gieger, Christian %A Lakka, Timo A %A Lehtimäki, Terho %A Kari E North %A Oldehinkel, Albertine J %A Brenda W J H Penninx %A Snieder, Harold %A Wang, Ya-Xing %A David R Weir %A Zheng, Wei %A Michele K Evans %A Gauderman, W James %A Gudnason, Vilmundur %A Horta, Bernardo L %A Liu, Ching-Ti %A Dennis O Mook-Kanamori %A Alanna C Morrison %A Pereira, Alexandre C %A Psaty, Bruce M %A Amin, Najaf %A Fox, Ervin R %A Charles Kooperberg %A Sim, Xueling %A Laura Bierut %A Rotter, Jerome I %A Sharon L R Kardia %A Franceschini, Nora %A Rao, Dabeeru C %A Myriam Fornage %K blood pressure traits %X

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

%B Human Genetics and Genomics Advances %V 2 %P 100013 %G eng %N 1 %R 10.1016/j.xhgg.2020.100013 %0 Journal Article %J Translational Psychiatry %D 2020 %T Genome-wide association study of cognitive function in diverse Hispanics/Latinos: results from the Hispanic Community Health Study/Study of Latinos. %A Jian, Xueqiu %A Sofer, Tamar %A Wassim Tarraf %A Bressler, Jan %A Jessica Faul %A Zhao, Wei %A Scott M Ratliff %A Lamar, Melissa %A Lenore J Launer %A Laurie, Cathy C %A Schneiderman, Neil %A David R Weir %A Wright, Clinton B %A Kristine Yaffe %A Zeng, Donglin %A DeCarli, Charles %A Thomas H Mosley %A Smith, Jennifer A %A Hector M González %A Myriam Fornage %K Aged %K Cognition %K Genome-Wide Association Study %K Hispanic or Latino %K Humans %K Middle Aged %K Neuropsychological tests %K Public Health %K Ubiquitin-Conjugating Enzymes %X

Cognitive function such as reasoning, attention, memory, and language is strongly correlated with brain aging. Compared to non-Hispanic whites, Hispanics/Latinos have a higher risk of cognitive impairment and dementia. The genetic determinants of cognitive function have not been widely explored in this diverse and admixed population. We conducted a genome-wide association analysis of cognitive function in up to 7600 middle aged and older Hispanics/Latinos (mean = 55 years) from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL). Four cognitive measures were examined: the Brief Spanish English Verbal Learning Test (B-SEVLT), the Word Fluency Test (WFT), the Digit Symbol Substitution Test (DSST), the Six-Item Screener (SIS). Four novel loci were identified: one for B-SEVLT at 4p14, two for WFT at 3p14.1 and 6p21.32, and one for DSST at 10p13. These loci implicate genes highly expressed in brain and previously connected to neurological diseases (UBE2K, FRMD4B, the HLA gene complex). By applying tissue-specific gene expression prediction models to our genotype data, additional genes highly expressed in brain showed suggestive associations with cognitive measures possibly indicating novel biological mechanisms, including IFT122 in the hippocampus for SIS, SNX31 in the basal ganglia for B-SEVLT, RPS6KB2 in the frontal cortex for WFT, and CSPG5 in the hypothalamus for DSST. These findings provide new information about the genetic determinants of cognitive function in this unique population. In addition, we derived a measure of general cognitive function based on these cognitive tests and generated genome-wide association summary results, providing a resource to the research community for comparison, replication, and meta-analysis in future genetic studies in Hispanics/Latinos.

%B Translational Psychiatry %V 10 %P 245 %G eng %N 1 %R 10.1038/s41398-020-00930-2 %0 Journal Article %J Molecular Psychiatry %D 2020 %T Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. %A Erzurumluoglu, A Mesut %A Liu, Mengzhen %A Jackson, Victoria E %A Barnes, Daniel R %A Datta, Gargi %A Melbourne, Carl A %A Young, Robin %A Batini, Chiara %A Surendran, Praveen %A Jiang, Tao %A Adnan, Sheikh Daud %A Afaq, Saima %A Agrawal, Arpana %A Altmaier, Elisabeth %A Antoniou, Antonis C %A Asselbergs, Folkert W %A Baumbach, Clemens %A Laura Bierut %A Bertelsen, Sarah %A Boehnke, Michael %A Bots, Michiel L %A Brazel, David M %A Chambers, John C %A Chang-Claude, Jenny %A Chen, Chu %A Corley, Janie %A Chou, Yi-Ling %A David, Sean P %A de Boer, Rudolf A %A Christiaan de Leeuw %A Joe G Dennis %A Dominiczak, Anna F %A Dunning, Alison M %A Easton, Douglas F %A Charles B Eaton %A Elliott, Paul %A Evangelou, Evangelos %A Jessica Faul %A Tatiana Foroud %A Goate, Alison %A Gong, Jian %A Hans-Jörgen Grabe %A Jeffrey Haessler %A Christopher A Haiman %A Hallmans, Göran %A Anke R Hammerschlag %A Sarah E Harris %A Andrew T Hattersley %A Andrew C Heath %A Hsu, Chris %A Iacono, William G %A Kanoni, Stavroula %A Kapoor, Manav %A Kaprio, Jaakko %A Sharon L R Kardia %A Karpe, Fredrik %A Kontto, Jukka %A Kooner, Jaspal S %A Charles Kooperberg %A Kuulasmaa, Kari %A Laakso, Markku %A Lai, Dongbing %A Langenberg, Claudia %A Le, Nhung %A Lettre, Guillaume %A Loukola, Anu %A Luan, Jian'an %A Pamela A F Madden %A Mangino, Massimo %A Riccardo E Marioni %A Marouli, Eirini %A Marten, Jonathan %A Nicholas G Martin %A McGue, Matt %A Michailidou, Kyriaki %A Mihailov, Evelin %A Moayyeri, Alireza %A Moitry, Marie %A Müller-Nurasyid, Martina %A Naheed, Aliya %A Nauck, Matthias %A Neville, Matthew J %A Sune Fallgaard Nielsen %A Kari E North %A Markus Perola %A Pharoah, Paul D P %A Pistis, Giorgio %A Tinca J Polderman %A Posthuma, Danielle %A Neil Poulter %A Qaiser, Beenish %A Rasheed, Asif %A Reiner, Alex %A Renstrom, Frida %A Rice, John %A Rohde, Rebecca %A Rolandsson, Olov %A Nilesh J Samani %A Samuel, Maria %A Schlessinger, David %A H Steven Scholte %A Scott, Robert A %A Peter Sever %A Shao, Yaming %A Shrine, Nick %A Smith, Jennifer A %A John M Starr %A Kathleen E Stirrups %A Stram, Danielle %A Heather M Stringham %A Tachmazidou, Ioanna %A Tardif, Jean-Claude %A Thompson, Deborah J %A Hilary A Tindle %A Tragante, Vinicius %A Trompet, Stella %A Turcot, Valérie %A Tyrrell, Jessica %A Vaartjes, Ilonca %A Van Der Leij, Andries R %A van der Meer, Peter %A Varga, Tibor V %A Verweij, Niek %A Völzke, Henry %A Wareham, Nicholas J %A Warren, Helen R %A David R Weir %A Weiss, Stefan %A Wetherill, Leah %A Yaghootkar, Hanieh %A Yavas, Ersin %A Jiang, Yu %A Chen, Fang %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Wei %A Zhao, Wei %A Zhou, Kaixin %A Amouyel, Philippe %A Blankenberg, Stefan %A Caulfield, Mark J %A Chowdhury, Rajiv %A Francesco Cucca %A Ian J Deary %A Deloukas, Panos %A Di Angelantonio, Emanuele %A Marco M Ferrario %A Ferrières, Jean %A Franks, Paul W %A Timothy M Frayling %A Frossard, Philippe %A Hall, Ian P %A Caroline Hayward %A Jansson, Jan-Håkan %A Jukema, J Wouter %A Kee, Frank %A Männistö, Satu %A Andres Metspalu %A Munroe, Patricia B %A Børge G Nordestgaard %A Palmer, Colin N A %A Veikko Salomaa %A Sattar, Naveed %A Timothy Spector %A David P Strachan %A van der Harst, Pim %A Zeggini, Eleftheria %A Saleheen, Danish %A Adam S Butterworth %A Wain, Louise V %A Gonçalo R Abecasis %A Danesh, John %A Tobin, Martin D %A Scott Vrieze %A Liu, Dajiang J %A Howson, Joanna M M %K Biological Specimen Banks %K Databases, Factual %K Europe %K Exome %K Female %K Genetic Loci %K Humans %K Male %K Polymorphism, Single Nucleotide %K Smoking %K United Kingdom %X

