TY - JOUR T1 - Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. JF - Human Genetics and Genomics Advances Y1 - 2021 A1 - Sun, Daokun A1 - Melissa Richard A1 - Musani, Solomon K A1 - Yun Ju Sung A1 - Thomas W Winkler A1 - Schwander, Karen A1 - Jin-Fang Chai A1 - Guo, Xiuqing A1 - Kilpeläinen, Tuomas O A1 - Vojinovic, Dina A1 - Aschard, Hugues A1 - Traci M Bartz A1 - Bielak, Lawrence F A1 - Brown, Michael R A1 - Chitrala, Kumaraswamy A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Liu, Yongmei A1 - Alisa Manning A1 - Noordam, Raymond A1 - Smith, Albert V A1 - Sarah E Harris A1 - Kühnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Ilja M Nolte A1 - Rauramaa, Rainer A1 - van der Most, Peter J A1 - Wang, Rujia A1 - Erin B Ware A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Dan E Arking A1 - Donna K Arnett A1 - Barac, Ana A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Chakravarti, Aravinda A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - Davigulus, Martha L A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Vries, Paul S A1 - Delaney, Joseph A C A1 - Ana V Diez Roux A1 - Dörr, Marcus A1 - Jessica Faul A1 - Fretts, Amanda M A1 - Gallo, Linda C A1 - Hans-Jörgen Grabe A1 - Gu, C Charles A1 - Tamara B Harris A1 - Hartman, Catharina C A A1 - Heikkinen, Sami A1 - Ikram, M Arfan A1 - Isasi, Carmen A1 - Johnson, W Craig A1 - Jost Bruno Jonas A1 - Kaplan, Robert C A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Levy, Daniel A1 - Liu, Jianjun A1 - Kurt Lohman A1 - Luik, Annemarie I A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - Jeff O'Connell A1 - Walter R Palmas A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Pulkki-Raback, Laura A1 - Raffel, Leslie J A1 - Reiner, Alex P A1 - Kenneth Rice A1 - Robinson, Jennifer G A1 - Rosendaal, Frits R A1 - Schmidt, Carsten Oliver A1 - Schreiner, Pamela J A1 - Schwettmann, Lars A1 - Shikany, James M A1 - Shu, Xiao-Ou A1 - Stephen Sidney A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent A1 - André G Uitterlinden A1 - Cornelia M van Duijn A1 - Waldenberger, Melanie A1 - Wee, Hwee-Lin A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Zeng, Donglin A1 - Zhao, Wei A1 - Zhu, Xiaofeng A1 - Alan B Zonderman A1 - Becker, Diane M A1 - Ian J Deary A1 - Gieger, Christian A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Kari E North A1 - Oldehinkel, Albertine J A1 - Brenda W J H Penninx A1 - Snieder, Harold A1 - Wang, Ya-Xing A1 - David R Weir A1 - Zheng, Wei A1 - Michele K Evans A1 - Gauderman, W James A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Liu, Ching-Ti A1 - Dennis O Mook-Kanamori A1 - Alanna C Morrison A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Amin, Najaf A1 - Fox, Ervin R A1 - Charles Kooperberg A1 - Sim, Xueling A1 - Laura Bierut A1 - Rotter, Jerome I A1 - Sharon L R Kardia A1 - Franceschini, Nora A1 - Rao, Dabeeru C A1 - Myriam Fornage KW - blood pressure traits AB -

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.

