%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 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 Psychol Med %D 2016 %T Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies. %A Demirkan, A %A J. Lahti %A Nese Direk %A Viktorin, A. %A Kathryn L Lunetta %A Antonio Terracciano %A Michael A Nalls %A Toshiko Tanaka %A Karin Hek %A Myriam Fornage %A Jürgen Wellmann %A Marilyn C Cornelis %A Ollila, H. M. %A Lei Yu %A Luke C Pilling %A Isaacs, A %A Aarno Palotie %A Wei Vivian Zhuang %A Alan B Zonderman %A Jessica Faul %A Angelina R Sutin %A Osorio Meirelles %A Mulas, A %A Hofman, A %A André G Uitterlinden %A Fernando Rivadeneira %A Markus Perola %A Wei Zhao %A Veikko Salomaa %A Kristine Yaffe %A Luik, A I %A Yongmei Liu %A Ding, J %A Paul Lichtenstein %A Landén, M %A Elisabeth Widen %A David R Weir %A David J Llewellyn %A Murray, A %A Sharon L R Kardia %A Johan G Eriksson %A Karestan C Koenen %A Patrik K E Magnusson %A Luigi Ferrucci %A Thomas H Mosley %A Francesco Cucca %A Ben A Oostra %A David A Bennett %A Paunio, T. %A Klaus Berger %A Tamara B Harris %A Nancy L Pedersen %A Joanne M Murabito %A Henning Tiemeier %A Cornelia M van Duijn %A Katri Räikkönen %K depression %K Depressive Disorder, Major %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Receptor, Melatonin, MT1 %K Somatoform Disorders %X

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.

METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).

RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity.

CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

%B Psychol Med %V 46 %P 1613-23 %8 2016 06 %G eng %U https://www.ncbi.nlm.nih.gov/pubmed/26997408 %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26997408?dopt=Abstract %R 10.1017/S0033291715002081 %0 Journal Article %J Alzheimers Dement %D 2011 %T Sources of variability in estimates of the prevalence of Alzheimer's disease in the United States. %A Robert S Wilson %A David R Weir %A Sue E Leurgans %A Denis A Evans %A Liesi Hebert %A Kenneth M. Langa %A Brenda L Plassman %A Brent J. Small %A David A Bennett %K Aged %K Aged, 80 and over %K Alzheimer disease %K Community Health Planning %K Comorbidity %K Dementia %K Diagnosis, Differential %K Female %K Humans %K Incidence %K Male %K Prevalence %K United States %X

BACKGROUND: The prevalence of Alzheimer's disease (AD) in the United States was estimated at 2.3 million in 2002 by the Aging, Demographics, and Memory Study (ADAMS), which is almost 50% less than the estimate of 4.5 million in 2000 derived from the Chicago Health and Aging Project.

METHODS: We considered how differences in diagnostic criteria may have contributed to these differences in AD prevalence.

RESULTS: We identified several important differences in diagnostic criteria that may have contributed to the differing estimates of AD prevalence. Two factors were especially noteworthy. First, the Diagnostic and Statistical Manual of Mental Disorders III-R and IV criteria of functional limitation documented by an informant used in ADAMS effectively concentrated the diagnosis of dementia toward a relatively higher level of cognitive impairment. ADAMS separately identified a category of cognitive impairment not dementia and within that group there were a substantial number of cases with "prodromal" AD (a maximum of 1.95 million with upweighting). Second, a substantial proportion of dementia in ADAMS was attributed to either vascular disease (representing a maximum of 0.59 million with upweighting) or undetermined etiology (a maximum of 0.34 million), whereas most dementia, including mixed dementia, was attributed to AD in the Chicago Health and Aging Project.

CONCLUSION: The diagnosis of AD in population studies is a complex process. When a diagnosis of AD excludes persons meeting criteria for vascular dementia, when not all persons with dementia are assigned an etiology, and when a diagnosis of dementia requires an informant report of functional limitations, the prevalence is substantially lower and the diagnosed cases most likely have a relatively higher level of impairment.

%B Alzheimers Dement %I 7 %V 7 %P 74-9 %8 2011 Jan %G eng %N 1 %L newpubs20110328_Wilson.pdf %1 http://www.ncbi.nlm.nih.gov/pubmed/21255745?dopt=Abstract %2 PMC3145367 %4 Epidemiology/Dementia/Alzheimers disease/Vascular dementia/Mild cognitive impairment/Cognitive impairment no dementia %$ 24590 %R 10.1016/j.jalz.2010.11.006