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

%B Molecular Psychiatry %V 25 %P 2392-2409 %G eng %N 10 %R 10.1038/s41380-018-0313-0 %0 Journal Article %J Nature Genetics %D 2019 %T Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. %A Liu, Mengzhen %A Jiang, Yu %A Wedow, Robbee %A Li, Yue %A Brazel, David M %A Chen, Fang %A Datta, Gargi %A Davila-Velderrain, Jose %A McGuire, Daniel %A Tian, Chao %A Zhan, Xiaowei %A Choquet, Hélène %A Docherty, Anna R %A Jessica Faul %A Foerster, Johanna R %A Fritsche, Lars G %A Gabrielsen, Maiken Elvestad %A Gordon, Scott D %A Jeffrey Haessler %A Jouke-Jan Hottenga %A Huang, Hongyan %A Jang, Seon-Kyeong %A Philip R Jansen %A Ling, Yueh %A Mägi, Reedik %A Matoba, Nana %A McMahon, George %A Mulas, Antonella %A Orrù, Valeria %A Palviainen, Teemu %A Anita Pandit %A Reginsson, Gunnar W %A Skogholt, Anne Heidi %A Smith, Jennifer A %A Taylor, Amy E %A Turman, Constance %A Gonneke Willemsen %A Young, Hannah %A Young, Kendra A %A Zajac, Gregory J M %A Zhao, Wei %A Zhou, Wei %A Bjornsdottir, Gyda %A Boardman, Jason D %A Boehnke, Michael %A Dorret I Boomsma %A Chen, Chu %A Francesco Cucca %A Davies, Gareth E %A Charles B Eaton %A Ehringer, Marissa A %A Tõnu Esko %A Fiorillo, Edoardo %A Gillespie, Nathan A %A Gudbjartsson, Daniel F %A Haller, Toomas %A Kathleen Mullan Harris %A Andrew C Heath %A Hewitt, John K %A Hickie, Ian B %A Hokanson, John E %A Hopfer, Christian J %A Hunter, David J %A Iacono, William G %A Johnson, Eric O %A Kamatani, Yoichiro %A Sharon L R Kardia %A Matthew C Keller %A Kellis, Manolis %A Charles Kooperberg %A Kraft, Peter %A Krauter, Kenneth S %A Laakso, Markku %A Penelope A Lind %A Loukola, Anu %A Lutz, Sharon M %A Pamela A F Madden %A Nicholas G Martin %A McGue, Matt %A Matthew B McQueen %A Sarah E Medland %A Andres Metspalu %A Mohlke, Karen L %A Nielsen, Jonas B %A Okada, Yukinori %A Peters, Ulrike %A Tinca J Polderman %A Posthuma, Danielle %A Reiner, Alexander P %A Rice, John P %A Rimm, Eric %A Rose, Richard J %A Runarsdottir, Valgerdur %A Stallings, Michael C %A Stančáková, Alena %A Stefansson, Hreinn %A Thai, Khanh K %A Hilary A Tindle %A Tyrfingsson, Thorarinn %A Wall, Tamara L %A David R Weir %A Weisner, Constance %A Whitfield, John B %A Winsvold, Bendik Slagsvold %A Yin, Jie %A Zuccolo, Luisa %A Laura Bierut %A Hveem, Kristian %A Lee, James J %A Munafò, Marcus R %A Saccone, Nancy L %A Willer, Cristen J %A Marilyn C Cornelis %A David, Sean P %A Hinds, David A %A Jorgenson, Eric %A Kaprio, Jaakko %A Stitzel, Jerry A %A Stefansson, Kari %A Thorgeirsson, Thorgeir E %A Gonçalo R Abecasis %A Liu, Dajiang J %A Scott Vrieze %K Alcohol Drinking %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Phenotype %K Risk %K Smoking %K Tobacco %K Tobacco Use Disorder %X

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

%B Nature Genetics %V 51 %P 237-244 %G eng %N 2 %R 10.1038/s41588-018-0307-5 %0 Journal Article %J European Journal of Human Genetics %D 2019 %T Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31. %A Wang, Heming %A Nandakumar, Priyanka %A Tekola-Ayele, Fasil %A Bamidele O Tayo %A Erin B Ware %A Gu, C Charles %A Lu, Yingchang %A Yao, Jie %A Zhao, Wei %A Smith, Jennifer A %A Hellwege, Jacklyn N %A Guo, Xiuqing %A Edwards, Todd L %A Ruth J F Loos %A Donna K Arnett %A Myriam Fornage %A Charles N Rotimi %A Sharon L R Kardia %A Cooper, Richard S %A Rao, D C %A Georg B Ehret %A Chakravarti, Aravinda %A Zhu, Xiaofeng %K African Americans %K Chromosomes, Human, Pair 1 %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Hypertension %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %X

High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.