VL - 2 IS - 1 ER - TY - JOUR T1 - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. JF - Nature Communications Y1 - 2019 A1 - Kilpeläinen, Tuomas O A1 - Bentley, Amy R A1 - Noordam, Raymond A1 - Yun Ju Sung A1 - Schwander, Karen A1 - Thomas W Winkler A1 - Jakupović, Hermina A1 - Daniel I Chasman A1 - Alisa Manning A1 - Ntalla, Ioanna A1 - Aschard, Hugues A1 - Brown, Michael R A1 - de Las Fuentes, Lisa A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Feitosa, Mary F A1 - Kho, Minjung A1 - Musani, Solomon K A1 - Melissa Richard A1 - Wang, Heming A1 - Wang, Zhe A1 - Traci M Bartz A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Li, Changwei A1 - Kurt Lohman A1 - Marten, Jonathan A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Jin-Fang Chai A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Graff, Mariaelisa A1 - Sarah E Harris A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Jing Hua Zhao A1 - Kraja, Aldi T A1 - Kühnel, Brigitte A1 - Laguzzi, Federica A1 - Lyytikäinen, Leo-Pekka A1 - Ilja M Nolte A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Rueedi, Rico A1 - Heather M Stringham A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Verweij, Niek A1 - Erin B Ware A1 - Wen, Wanqing A1 - Li, Xiaoyin A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Donna K Arnett A1 - Boerwinkle, Eric A1 - Brumat, Marco A1 - Brian E Cade A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Concas, Maria Pina A1 - Connell, John A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Demirkan, Ayse A1 - Ding, Jingzhong A1 - Charles B Eaton A1 - Jessica Faul A1 - Friedlander, Yechiel A1 - Gabriel, Kelley P A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Tamara B Harris A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven C A1 - Ikram, M Arfan A1 - Jost Bruno Jonas A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Stephen B Kritchevsky A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Lenore J Launer A1 - Leander, Karin A1 - Lemaitre, Rozenn N A1 - Lewis, Cora E A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Mägi, Reedik A1 - Manichaikul, Ani A1 - Meitinger, Thomas A1 - Andres Metspalu A1 - Milaneschi, Yuri A1 - Mohlke, Karen L A1 - Thomas H Mosley A1 - Murray, Alison D A1 - Michael A Nalls A1 - Nang, Ei-Ei Khaing A1 - Nelson, Christopher P A1 - Nona, Sotoodehnia A1 - Norris, Jill M A1 - Nwuba, Chiamaka Vivian A1 - Jeff O'Connell A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pazoki, Raha A1 - Nancy L Pedersen A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - David J Porteous A1 - Poveda, Alaitz A1 - Olli T Raitakari A1 - Rich, Stephen S A1 - Neil Risch A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schreiner, Pamela J A1 - Scott, Robert A A1 - Stephen Sidney A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Sofer, Tamar A1 - John M Starr A1 - Sternfeld, Barbara A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Kent D Taylor A1 - Tsai, Michael Y A1 - Tuomilehto, Jaakko A1 - André G Uitterlinden A1 - van der Ende, M Yldau A1 - van Heemst, Diana A1 - Voortman, Trudy A1 - Waldenberger, Melanie A1 - Wennberg, Patrik A1 - Wilson, Gregory A1 - Xiang, Yong-Bing A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Alan B Zonderman A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - de Faire, Ulf A1 - Ian J Deary A1 - Elliott, Paul A1 - Tõnu Esko A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Paolo P. Gasparini A1 - Gieger, Christian A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Patrik K E Magnusson A1 - Oldehinkel, Albertine J A1 - Brenda W J H Penninx A1 - Nilesh J Samani A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Jana V. van Vliet-Ostaptchouk A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wang, Ya X A1 - Wareham, Nicholas J A1 - David R Weir A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Michele K Evans A1 - Franks, Paul W A1 - Gudnason, Vilmundur A1 - Caroline Hayward A1 - Horta, Bernardo L A1 - Tanika N Kelly A1 - Liu, Yongmei A1 - Kari E North A1 - Pereira, Alexandre C A1 - Ridker, Paul M A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - Fox, Ervin R A1 - Sharon L R Kardia A1 - Liu, Ching-Ti A1 - Dennis O Mook-Kanamori A1 - Province, Michael A A1 - Redline, Susan A1 - Cornelia M van Duijn A1 - Rotter, Jerome I A1 - Charles Kooperberg A1 - Gauderman, W James A1 - Psaty, Bruce M A1 - Kenneth Rice A1 - Munroe, Patricia B A1 - Myriam Fornage A1 - Cupples, L Adrienne A1 - Charles N Rotimi A1 - Alanna C Morrison A1 - Rao, Dabeeru C A1 - Ruth J F Loos KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Asians KW - Blacks KW - Brazil KW - Calcium-Binding Proteins KW - Cholesterol KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Exercise KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Hispanic or Latino KW - Humans KW - LIM-Homeodomain Proteins KW - Lipid Metabolism KW - Lipids KW - Male KW - Membrane Proteins KW - Microtubule-Associated Proteins KW - Middle Aged KW - Muscle Proteins KW - Nerve Tissue Proteins KW - Transcription Factors KW - Triglycerides KW - Whites KW - Young Adult AB -

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.

VL - 10 IS - 1 ER - TY - JOUR T1 - Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. JF - Nature Communications Y1 - 2017 A1 - Joshi, Peter K A1 - Nicola Pirastu A1 - Kentistou, Katherine A A1 - Fischer, Krista A1 - Edith Hofer A1 - Schraut, Katharina E A1 - Clark, David W A1 - Nutile, Teresa A1 - Barnes, Catriona L K A1 - Paul Rhj Timmers A1 - Shen, Xia A1 - Gandin, Ilaria A1 - McDaid, Aaron F A1 - Hansen, Thomas Folkmann A1 - Gordon, Scott D A1 - Giulianini, Franco A1 - Boutin, Thibaud S A1 - Abdellaoui, Abdel A1 - Zhao, Wei A1 - Medina-Gomez, Carolina A1 - Traci M Bartz A1 - Trompet, Stella A1 - Leslie A Lange A1 - Raffield, Laura A1 - van der Spek, Ashley A1 - Galesloot, Tessel E A1 - Proitsi, Petroula A1 - Yanek, Lisa R A1 - Bielak, Lawrence F A1 - Payton, Antony A1 - Murgia, Federico A1 - Concas, Maria Pina A1 - Biino, Ginevra A1 - Tajuddin, Salman M A1 - Seppälä, Ilkka A1 - Amin, Najaf A1 - Boerwinkle, Eric A1 - Børglum, Anders D A1 - Campbell, Archie A1 - Ellen W Demerath A1 - Demuth, Ilja A1 - Jessica Faul A1 - Ford, Ian A1 - Gialluisi, Alessandro A1 - Gögele, Martin A1 - Graff, Mariaelisa A1 - Aroon Hingorani A1 - Jouke-Jan Hottenga A1 - Hougaard, David M A1 - Hurme, Mikko A A1 - Ikram, M Arfan A1 - Jylhä, Marja A1 - Kuh, Diana A1 - Ligthart, Lannie A1 - Lill, Christina M A1 - Lindenberger, Ulman A1 - Lumley, Thomas A1 - Mägi, Reedik A1 - Marques-Vidal, Pedro A1 - Sarah E Medland A1 - Lili Milani A1 - Nagy, Reka A1 - William E R Ollier A1 - Peyser, Patricia A A1 - Pramstaller, Peter P A1 - Ridker, Paul M A1 - Fernando Rivadeneira A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Slagboom, P Eline A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Steinhagen-Thiessen, Elisabeth A1 - van Rooij, Frank J A A1 - Verbeek, André L A1 - Vermeulen, Sita H A1 - Vollenweider, Peter A1 - Wang, Yunpeng A1 - Werge, Thomas A1 - Whitfield, John B A1 - Alan B Zonderman A1 - Lehtimäki, Terho A1 - Michele K Evans A1 - Pirastu, Mario A1 - Fuchsberger, Christian A1 - Bertram, Lars A1 - Pendleton, Neil A1 - Sharon L R Kardia A1 - Ciullo, Marina A1 - Becker, Diane M A1 - Wong, Andrew A1 - Psaty, Bruce M A1 - Cornelia M van Duijn A1 - Wilson, James G A1 - Jukema, J Wouter A1 - Lambertus A Kiemeney A1 - André G Uitterlinden A1 - Franceschini, Nora A1 - Kari E North A1 - David R Weir A1 - Andres Metspalu A1 - Dorret I Boomsma A1 - Caroline Hayward A1 - Daniel I Chasman A1 - Nicholas G Martin A1 - Sattar, Naveed A1 - Campbell, Harry A1 - Tõnu Esko A1 - Kutalik, Zoltán A1 - James F Wilson KW - Alleles KW - Body Mass Index KW - Coronary Disease KW - Education KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - HLA-DQ alpha-Chains KW - HLA-DRB1 Chains KW - Humans KW - Insulin Resistance KW - Life Style KW - Lipoprotein(a) KW - Lipoproteins, HDL KW - Longevity KW - Lung Neoplasms KW - Obesity KW - Polymorphism, Single Nucleotide KW - Smoking KW - Socioeconomic factors AB -