%B European Journal of Human Genetics %V 27 %P 269-277 %G eng %N 2 %R 10.1038/s41431-018-0277-1 %0 Journal Article %J Biological Psychiatry %D 2019 %T Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use. %A Brazel, David M %A Jiang, Yu %A Hughey, Jordan M %A Turcot, Valérie %A Zhan, Xiaowei %A Gong, Jian %A Batini, Chiara %A Weissenkampen, J Dylan %A Liu, Mengzhen %A Barnes, Daniel R %A Bertelsen, Sarah %A Chou, Yi-Ling %A Erzurumluoglu, A Mesut %A Jessica Faul %A Jeffrey Haessler %A Anke R Hammerschlag %A Hsu, Chris %A Kapoor, Manav %A Lai, Dongbing %A Le, Nhung %A Christiaan de Leeuw %A Loukola, Anu %A Mangino, Massimo %A Melbourne, Carl A %A Pistis, Giorgio %A Qaiser, Beenish %A Rohde, Rebecca %A Shao, Yaming %A Heather M Stringham %A Wetherill, Leah %A Zhao, Wei %A Agrawal, Arpana %A Laura Bierut %A Chen, Chu %A Charles B Eaton %A Goate, Alison %A Christopher A Haiman %A Andrew C Heath %A Iacono, William G %A Nicholas G Martin %A Tinca J Polderman %A Reiner, Alex %A Rice, John %A Schlessinger, David %A H Steven Scholte %A Smith, Jennifer A %A Tardif, Jean-Claude %A Hilary A Tindle %A Van Der Leij, Andries R %A Boehnke, Michael %A Chang-Claude, Jenny %A Francesco Cucca %A David, Sean P %A Tatiana Foroud %A Howson, Joanna M M %A Sharon L R Kardia %A Charles Kooperberg %A Laakso, Markku %A Lettre, Guillaume %A Pamela A F Madden %A McGue, Matt %A Kari E North %A Posthuma, Danielle %A Timothy Spector %A Stram, Daniel %A Tobin, Martin D %A David R Weir %A Kaprio, Jaakko %A Gonçalo R Abecasis %A Liu, Dajiang J %A Scott Vrieze %K Alcohol Drinking %K Databases, Genetic %K Exome %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Humans %K Oligonucleotide Array Sequence Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Smoking %X

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.

METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.

RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.

CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

%B Biological Psychiatry %V 85 %P 946-955 %G eng %N 11 %R 10.1016/j.biopsych.2018.11.024 %0 Journal Article %J Nature Communications %D 2019 %T Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. %A Kilpeläinen, Tuomas O %A Bentley, Amy R %A Noordam, Raymond %A Yun Ju Sung %A Schwander, Karen %A Thomas W Winkler %A Jakupović, Hermina %A Daniel I Chasman %A Alisa Manning %A Ntalla, Ioanna %A Aschard, Hugues %A Brown, Michael R %A de Las Fuentes, Lisa %A Franceschini, Nora %A Guo, Xiuqing %A Vojinovic, Dina %A Aslibekyan, Stella %A Feitosa, Mary F %A Kho, Minjung %A Musani, Solomon K %A Melissa Richard %A Wang, Heming %A Wang, Zhe %A Traci M Bartz %A Bielak, Lawrence F %A Campbell, Archie %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Li, Changwei %A Kurt Lohman %A Marten, Jonathan %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Jin-Fang Chai %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Graff, Mariaelisa %A Sarah E Harris %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Jing Hua Zhao %A Kraja, Aldi T %A Kühnel, Brigitte %A Laguzzi, Federica %A Lyytikäinen, Leo-Pekka %A Ilja M Nolte %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Rueedi, Rico %A Heather M Stringham %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Verweij, Niek %A Erin B Ware %A Wen, Wanqing %A Li, Xiaoyin %A Yanek, Lisa R %A Amin, Najaf %A Donna K Arnett %A Boerwinkle, Eric %A Brumat, Marco %A Brian E Cade %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Concas, Maria Pina %A Connell, John %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Demirkan, Ayse %A Ding, Jingzhong %A Charles B Eaton %A Jessica Faul %A Friedlander, Yechiel %A Gabriel, Kelley P %A Ghanbari, Mohsen %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Tamara B Harris %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven C %A Ikram, M Arfan %A Jost Bruno Jonas %A Koh, Woon-Puay %A Komulainen, Pirjo %A Krieger, Jose E %A Stephen B Kritchevsky %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Lenore J Launer %A Leander, Karin %A Lemaitre, Rozenn N %A Lewis, Cora E %A Liang, Jingjing %A Liu, Jianjun %A Mägi, Reedik %A Manichaikul, Ani %A Meitinger, Thomas %A Andres Metspalu %A Milaneschi, Yuri %A Mohlke, Karen L %A Thomas H Mosley %A Murray, Alison D %A Michael A Nalls %A Nang, Ei-Ei Khaing %A Nelson, Christopher P %A Nona, Sotoodehnia %A Norris, Jill M %A Nwuba, Chiamaka Vivian %A Jeff O'Connell %A Palmer, Nicholette D %A Papanicolau, George J %A Pazoki, Raha %A Nancy L Pedersen %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A David J Porteous %A Poveda, Alaitz %A Olli T Raitakari %A Rich, Stephen S %A Neil Risch %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schreiner, Pamela J %A Scott, Robert A %A Stephen Sidney %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Sofer, Tamar %A John M Starr %A Sternfeld, Barbara %A Strauch, Konstantin %A Tang, Hua %A Kent D Taylor %A Tsai, Michael Y %A Tuomilehto, Jaakko %A André G Uitterlinden %A van der Ende, M Yldau %A van Heemst, Diana %A Voortman, Trudy %A Waldenberger, Melanie %A Wennberg, Patrik %A Wilson, Gregory %A Xiang, Yong-Bing %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Alan B Zonderman %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A de Faire, Ulf %A Ian J Deary %A Elliott, Paul %A Tõnu Esko %A Freedman, Barry I %A Froguel, Philippe %A Paolo P. Gasparini %A Gieger, Christian %A Kato, Norihiro %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Patrik K E Magnusson %A Oldehinkel, Albertine J %A Brenda W J H Penninx %A Nilesh J Samani %A Shu, Xiao-Ou %A van der Harst, Pim %A Jana V. van Vliet-Ostaptchouk %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wang, Ya X %A Wareham, Nicholas J %A David R Weir %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Michele K Evans %A Franks, Paul W %A Gudnason, Vilmundur %A Caroline Hayward %A Horta, Bernardo L %A Tanika N Kelly %A Liu, Yongmei %A Kari E North %A Pereira, Alexandre C %A Ridker, Paul M %A Tai, E Shyong %A van Dam, Rob M %A Fox, Ervin R %A Sharon L R Kardia %A Liu, Ching-Ti %A Dennis O Mook-Kanamori %A Province, Michael A %A Redline, Susan %A Cornelia M van Duijn %A Rotter, Jerome I %A Charles Kooperberg %A Gauderman, W James %A Psaty, Bruce M %A Kenneth Rice %A Munroe, Patricia B %A Myriam Fornage %A Cupples, L Adrienne %A Charles N Rotimi %A Alanna C Morrison %A Rao, Dabeeru C %A Ruth J F Loos %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asians %K Blacks %K Brazil %K Calcium-Binding Proteins %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K Exercise %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Hispanic or Latino %K Humans %K LIM-Homeodomain Proteins %K Lipid Metabolism %K Lipids %K Male %K Membrane Proteins %K Microtubule-Associated Proteins %K Middle Aged %K Muscle Proteins %K Nerve Tissue Proteins %K Transcription Factors %K Triglycerides %K Whites %K Young Adult %X