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.

VL - 8 IS - 1 ER - TY - JOUR T1 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. JF - Circulation: Cardiovascular Genetics Y1 - 2017 A1 - Kraja, Aldi T A1 - Cook, James P A1 - Warren, Helen R A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Evangelou, Evangelos A1 - Alisa Manning A1 - Grarup, Niels A1 - Drenos, Fotios A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Amin, Najaf A1 - Alexandra I Blakemore A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Farmaki, Aliki-Eleni A1 - Fava, Cristiano A1 - Ferreira, Teresa A1 - Herzig, Karl-Heinz A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Sarah E Harris A1 - Have, Christian T A1 - Havulinna, Aki S A1 - Zhang, He A1 - Jørgensen, Marit E A1 - Käräjämäki, AnneMari A1 - Charles Kooperberg A1 - Linneberg, Allan A1 - Little, Louis A1 - Liu, Yongmei A1 - Bonnycastle, Lori L A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Malerba, Giovanni A1 - Riccardo E Marioni A1 - Mei, Hao A1 - Menni, Cristina A1 - Alanna C Morrison A1 - Padmanabhan, Sandosh A1 - Walter R Palmas A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Nigel W Rayner A1 - Riaz, Muhammad A1 - Rice, Ken A1 - Melissa Richard A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Stančáková, Alena A1 - Kathleen E Stirrups A1 - Tragante, Vinicius A1 - Tuomi, Tiinamaija A1 - Tzoulaki, Ioanna A1 - Varga, Tibor V A1 - Weiss, Stefan A1 - Yiorkas, Andrianos M A1 - Young, Robin A1 - Zhang, Weihua A1 - Barnes, Michael R A1 - Cabrera, Claudia P A1 - Gao, He A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Chambers, John C A1 - Connell, John M A1 - Cramer Christensen A1 - de Boer, Rudolf A A1 - Ian J Deary A1 - George Dedoussis A1 - Deloukas, Panos A1 - Dominiczak, Anna F A1 - Dörr, Marcus A1 - Joehanes, Roby A1 - Edwards, Todd L A1 - Tõnu Esko A1 - Myriam Fornage A1 - Franceschini, Nora A1 - Franks, Paul W A1 - Gambaro, Giovanni A1 - Leif C Groop A1 - Hallmans, Göran A1 - Hansen, Torben A1 - Caroline Hayward A1 - Heikki, Oksa A1 - Ingelsson, Erik A1 - Tuomilehto, Jaakko A1 - Järvelin, Marjo-Riitta A1 - Sharon L R Kardia A1 - Karpe, Fredrik A1 - Kooner, Jaspal S A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Lars Lind A1 - Ruth J F Loos A1 - Laakso, Markku A1 - McCarthy, Mark I A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Morris, Andrew P A1 - Palmer, Colin N A A1 - Pedersen, Oluf A1 - Polasek, Ozren A1 - Neil Poulter A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Veikko Salomaa A1 - Nilesh J Samani A1 - Peter Sever A1 - Skaaby, Tea A1 - Stafford, Jeanette M A1 - John M Starr A1 - van der Harst, Pim A1 - van der Meer, Peter A1 - Cornelia M van Duijn A1 - Vergnaud, Anne-Claire A1 - Gudnason, Vilmundur A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Willer, Cristen J A1 - Daniel Witte A1 - Zeggini, Eleftheria A1 - Saleheen, Danish A1 - Adam S Butterworth A1 - Danesh, John A1 - Asselbergs, Folkert W A1 - Wain, Louise V A1 - Georg B Ehret A1 - Daniel I Chasman A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Howson, Joanna M M KW - Antiporters KW - Blood pressure KW - Cell Adhesion Molecules, Neuronal KW - Databases, Factual KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Microfilament Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Receptors, Lymphocyte Homing AB -