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

%B Nature Communications %V 10 %P 376 %G eng %N 1 %R 10.1038/s41467-018-08008-w %0 Journal Article %J Nature Human Behaviour %D 2019 %T New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders. %A Evangelou, Evangelos %A Gao, He %A Chu, Congying %A Ntritsos, Georgios %A Blakeley, Paul %A Butts, Andrew R %A Pazoki, Raha %A Suzuki, Hideaki %A Koskeridis, Fotios %A Yiorkas, Andrianos M %A Karaman, Ibrahim %A Elliott, Joshua %A Luo, Qiang %A Aeschbacher, Stefanie %A Traci M Bartz %A Baumeister, Sebastian E %A Braund, Peter S %A Brown, Michael R %A Brody, Jennifer A %A Clarke, Toni-Kim %A Dimou, Niki %A Jessica Faul %A Homuth, Georg %A Jackson, Anne U %A Kentistou, Katherine A %A Joshi, Peter K %A Lemaitre, Rozenn N %A Penelope A Lind %A Lyytikäinen, Leo-Pekka %A Mangino, Massimo %A Milaneschi, Yuri %A Nelson, Christopher P %A Ilja M Nolte %A Perälä, Mia-Maria %A Polasek, Ozren %A David J Porteous %A Scott M Ratliff %A Smith, Jennifer A %A Stančáková, Alena %A Teumer, Alexander %A Tuominen, Samuli %A Thériault, Sébastien %A Vangipurapu, Jagadish %A Whitfield, John B %A Wood, Alexis %A Yao, Jie %A Yu, Bing %A Zhao, Wei %A Dan E Arking %A Auvinen, Juha %A Liu, Chunyu %A Männikkö, Minna %A Risch, Lorenz %A Rotter, Jerome I %A Snieder, Harold %A Veijola, Juha %A Alexandra I Blakemore %A Boehnke, Michael %A Campbell, Harry %A Conen, David %A Johan G Eriksson %A Hans-Jörgen Grabe %A Guo, Xiuqing %A van der Harst, Pim %A Catharina A Hartman %A Caroline Hayward %A Andrew C Heath %A Järvelin, Marjo-Riitta %A Kähönen, Mika %A Sharon L R Kardia %A Kühne, Michael %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lehtimäki, Terho %A McIntosh, Andrew M %A Mohlke, Karen L %A Alanna C Morrison %A Nicholas G Martin %A Oldehinkel, Albertine J %A Brenda W J H Penninx %A Psaty, Bruce M %A Olli T Raitakari %A Rudan, Igor %A Nilesh J Samani %A Scott, Laura J %A Timothy Spector %A Verweij, Niek %A David R Weir %A James F Wilson %A Levy, Daniel %A Tzoulaki, Ioanna %A Bell, Jimmy D %A Matthews, Paul M %A Rothenfluh, Adrian %A Desrivières, Sylvane %A Schumann, Gunter %A Elliott, Paul %K Adult %K Aged %K Alcohol Drinking %K Alcoholism %K Brain %K Female %K genes %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Disorders %K Middle Aged %K Neuroimaging %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Schizophrenia %K Whites %X

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

%B Nature Human Behaviour %V 3 %P 950-961 %G eng %N 9 %R 10.1038/s41562-019-0653-z %0 Journal Article %J Nature Communications %D 2018 %T Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. %A Gail Davies %A Lam, Max %A Sarah E Harris %A Joey W Trampush %A Luciano, Michelle %A W David Hill %A Hagenaars, Saskia P %A Ritchie, Stuart J %A Riccardo E Marioni %A Fawns-Ritchie, Chloe %A David C Liewald %A Okely, Judith A %A Ahola-Olli, Ari V %A Barnes, Catriona L K %A Bertram, Lars %A Joshua C. Bis %A Katherine E Burdick %A Christoforou, Andrea %A DeRosse, Pamela %A Djurovic, Srdjan %A Espeseth, Thomas %A Giakoumaki, Stella %A Giddaluru, Sudheer %A Gustavson, Daniel E %A Caroline Hayward %A Edith Hofer %A Ikram, M Arfan %A Karlsson, Robert %A Knowles, Emma %A Lahti, Jari %A Leber, Markus %A Li, Shuo %A Mather, Karen A %A Melle, Ingrid %A Morris, Derek %A Christopher J Oldmeadow %A Palviainen, Teemu %A Payton, Antony %A Pazoki, Raha %A Katja E Petrovic %A Chandra A Reynolds %A Sargurupremraj, Muralidharan %A Scholz, Markus %A Smith, Jennifer A %A Smith, Albert V %A Terzikhan, Natalie %A Thalamuthu, Anbupalam %A Trompet, Stella %A Sven J van der Lee %A Erin B Ware %A Windham, B Gwen %A Margaret J Wright %A Yang, Jingyun %A Yu, Jin %A Ames, David %A Amin, Najaf %A Amouyel, Philippe %A Andreassen, Ole A %A Armstrong, Nicola J %A Assareh, Amelia A %A John R. Attia %A Attix, Deborah %A Avramopoulos, Dimitrios %A David A Bennett %A Böhmer, Anne C %A Patricia A. Boyle %A Brodaty, Henry %A Campbell, Harry %A Tyrone D. Cannon %A Elizabeth T. Cirulli %A Congdon, Eliza %A Conley, Emily Drabant %A Corley, Janie %A Cox, Simon R %A Dale, Anders M %A Dehghan, Abbas %A Danielle M. Dick %A Dickinson, Dwight %A Johan G Eriksson %A Evangelou, Evangelos %A Jessica Faul %A Ford, Ian %A Nelson A. Freimer %A Gao, He %A Giegling, Ina %A Gillespie, Nathan A %A Gordon, Scott D %A Gottesman, Rebecca F %A Michael E Griswold %A Gudnason, Vilmundur %A Tamara B Harris %A Hartmann, Annette M %A Hatzimanolis, Alex %A Gerardo Heiss %A Holliday, Elizabeth G %A Joshi, Peter K %A Kähönen, Mika %A Sharon L R Kardia %A Ida Karlsson %A Kleineidam, Luca %A David S Knopman %A Kochan, Nicole A %A Konte, Bettina %A Kwok, John B %A Stephanie Le Hellard %A Lee, Teresa %A Lehtimäki, Terho %A Li, Shu-Chen %A Lill, Christina M %A Liu, Tian %A Koini, Marisa %A London, Edythe %A Longstreth, Will T %A Lopez, Oscar L %A Loukola, Anu %A Luck, Tobias %A Astri J Lundervold %A Lundquist, Anders %A Lyytikäinen, Leo-Pekka %A Nicholas G Martin %A Grant W Montgomery %A Murray, Alison D %A Anna C Need %A Noordam, Raymond %A Nyberg, Lars %A William E R Ollier %A Papenberg, Goran %A Pattie, Alison %A Polasek, Ozren %A Russell A Poldrack %A Psaty, Bruce M %A Reppermund, Simone %A Steffi G Riedel-Heller %A Rose, Richard J %A Rotter, Jerome I %A Roussos, Panos %A Rovio, Suvi P %A Saba, Yasaman %A Fred W Sabb %A Sachdev, Perminder S %A Satizabal, Claudia L %A Schmid, Matthias %A Rodney J Scott %A Matthew A Scult %A Simino, Jeannette %A Slagboom, P Eline %A Smyrnis, Nikolaos %A Soumaré, Aïcha %A Nikos C Stefanis %A Stott, David J %A Richard E Straub %A Sundet, Kjetil %A Taylor, Adele M %A Kent D Taylor %A Tzoulaki, Ioanna %A Tzourio, Christophe %A André G Uitterlinden %A Vitart, Veronique %A Aristotle N Voineskos %A Kaprio, Jaakko %A Wagner, Michael %A Wagner, Holger %A Weinhold, Leonie %A Wen, K Hoyan %A Elisabeth Widen %A Yang, Qiong %A Zhao, Wei %A Hieab H Adams %A Dan E Arking %A Robert M Bilder %A Bitsios, Panos %A Boerwinkle, Eric %A Chiba-Falek, Ornit %A Corvin, Aiden %A Philip L de Jager %A Debette, Stéphanie %A Donohoe, Gary %A Elliott, Paul %A Fitzpatrick, Annette L %A Gill, Michael %A David C. Glahn %A Hägg, Sara %A Narelle K Hansell %A Ahmad R Hariri %A Ikram, M Kamran %A Jukema, J Wouter %A Vuoksimaa, Eero %A Matthew C Keller %A Kremen, William S %A Lenore J Launer %A Lindenberger, Ulman %A Aarno Palotie %A Nancy L Pedersen %A Pendleton, Neil %A David J Porteous %A Katri Räikkönen %A Olli T Raitakari %A Ramirez, Alfredo %A Reinvang, Ivar %A Rudan, Igor %A Schmidt, Reinhold %A Schmidt, Helena %A Peter W Schofield %A Peter R Schofield %A John M Starr %A Vidar M Steen %A Trollor, Julian N %A Turner, Steven T %A Cornelia M van Duijn %A Villringer, Arno %A Daniel R Weinberger %A David R Weir %A James F Wilson %A Anil K. Malhotra %A McIntosh, Andrew M %A Gale, Catharine R %A Seshadri, Sudha %A Thomas H Mosley %A Bressler, Jan %A Lencz, Todd %A Ian J Deary %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cognition %K Genetic Loci %K Genetic Predisposition to Disease %K Humans %K Mental Disorders %K Middle Aged %K Multifactorial Inheritance %K Neurodegenerative Diseases %K Neurodevelopmental Disorders %K Polymorphism, Single Nucleotide %K Reaction Time %K Young Adult %X