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (<5×10) for BP, of which 4 are new BP loci: rs9678851 (missense, ), rs7437940 (), rs13303 (missense, ), and rs1055144 (). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, ) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at ) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

VL - 10 IS - 5 ER - TY - JOUR T1 - Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. JF - PLoS Genetics Y1 - 2017 A1 - Liang, Jingjing A1 - Le, Thu H A1 - Digna R Velez Edwards A1 - Bamidele O Tayo A1 - Gaulton, Kyle J A1 - Smith, Jennifer A A1 - Lu, Yingchang A1 - Jensen, Richard A A1 - Chen, Guanjie A1 - Yanek, Lisa R A1 - Schwander, Karen A1 - Tajuddin, Salman M A1 - Sofer, Tamar A1 - Kim, Wonji A1 - Kayima, James A1 - McKenzie, Colin A A1 - Fox, Ervin A1 - Michael A Nalls A1 - Young, J Hunter A1 - Yan V Sun A1 - Lane, Jacqueline M A1 - Cechova, Sylvia A1 - Zhou, Jie A1 - Tang, Hua A1 - Myriam Fornage A1 - Musani, Solomon K A1 - Wang, Heming A1 - Lee, Juyoung A1 - Adeyemo, Adebowale A1 - Dreisbach, Albert W A1 - Forrester, Terrence A1 - Chu, Pei-Lun A1 - Anne Cappola A1 - Michele K Evans A1 - Alanna C Morrison A1 - Martin, Lisa W A1 - Kerri Wiggins A1 - Hui, Qin A1 - Zhao, Wei A1 - Jackson, Rebecca D A1 - Erin B Ware A1 - Jessica Faul A1 - Reiner, Alex P A1 - Bray, Michael A1 - Denny, Joshua C A1 - Thomas H Mosley A1 - Walter R Palmas A1 - Guo, Xiuqing A1 - George J Papanicolaou A1 - Alan Penman A1 - Polak, Joseph F A1 - Kenneth Rice A1 - Taylor, Ken D A1 - Boerwinkle, Eric A1 - Erwin P Bottinger A1 - Liu, Kiang A1 - Neil Risch A1 - Hunt, Steven C A1 - Charles Kooperberg A1 - Alan B Zonderman A1 - Laurie, Cathy C A1 - Becker, Diane M A1 - Cai, Jianwen A1 - Ruth J F Loos A1 - Psaty, Bruce M A1 - David R Weir A1 - Sharon L R Kardia A1 - Donna K Arnett A1 - Won, Sungho A1 - Edwards, Todd L A1 - Redline, Susan A1 - Cooper, Richard S A1 - Rao, D C A1 - Rotter, Jerome I A1 - Charles N Rotimi A1 - Levy, Daniel A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Franceschini, Nora KW - African Americans KW - Animals KW - Basic Helix-Loop-Helix Transcription Factors KW - Blood pressure KW - Cadherins KW - Case-Control Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Membrane Proteins KW - Mice KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide AB -

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.