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

%B Nature Communications %V 9 %P 2098 %G eng %N 1 %R 10.1038/s41467-018-04362-x %0 Journal Article %J Biological Psychiatry %D 2017 %T An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype. %A Nese Direk %A Williams, Stephanie %A Smith, Jennifer A %A Ripke, Stephan %A Air, Tracy %A Amare, Azmeraw T %A Amin, Najaf %A Baune, Bernhard T %A David A Bennett %A Blackwood, Douglas H R %A Dorret I Boomsma %A Breen, Gerome %A Buttenschøn, Henriette N %A Byrne, Enda M %A Børglum, Anders D %A Castelao, Enrique %A Cichon, Sven %A Clarke, Toni-Kim %A Marilyn C Cornelis %A Dannlowski, Udo %A Philip L de Jager %A Demirkan, Ayse %A Domenici, Enrico %A Cornelia M van Duijn %A Dunn, Erin C %A Johan G Eriksson %A Tõnu Esko %A Jessica Faul %A Luigi Ferrucci %A Myriam Fornage %A Eco J. C. de Geus %A Gill, Michael %A Gordon, Scott D %A Hans-Jörgen Grabe %A van Grootheest, Gerard %A Hamilton, Steven P %A Catharina A Hartman %A Andrew C Heath %A Karin Hek %A Hofman, Albert %A Homuth, Georg %A Horn, Carsten %A Jouke-Jan Hottenga %A Sharon L R Kardia %A Kloiber, Stefan %A Karestan C Koenen %A Kutalik, Zoltán %A Ladwig, Karl-Heinz %A Lahti, Jari %A Douglas F Levinson %A Lewis, Cathryn M %A Lewis, Glyn %A Li, Qingqin S %A David J Llewellyn %A Lucae, Susanne %A Kathryn L Lunetta %A MacIntyre, Donald J %A Pamela A F Madden %A Nicholas G Martin %A McIntosh, Andrew M %A Andres Metspalu %A Milaneschi, Yuri %A Grant W Montgomery %A Mors, Ole %A Thomas H Mosley %A Joanne M Murabito %A Müller-Myhsok, Bertram %A Markus M Nöthen %A Nyholt, Dale R %A O'Donovan, Michael C %A Brenda W J H Penninx %A Pergadia, Michele L %A Perlis, Roy %A Potash, James B %A Preisig, Martin %A Shaun M Purcell %A Quiroz, Jorge A %A Katri Räikkönen %A Rice, John P %A Rietschel, Marcella %A Rivera, Margarita %A Schulze, Thomas G %A Shi, Jianxin %A Shyn, Stanley %A Sinnamon, Grant C %A Johannes H Smit %A Smoller, Jordan W %A Snieder, Harold %A Toshiko Tanaka %A Tansey, Katherine E %A Teumer, Alexander %A Uher, Rudolf %A Umbricht, Daniel %A Van der Auwera, Sandra %A Erin B Ware %A David R Weir %A Weissman, Myrna M %A Gonneke Willemsen %A Yang, Jingyun %A Zhao, Wei %A Henning Tiemeier %A Patrick F. Sullivan %K Acid Anhydride Hydrolases %K depression %K Depressive Disorder %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Neoplasm Proteins %K Phenotype %K Whites %X

BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.

METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.

RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10).

CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

%B Biological Psychiatry %V 82 %P 322-329 %G eng %N 5 %R 10.1016/j.biopsych.2016.11.013 %0 Journal Article %J PLoS Genetics %D 2017 %T Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium. %A Ng, Maggie C Y %A Graff, Mariaelisa %A Lu, Yingchang %A Justice, Anne E %A Mudgal, Poorva %A Liu, Ching-Ti %A Young, Kristin %A Yanek, Lisa R %A Feitosa, Mary F %A Wojczynski, Mary K %A Rand, Kristin %A Brody, Jennifer A %A Brian E Cade %A Dimitrov, Latchezar %A Duan, Qing %A Guo, Xiuqing %A Leslie A Lange %A Michael A Nalls %A Okut, Hayrettin %A Tajuddin, Salman M %A Bamidele O Tayo %A Vedantam, Sailaja %A Bradfield, Jonathan P %A Chen, Guanjie %A Chen, Wei-Min %A Chesi, Alessandra %A Irvin, Marguerite R %A Padhukasahasram, Badri %A Smith, Jennifer A %A Zheng, Wei %A Matthew A. Allison %A Ambrosone, Christine B %A Bandera, Elisa V %A Traci M Bartz %A Berndt, Sonja I %A Bernstein, Leslie %A Blot, William J %A Erwin P Bottinger %A John Carpten %A Chanock, Stephen J %A Chen, Yii-Der Ida %A Conti, David V %A Cooper, Richard S %A Myriam Fornage %A Freedman, Barry I %A Garcia, Melissa %A Phyllis J Goodman %A Hsu, Yu-Han H %A Hu, Jennifer %A Huff, Chad D %A Ingles, Sue A %A John, Esther M %A Rick A Kittles %A Eric A Klein %A Li, Jin %A McKnight, Barbara %A Nayak, Uma %A Nemesure, Barbara %A Ogunniyi, Adesola %A Olshan, Andrew %A Press, Michael F %A Rohde, Rebecca %A Rybicki, Benjamin A %A Babatunde Salako %A Sanderson, Maureen %A Shao, Yaming %A David S Siscovick %A Stanford, Janet L %A Stevens, Victoria L %A Stram, Alex %A Strom, Sara S %A Vaidya, Dhananjay %A Witte, John S %A Yao, Jie %A Zhu, Xiaofeng %A Ziegler, Regina G %A Alan B Zonderman %A Adeyemo, Adebowale %A Ambs, Stefan %A Cushman, Mary %A Jessica Faul %A Hakonarson, Hakon %A Levin, Albert M %A Nathanson, Katherine L %A Erin B Ware %A David R Weir %A Zhao, Wei %A Zhi, Degui %A Donna K Arnett %A Grant, Struan F A %A Sharon L R Kardia %A Oloapde, Olufunmilayo I %A Rao, D C %A Charles N Rotimi %A Sale, Michele M %A L Keoki Williams %A Zemel, Babette S %A Becker, Diane M %A Ingrid B Borecki %A Michele K Evans %A Tamara B Harris %A Hirschhorn, Joel N %A Li, Yun %A Patel, Sanjay R %A Psaty, Bruce M %A Rotter, Jerome I %A Wilson, James G %A Bowden, Donald W %A Cupples, L Adrienne %A Christopher A Haiman %A Ruth J F Loos %A Kari E North %K Adiposity %K Anthropometry %K Blacks %K Body Mass Index %K Chromosome Mapping %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Obesity %K Polymorphism, Single Nucleotide %K Serine Endopeptidases %K Transcription Factor 7-Like 2 Protein %K Waist-Hip Ratio %K Whites %X

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

%B PLoS Genetics %V 13 %P e1006719 %G eng %N 4 %R 10.1371/journal.pgen.1006719 %0 Journal Article %J Nature Communications %D 2017 %T Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. %A Joshi, Peter K %A Nicola Pirastu %A Kentistou, Katherine A %A Fischer, Krista %A Edith Hofer %A Schraut, Katharina E %A Clark, David W %A Nutile, Teresa %A Barnes, Catriona L K %A Paul Rhj Timmers %A Shen, Xia %A Gandin, Ilaria %A McDaid, Aaron F %A Hansen, Thomas Folkmann %A Gordon, Scott D %A Giulianini, Franco %A Boutin, Thibaud S %A Abdellaoui, Abdel %A Zhao, Wei %A Medina-Gomez, Carolina %A Traci M Bartz %A Trompet, Stella %A Leslie A Lange %A Raffield, Laura %A van der Spek, Ashley %A Galesloot, Tessel E %A Proitsi, Petroula %A Yanek, Lisa R %A Bielak, Lawrence F %A Payton, Antony %A Murgia, Federico %A Concas, Maria Pina %A Biino, Ginevra %A Tajuddin, Salman M %A Seppälä, Ilkka %A Amin, Najaf %A Boerwinkle, Eric %A Børglum, Anders D %A Campbell, Archie %A Ellen W Demerath %A Demuth, Ilja %A Jessica Faul %A Ford, Ian %A Gialluisi, Alessandro %A Gögele, Martin %A Graff, Mariaelisa %A Aroon Hingorani %A Jouke-Jan Hottenga %A Hougaard, David M %A Hurme, Mikko A %A Ikram, M Arfan %A Jylhä, Marja %A Kuh, Diana %A Ligthart, Lannie %A Lill, Christina M %A Lindenberger, Ulman %A Lumley, Thomas %A Mägi, Reedik %A Marques-Vidal, Pedro %A Sarah E Medland %A Lili Milani %A Nagy, Reka %A William E R Ollier %A Peyser, Patricia A %A Pramstaller, Peter P %A Ridker, Paul M %A Fernando Rivadeneira %A Ruggiero, Daniela %A Saba, Yasaman %A Schmidt, Reinhold %A Schmidt, Helena %A Slagboom, P Eline %A Smith, Blair H %A Smith, Jennifer A %A Sotoodehnia, Nona %A Steinhagen-Thiessen, Elisabeth %A van Rooij, Frank J A %A Verbeek, André L %A Vermeulen, Sita H %A Vollenweider, Peter %A Wang, Yunpeng %A Werge, Thomas %A Whitfield, John B %A Alan B Zonderman %A Lehtimäki, Terho %A Michele K Evans %A Pirastu, Mario %A Fuchsberger, Christian %A Bertram, Lars %A Pendleton, Neil %A Sharon L R Kardia %A Ciullo, Marina %A Becker, Diane M %A Wong, Andrew %A Psaty, Bruce M %A Cornelia M van Duijn %A Wilson, James G %A Jukema, J Wouter %A Lambertus A Kiemeney %A André G Uitterlinden %A Franceschini, Nora %A Kari E North %A David R Weir %A Andres Metspalu %A Dorret I Boomsma %A Caroline Hayward %A Daniel I Chasman %A Nicholas G Martin %A Sattar, Naveed %A Campbell, Harry %A Tõnu Esko %A Kutalik, Zoltán %A James F Wilson %K Alleles %K Body Mass Index %K Coronary Disease %K Education %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K HLA-DQ alpha-Chains %K HLA-DRB1 Chains %K Humans %K Insulin Resistance %K Life Style %K Lipoprotein(a) %K Lipoproteins, HDL %K Longevity %K Lung Neoplasms %K Obesity %K Polymorphism, Single Nucleotide %K Smoking %K Socioeconomic factors %X

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

%B Nature Communications %V 8 %P 910 %G eng %N 1 %R 10.1038/s41467-017-00934-5 %0 Journal Article %J PLoS Genetics %D 2017 %T Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. %A Liang, Jingjing %A Le, Thu H %A Digna R Velez Edwards %A Bamidele O Tayo %A Gaulton, Kyle J %A Smith, Jennifer A %A Lu, Yingchang %A Jensen, Richard A %A Chen, Guanjie %A Yanek, Lisa R %A Schwander, Karen %A Tajuddin, Salman M %A Sofer, Tamar %A Kim, Wonji %A Kayima, James %A McKenzie, Colin A %A Fox, Ervin %A Michael A Nalls %A Young, J Hunter %A Yan V Sun %A Lane, Jacqueline M %A Cechova, Sylvia %A Zhou, Jie %A Tang, Hua %A Myriam Fornage %A Musani, Solomon K %A Wang, Heming %A Lee, Juyoung %A Adeyemo, Adebowale %A Dreisbach, Albert W %A Forrester, Terrence %A Chu, Pei-Lun %A Anne Cappola %A Michele K Evans %A Alanna C Morrison %A Martin, Lisa W %A Kerri Wiggins %A Hui, Qin %A Zhao, Wei %A Jackson, Rebecca D %A Erin B Ware %A Jessica Faul %A Reiner, Alex P %A Bray, Michael %A Denny, Joshua C %A Thomas H Mosley %A Walter R Palmas %A Guo, Xiuqing %A George J Papanicolaou %A Alan Penman %A Polak, Joseph F %A Kenneth Rice %A Taylor, Ken D %A Boerwinkle, Eric %A Erwin P Bottinger %A Liu, Kiang %A Neil Risch %A Hunt, Steven C %A Charles Kooperberg %A Alan B Zonderman %A Laurie, Cathy C %A Becker, Diane M %A Cai, Jianwen %A Ruth J F Loos %A Psaty, Bruce M %A David R Weir %A Sharon L R Kardia %A Donna K Arnett %A Won, Sungho %A Edwards, Todd L %A Redline, Susan %A Cooper, Richard S %A Rao, D C %A Rotter, Jerome I %A Charles N Rotimi %A Levy, Daniel %A Chakravarti, Aravinda %A Zhu, Xiaofeng %A Franceschini, Nora %K African Americans %K Animals %K Basic Helix-Loop-Helix Transcription Factors %K Blood pressure %K Cadherins %K Case-Control Studies %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Membrane Proteins %K Mice %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %X