VL - 13 IS - 5 ER - TY - JOUR T1 - SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. JF - Journal of the American Society of Nephrology Y1 - 2017 A1 - Li, Man A1 - Li, Yong A1 - Weeks, Olivia A1 - Mijatovic, Vladan A1 - Teumer, Alexander A1 - Huffman, Jennifer E A1 - Tromp, Gerard A1 - Fuchsberger, Christian A1 - Gorski, Mathias A1 - Lyytikäinen, Leo-Pekka A1 - Nutile, Teresa A1 - Sedaghat, Sanaz A1 - Sorice, Rossella A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Ahluwalia, Tarunveer S A1 - Dan E Arking A1 - Bihlmeyer, Nathan A A1 - Böger, Carsten A A1 - Carroll, Robert J A1 - Daniel I Chasman A1 - Marilyn C Cornelis A1 - Dehghan, Abbas A1 - Jessica Faul A1 - Feitosa, Mary F A1 - Gambaro, Giovanni A1 - Paolo P. Gasparini A1 - Giulianini, Franco A1 - Iris M Heid A1 - Huang, Jinyan A1 - Imboden, Medea A1 - Jackson, Anne U A1 - Janina Jeff A1 - Jhun, Min A A1 - Katz, Ronit A1 - Kifley, Annette A1 - Kilpeläinen, Tuomas O A1 - Kumar, Ashish A1 - Laakso, Markku A1 - Li-Gao, Ruifang A1 - Kurt Lohman A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Malerba, Giovanni A1 - Mihailov, Evelin A1 - Mohlke, Karen L A1 - Dennis O Mook-Kanamori A1 - Robino, Antonietta A1 - Ruderfer, Douglas A1 - Salvi, Erika A1 - Schick, Ursula M A1 - Schulz, Christina-Alexandra A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Traglia, Michela A1 - Laura M Yerges-Armstrong A1 - Zhao, Wei A1 - Goodarzi, Mark O A1 - Kraja, Aldi T A1 - Liu, Chunyu A1 - Wessel, Jennifer A1 - Boerwinkle, Eric A1 - Ingrid B Borecki A1 - Bork-Jensen, Jette A1 - Erwin P Bottinger A1 - Braga, Daniele A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carey, David J A1 - Cramer Christensen A1 - Coresh, Josef A1 - Crook, Errol A1 - Curhan, Gary C A1 - Cusi, Daniele A1 - de Boer, Ian H A1 - de Vries, Aiko P J A1 - Denny, Joshua C A1 - Devuyst, Olivier A1 - Dreisbach, Albert W A1 - Endlich, Karlhans A1 - Tõnu Esko A1 - Franco, Oscar H A1 - Fulop, Tibor A1 - Gerhard, Glenn S A1 - Glümer, Charlotte A1 - Gottesman, Omri A1 - Grarup, Niels A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Tamara B Harris A1 - Caroline Hayward A1 - Lynne J Hocking A1 - Hofman, Albert A1 - Hu, Frank B A1 - Husemoen, Lise Lotte N A1 - Jackson, Rebecca D A1 - Jørgensen, Torben A1 - Jørgensen, Marit E A1 - Kähönen, Mika A1 - Sharon L R Kardia A1 - König, Wolfgang A1 - Charles Kooperberg A1 - Kriebel, Jennifer A1 - Lenore J Launer A1 - Lauritzen, Torsten A1 - Lehtimäki, Terho A1 - Levy, Daniel A1 - Linksted, Pamela A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Ruth J F Loos A1 - Lupo, Antonio A1 - Meisinger, Christine A1 - Melander, Olle A1 - Andres Metspalu A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Nürnberg, Peter A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pedersen, Oluf A1 - Peters, Annette A1 - Peters, Ulrike A1 - Polasek, Ozren A1 - David J Porteous A1 - Nicole M Probst-Hensch A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Olli T Raitakari A1 - Reiner, Alex P A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Fernando Rivadeneira A1 - Rossouw, Jacques E A1 - Schmidt, Frank A1 - David S Siscovick A1 - Soranzo, Nicole A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Stephen T Turner A1 - André G Uitterlinden A1 - Ulivi, Sheila A1 - Velayutham, Dinesh A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wang, Jie Jin A1 - David R Weir A1 - Daniel Witte A1 - Kuivaniemi, Helena A1 - Caroline S Fox A1 - Franceschini, Nora A1 - Goessling, Wolfram A1 - Köttgen, Anna A1 - Chu, Audrey Y KW - Animals KW - Exome KW - Genetic Loci KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - kidney KW - Protein Tyrosine Phosphatases KW - Proto-Oncogene Proteins KW - Son of Sevenless Proteins KW - Zebrafish AB -

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.

VL - 28 IS - 3 ER - TY - JOUR T1 - Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. JF - Nat Genet Y1 - 2016 A1 - Liu, Chunyu A1 - Kraja, Aldi T A1 - Jennifer A Smith A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Joshua C. Bis A1 - Kenneth Rice A1 - Alanna C Morrison A1 - Lu, Yingchang A1 - Weiss, Stefan A1 - Guo, Xiuqing A1 - Walter R Palmas A1 - Martin, Lisa W A1 - Yii-Der I Chen A1 - Surendran, Praveen A1 - Drenos, Fotios A1 - Cook, James P A1 - Auer, Paul L A1 - Chu, Audrey Y A1 - Giri, Ayush A1 - Wei Zhao A1 - Jakobsdottir, Johanna A1 - Lin, Li-An A1 - Stafford, Jeanette M A1 - Amin, Najaf A1 - Mei, Hao A1 - Yao, Jie A1 - Voorman, Arend A1 - Larson, Martin G A1 - Grove, Megan L A1 - Albert Vernon Smith A1 - Hwang, Shih-Jen A1 - Chen, Han A1 - Huan, Tianxiao A1 - Kosova, Gulum A1 - Stitziel, Nathan O A1 - Kathiresan, Sekar A1 - Nilesh J Samani A1 - Schunkert, Heribert A1 - Deloukas, Panos A1 - Li, Man A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Gorski, Mathias A1 - Charles Kooperberg A1 - George J Papanicolaou A1 - Rossouw, Jacques E A1 - Jessica Faul A1 - Sharon L R Kardia A1 - Bouchard, Claude A1 - Raffel, Leslie J A1 - André G Uitterlinden A1 - Franco, Oscar H A1 - Ramachandran S Vasan A1 - O'Donnell, Christopher J A1 - Kent D Taylor A1 - Liu, Kiang A1 - Erwin P Bottinger A1 - Gottesman, Omri A1 - Daw, E Warwick A1 - Giulianini, Franco A1 - Ganesh, Santhi A1 - Salfati, Elias A1 - Tamara B Harris A1 - Lenore J Launer A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Rettig, Rainer A1 - Völzke, Henry A1 - Eric S Kim A1 - Lee, Wen-Jane A1 - Lee, I-Te A1 - Sheu, Wayne H-H A1 - Tsosie, Krystal S A1 - Digna R Velez Edwards A1 - Yongmei Liu A1 - Correa, Adolfo A1 - David R Weir A1 - Völker, Uwe A1 - Ridker, Paul M A1 - Boerwinkle, Eric A1 - Gudnason, Vilmundur A1 - Reiner, Alexander P A1 - Cornelia M van Duijn A1 - Ingrid B Borecki A1 - Edwards, Todd L A1 - Chakravarti, Aravinda A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Ruth J F Loos A1 - Myriam Fornage A1 - Georg B Ehret A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Daniel I Chasman AB -