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

%B PLoS Genetics %V 13 %P e1006728 %G eng %N 5 %R 10.1371/journal.pgen.1006728 %0 Journal Article %J Journal of the American Society of Nephrology %D 2017 %T SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. %A Li, Man %A Li, Yong %A Weeks, Olivia %A Mijatovic, Vladan %A Teumer, Alexander %A Huffman, Jennifer E %A Tromp, Gerard %A Fuchsberger, Christian %A Gorski, Mathias %A Lyytikäinen, Leo-Pekka %A Nutile, Teresa %A Sedaghat, Sanaz %A Sorice, Rossella %A Tin, Adrienne %A Yang, Qiong %A Ahluwalia, Tarunveer S %A Dan E Arking %A Bihlmeyer, Nathan A %A Böger, Carsten A %A Carroll, Robert J %A Daniel I Chasman %A Marilyn C Cornelis %A Dehghan, Abbas %A Jessica Faul %A Feitosa, Mary F %A Gambaro, Giovanni %A Paolo P. Gasparini %A Giulianini, Franco %A Iris M Heid %A Huang, Jinyan %A Imboden, Medea %A Jackson, Anne U %A Janina Jeff %A Jhun, Min A %A Katz, Ronit %A Kifley, Annette %A Kilpeläinen, Tuomas O %A Kumar, Ashish %A Laakso, Markku %A Li-Gao, Ruifang %A Kurt Lohman %A Lu, Yingchang %A Mägi, Reedik %A Malerba, Giovanni %A Mihailov, Evelin %A Mohlke, Karen L %A Dennis O Mook-Kanamori %A Robino, Antonietta %A Ruderfer, Douglas %A Salvi, Erika %A Schick, Ursula M %A Schulz, Christina-Alexandra %A Smith, Albert V %A Smith, Jennifer A %A Traglia, Michela %A Laura M Yerges-Armstrong %A Zhao, Wei %A Goodarzi, Mark O %A Kraja, Aldi T %A Liu, Chunyu %A Wessel, Jennifer %A Boerwinkle, Eric %A Ingrid B Borecki %A Bork-Jensen, Jette %A Erwin P Bottinger %A Braga, Daniele %A Brandslund, Ivan %A Brody, Jennifer A %A Campbell, Archie %A Carey, David J %A Cramer Christensen %A Coresh, Josef %A Crook, Errol %A Curhan, Gary C %A Cusi, Daniele %A de Boer, Ian H %A de Vries, Aiko P J %A Denny, Joshua C %A Devuyst, Olivier %A Dreisbach, Albert W %A Endlich, Karlhans %A Tõnu Esko %A Franco, Oscar H %A Fulop, Tibor %A Gerhard, Glenn S %A Glümer, Charlotte %A Gottesman, Omri %A Grarup, Niels %A Gudnason, Vilmundur %A Hansen, Torben %A Tamara B Harris %A Caroline Hayward %A Lynne J Hocking %A Hofman, Albert %A Hu, Frank B %A Husemoen, Lise Lotte N %A Jackson, Rebecca D %A Jørgensen, Torben %A Jørgensen, Marit E %A Kähönen, Mika %A Sharon L R Kardia %A König, Wolfgang %A Charles Kooperberg %A Kriebel, Jennifer %A Lenore J Launer %A Lauritzen, Torsten %A Lehtimäki, Terho %A Levy, Daniel %A Linksted, Pamela %A Linneberg, Allan %A Liu, Yongmei %A Ruth J F Loos %A Lupo, Antonio %A Meisinger, Christine %A Melander, Olle %A Andres Metspalu %A Mitchell, Paul %A Nauck, Matthias %A Nürnberg, Peter %A Orho-Melander, Marju %A Parsa, Afshin %A Pedersen, Oluf %A Peters, Annette %A Peters, Ulrike %A Polasek, Ozren %A David J Porteous %A Nicole M Probst-Hensch %A Psaty, Bruce M %A Qi, Lu %A Olli T Raitakari %A Reiner, Alex P %A Rettig, Rainer %A Ridker, Paul M %A Fernando Rivadeneira %A Rossouw, Jacques E %A Schmidt, Frank %A David S Siscovick %A Soranzo, Nicole %A Strauch, Konstantin %A Toniolo, Daniela %A Stephen T Turner %A André G Uitterlinden %A Ulivi, Sheila %A Velayutham, Dinesh %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wang, Jie Jin %A David R Weir %A Daniel Witte %A Kuivaniemi, Helena %A Caroline S Fox %A Franceschini, Nora %A Goessling, Wolfram %A Köttgen, Anna %A Chu, Audrey Y %K Animals %K Exome %K Genetic Loci %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K kidney %K Protein Tyrosine Phosphatases %K Proto-Oncogene Proteins %K Son of Sevenless Proteins %K Zebrafish %X

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

%B Journal of the American Society of Nephrology %V 28 %P 981-994 %G eng %N 3 %R 10.1681/ASN.2016020131 %0 Journal Article %J Human Molecular Genetics %D 2015 %T Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals. %A Nead, Kevin T %A Li, Aihua %A Wehner, Mackenzie R %A Neupane, Binod %A Gustafsson, Stefan %A Adam S Butterworth %A Engert, James C %A Davis, A Darlene %A Hegele, Robert A %A Miller, Ruby %A den Hoed, Marcel %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Wareham, Nick %A Edwards, Todd L %A Hallmans, Göran %A Varga, Tibor V %A Sharon L R Kardia %A Smith, Jennifer A %A Zhao, Wei %A Jessica Faul %A David R Weir %A Mi, Jie %A Xi, Bo %A Quinteros, Samuel Canizales %A Cooper, Cyrus %A Sayer, Avan Aihie %A Jameson, Karen %A Grøntved, Anders %A Myriam Fornage %A Stephen Sidney %A Hanis, Craig L %A Highland, Heather M %A Häring, Hans-Ulrich %A Heni, Martin %A Lasky-Su, Jessica %A Weiss, Scott T %A Gerhard, Glenn S %A Still, Christopher %A Melka, Melkaey M %A Pausova, Zdenka %A Paus, Tomáš %A Grant, Struan F A %A Hakonarson, Hakon %A Price, R Arlen %A Wang, Kai %A Scherag, Andre %A Hebebrand, Johannes %A Hinney, Anke %A Franks, Paul W %A Timothy M Frayling %A McCarthy, Mark I %A Hirschhorn, Joel N %A Ruth J F Loos %A Ingelsson, Erik %A Gerstein, Hertzel C %A Yusuf, Salim %A Beyene, Joseph %A Anand, Sonia S %A Meyre, David %K Alleles %K Body Mass Index %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Obesity %K Odds Ratio %K Polymorphism, Single Nucleotide %K Proprotein Convertase 1 %X

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

%B Human Molecular Genetics %V 24 %P 3582-3594 %G eng %N 12 %R 10.1093/hmg/ddv097