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

VL - 48 IS - 10 ER - TY - JOUR T1 - Directional dominance on stature and cognition in diverse human populations. JF - Nature Y1 - 2015 A1 - Joshi, Peter K A1 - Tõnu Esko A1 - Mattsson, Hannele A1 - Eklund, Niina A1 - Gandin, Ilaria A1 - Nutile, Teresa A1 - Jackson, Anne U A1 - Schurmann, Claudia A1 - Albert Vernon Smith A1 - Zhang, Weihua A1 - Okada, Yukinori A1 - Stančáková, Alena A1 - Jessica Faul A1 - Wei Zhao A1 - Traci M Bartz A1 - Maria Pina Concas A1 - Franceschini, Nora A1 - Enroth, Stefan A1 - Vitart, Veronique A1 - Trompet, Stella A1 - Guo, Xiuqing A1 - Daniel I Chasman A1 - Jeff O'Connell A1 - Corre, Tanguy A1 - Nongmaithem, Suraj S A1 - Chen, Yuning A1 - Mangino, Massimo A1 - Ruggiero, Daniela A1 - Traglia, Michela A1 - Farmaki, Aliki-Eleni A1 - Kacprowski, Tim A1 - Bjonnes, Andrew A1 - van der Spek, Ashley A1 - Wu, Ying A1 - Giri, Anil K A1 - Yanek, Lisa R A1 - Wang, Lihua A1 - Edith Hofer A1 - Cornelius A Rietveld A1 - McLeod, Olga A1 - Marilyn C Cornelis A1 - Pattaro, Cristian A1 - Verweij, Niek A1 - Baumbach, Clemens A1 - Abdel Abdellaoui A1 - Warren, Helen R A1 - Vuckovic, Dragana A1 - Mei, Hao A1 - Bouchard, Claude A1 - Perry, John R B A1 - Cappellani, Stefania A1 - Saira S Mirza A1 - Benton, Miles C A1 - Broeckel, Ulrich A1 - Sarah E Medland A1 - Penelope A Lind A1 - Malerba, Giovanni A1 - Alexander W Drong A1 - Yengo, Loic A1 - Bielak, Lawrence F A1 - Zhi, Degui A1 - van der Most, Peter J A1 - Daniel Shriner A1 - Mägi, Reedik A1 - Hemani, Gibran A1 - Karaderi, Tugce A1 - Wang, Zhaoming A1 - Tian Liu A1 - Demuth, Ilja A1 - Jing Hua Zhao A1 - Meng, Weihua A1 - Lataniotis, Lazaros A1 - van der Laan, Sander W A1 - Bradfield, Jonathan P A1 - Andrew R Wood A1 - Bonnefond, Amelie A1 - Ahluwalia, Tarunveer S A1 - Hall, Leanne M A1 - Salvi, Erika A1 - Yazar, Seyhan A1 - Carstensen, Lisbeth A1 - de Haan, Hugoline G A1 - Abney, Mark A1 - Afzal, Uzma A1 - Matthew A. Allison A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Barr, R Graham A1 - Baumeister, Sebastian E A1 - Daniel J. Benjamin A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Erwin P Bottinger A1 - Campbell, Archie A1 - Chakravarti, Aravinda A1 - Chan, Yingleong A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Yii-Der I Chen A1 - Collins, Francis S A1 - Connell, John A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Gail Davies A1 - Dörr, Marcus A1 - Georg B Ehret A1 - Ellis, Stephen B A1 - Feenstra, Bjarke A1 - Feitosa, Mary F A1 - Ford, Ian A1 - Caroline S Fox A1 - Timothy M Frayling A1 - Friedrich, Nele A1 - Geller, Frank A1 - Scotland, Generation A1 - Gillham-Nasenya, Irina A1 - Gottesman, Omri A1 - Graff, Misa A1 - Grodstein, Francine A1 - Gu, Charles A1 - Haley, Chris A1 - Hammond, Christopher J A1 - Sarah E Harris A1 - Tamara B Harris A1 - Nicholas D Hastie A1 - Heard-Costa, Nancy L A1 - Heikkilä, Kauko A1 - Lynne J Hocking A1 - Homuth, Georg A1 - Jouke-Jan Hottenga A1 - Huang, Jinyan A1 - Huffman, Jennifer E A1 - Hysi, Pirro G A1 - Mohammed Arfan Ikram A1 - Ingelsson, Erik A1 - Joensuu, Anni A1 - Johansson, Åsa A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanoni, Stavroula A1 - Kerr, Shona M A1 - Khan, Nazir M A1 - Philipp D Koellinger A1 - Koistinen, Heikki A A1 - Kooner, Manraj K A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lahti, Jari A1 - Lenore J Launer A1 - Lea, Rodney A A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - David C Liewald A1 - Lars Lind A1 - Loh, Marie A1 - Lokki, Marja-Liisa A1 - London, Stephanie J A1 - Loomis, Stephanie J A1 - Loukola, Anu A1 - Lu, Yingchang A1 - Lumley, Thomas A1 - Lundqvist, Annamari A1 - Männistö, Satu A1 - Marques-Vidal, Pedro A1 - Masciullo, Corrado A1 - Matchan, Angela A1 - Mathias, Rasika A A1 - Matsuda, Koichi A1 - Meigs, James B A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Mentch, Frank D A1 - Mihailov, Evelin A1 - Lili Milani A1 - Montasser, May E A1 - Grant W Montgomery A1 - Alanna C Morrison A1 - Myers, Richard H A1 - Nadukuru, Rajiv A1 - Navarro, Pau A1 - Nelis, Mari A1 - Nieminen, Markku S A1 - Ilja M Nolte A1 - O'Connor, George T A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Walter R Palmas A1 - Pankow, James S A1 - Patarcic, Inga A1 - Pavani, Francesca A1 - Peyser, Patricia A A1 - Pietilainen, Kirsi A1 - Neil Poulter A1 - Prokopenko, Inga A1 - Ralhan, Sarju A1 - Redmond, Paul A1 - Rich, Stephen S A1 - Rissanen, Harri A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rose, Richard A1 - Cinzia Felicita Sala A1 - Babatunde Salako A1 - Veikko Salomaa A1 - Sarin, Antti-Pekka A1 - Saxena, Richa A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sennblad, Bengt A1 - Seshadri, Sudha A1 - Peter Sever A1 - Shrestha, Smeeta A1 - Smith, Blair H A1 - Jennifer A Smith A1 - Soranzo, Nicole A1 - Sotoodehnia, Nona A1 - Southam, Lorraine A1 - Stanton, Alice V A1 - Stathopoulou, Maria G A1 - Strauch, Konstantin A1 - Strawbridge, Rona J A1 - Suderman, Matthew J A1 - Tandon, Nikhil A1 - Tang, Sian-Tsun A1 - Kent D Taylor A1 - Bamidele O Tayo A1 - Töglhofer, Anna Maria A1 - Tomaszewski, Maciej A1 - Tšernikova, Natalia A1 - Tuomilehto, Jaakko A1 - André G Uitterlinden A1 - Vaidya, Dhananjay A1 - van Hylckama Vlieg, Astrid A1 - van Setten, Jessica A1 - Vasankari, Tuula A1 - Vedantam, Sailaja A1 - Vlachopoulou, Efthymia A1 - Vozzi, Diego A1 - Vuoksimaa, Eero A1 - Waldenberger, Melanie A1 - Erin B Ware A1 - Wentworth-Shields, William A1 - Whitfield, John B A1 - Sarah Wild A1 - Gonneke Willemsen A1 - Yajnik, Chittaranjan S A1 - Yao, Jie A1 - Zaza, Gianluigi A1 - Zhu, Xiaofeng A1 - Salem, Rany M A1 - Melbye, Mads A1 - Bisgaard, Hans A1 - Nilesh J Samani A1 - Cusi, Daniele A1 - Mackey, David A A1 - Cooper, Richard S A1 - Froguel, Philippe A1 - Pasterkamp, Gerard A1 - Grant, Struan F A A1 - Hakonarson, Hakon A1 - Luigi Ferrucci A1 - Scott, Robert A A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - George Dedoussis A1 - Deloukas, Panos A1 - Bertram, Lars A1 - Lindenberger, Ulman A1 - Berndt, Sonja I A1 - Lindgren, Cecilia M A1 - Nicholas J Timpson A1 - Tönjes, Anke A1 - Munroe, Patricia B A1 - Thorkild I. A. Sørensen A1 - Charles N Rotimi A1 - Donna K Arnett A1 - Oldehinkel, Albertine J A1 - Sharon L R Kardia A1 - Balkau, Beverley A1 - Gambaro, Giovanni A1 - Morris, Andrew P A1 - Johan G Eriksson A1 - Margaret J Wright A1 - Nicholas G Martin A1 - Hunt, Steven C A1 - John M Starr A1 - Ian J Deary A1 - Griffiths, Lyn R A1 - Henning Tiemeier A1 - Nicola Pirastu A1 - Kaprio, Jaakko A1 - Wareham, Nicholas J A1 - Pérusse, Louis A1 - Wilson, James G A1 - Giorgia G Girotto A1 - Caulfield, Mark J A1 - Olli T Raitakari A1 - Dorret I Boomsma A1 - Gieger, Christian A1 - van der Harst, Pim A1 - Hicks, Andrew A A1 - Kraft, Peter A1 - Sinisalo, Juha A1 - Knekt, Paul A1 - Johannesson, Magnus A1 - Patrik K E Magnusson A1 - Hamsten, Anders A1 - Schmidt, Reinhold A1 - Ingrid B Borecki A1 - Vartiainen, Erkki A1 - Becker, Diane M A1 - Bharadwaj, Dwaipayan A1 - Mohlke, Karen L A1 - Boehnke, Michael A1 - Cornelia M van Duijn A1 - Sanghera, Dharambir K A1 - Teumer, Alexander A1 - Zeggini, Eleftheria A1 - Andres Metspalu A1 - Paolo P. Gasparini A1 - Ulivi, Sheila A1 - Ober, Carole A1 - Toniolo, Daniela A1 - Rudan, Igor A1 - David J Porteous A1 - Ciullo, Marina A1 - Timothy Spector A1 - Caroline Hayward A1 - Dupuis, Josée A1 - Ruth J F Loos A1 - Alan F Wright A1 - Chandak, Giriraj R A1 - Vollenweider, Peter A1 - Alan R Shuldiner A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Sattar, Naveed A1 - Gyllensten, Ulf A1 - Kari E North A1 - Pirastu, Mario A1 - Psaty, Bruce M A1 - David R Weir A1 - Laakso, Markku A1 - Gudnason, Vilmundur A1 - Takahashi, Atsushi A1 - Chambers, John C A1 - Kooner, Jaspal S A1 - David P Strachan A1 - Campbell, Harry A1 - Joel N Hirschhron A1 - Markus Perola A1 - Polasek, Ozren A1 - James F Wilson KW - Biological Evolution KW - Blood pressure KW - Body Height KW - Cholesterol KW - Cognitive Ability KW - Cohort Studies KW - Education KW - Female KW - Forced Expiratory Volume KW - Genome KW - Homozygote KW - Humans KW - Lung Volume Measurements KW - Male KW - Phenotype AB -

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

VL - 523 IS - 7561 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26131930?dopt=Abstract ER - TY - JOUR T1 - Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. JF - Nat Genet Y1 - 2015 A1 - Day, Felix R A1 - Ruth, Katherine S A1 - Thompson, Deborah J A1 - Kathryn L Lunetta A1 - Pervjakova, Natalia A1 - Daniel I Chasman A1 - Stolk, Lisette A1 - Finucane, Hilary K A1 - Sulem, Patrick A1 - Bulik-Sullivan, Brendan A1 - Tõnu Esko A1 - Andrew D Johnson A1 - Elks, Cathy E A1 - Franceschini, Nora A1 - He, Chunyan A1 - Altmaier, Elisabeth A1 - Brody, Jennifer A A1 - Lude L Franke A1 - Huffman, Jennifer E A1 - Keller, Margaux F A1 - McArdle, Patrick F A1 - Nutile, Teresa A1 - Porcu, Eleonora A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Schick, Ursula M A1 - Jennifer A Smith A1 - Teumer, Alexander A1 - Traglia, Michela A1 - Vuckovic, Dragana A1 - Yao, Jie A1 - Wei Zhao A1 - Albrecht, Eva A1 - Amin, Najaf A1 - Corre, Tanguy A1 - Jouke-Jan Hottenga A1 - Mangino, Massimo A1 - Albert Vernon Smith A1 - Toshiko Tanaka A1 - Gonçalo R Abecasis A1 - Andrulis, Irene L A1 - Anton-Culver, Hoda A1 - Antoniou, Antonis C A1 - Arndt, Volker A1 - Alice M. Arnold A1 - Barbieri, Caterina A1 - Beckmann, Matthias W A1 - Beeghly-Fadiel, Alicia A1 - Benitez, Javier A1 - Bernstein, Leslie A1 - Bielinski, Suzette J A1 - Blomqvist, Carl A1 - Boerwinkle, Eric A1 - Bogdanova, Natalia V A1 - Bojesen, Stig E A1 - Manjeet K. Bolla A1 - Borresen-Dale, Anne-Lise A1 - Boutin, Thibaud S A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Brüning, Thomas A1 - Burwinkel, Barbara A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chapman, J Ross A1 - Yii-Der I Chen A1 - Chenevix-Trench, Georgia A1 - Couch, Fergus J A1 - Coviello, Andrea D A1 - Cox, Angela A1 - Czene, Kamila A1 - Darabi, Hatef A1 - De Vivo, Immaculata A1 - Ellen W Demerath A1 - Joe G Dennis A1 - Devilee, Peter A1 - Dörk, Thilo A1 - Dos-Santos-Silva, Isabel A1 - Dunning, Alison M A1 - John D Eicher A1 - Fasching, Peter A A1 - Jessica Faul A1 - Figueroa, Jonine A1 - Flesch-Janys, Dieter A1 - Gandin, Ilaria A1 - Melissa E Garcia A1 - García-Closas, Montserrat A1 - Giles, Graham G A1 - Giorgia G Girotto A1 - Goldberg, Mark S A1 - González-Neira, Anna A1 - Goodarzi, Mark O A1 - Grove, Megan L A1 - Gudbjartsson, Daniel F A1 - Guénel, Pascal A1 - Guo, Xiuqing A1 - Christopher A Haiman A1 - Hall, Per A1 - Hamann, Ute A1 - Henderson, Brian E A1 - Lynne J Hocking A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hooning, Maartje J A1 - John L Hopper A1 - Hu, Frank B A1 - Huang, Jinyan A1 - Humphreys, Keith A1 - Hunter, David J A1 - Jakubowska, Anna A1 - Jones, Samuel E A1 - Kabisch, Maria A1 - Karasik, David A1 - Knight, Julia A A1 - Kolcic, Ivana A1 - Charles Kooperberg A1 - Kosma, Veli-Matti A1 - Kriebel, Jennifer A1 - Kristensen, Vessela A1 - Lambrechts, Diether A1 - Langenberg, Claudia A1 - Li, Jingmei A1 - Li, Xin A1 - Lindström, Sara A1 - Yongmei Liu A1 - Luan, Jian'an A1 - Lubinski, Jan A1 - Mägi, Reedik A1 - Mannermaa, Arto A1 - Manz, Judith A1 - Margolin, Sara A1 - Marten, Jonathan A1 - Nicholas G Martin A1 - Masciullo, Corrado A1 - Meindl, Alfons A1 - Michailidou, Kyriaki A1 - Mihailov, Evelin A1 - Lili Milani A1 - Milne, Roger L A1 - Müller-Nurasyid, Martina A1 - Michael A Nalls A1 - Neale, Benjamin M A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Anne B Newman A1 - Børge G Nordestgaard A1 - Olson, Janet E A1 - Padmanabhan, Sandosh A1 - Peterlongo, Paolo A1 - Peters, Ulrike A1 - Petersmann, Astrid A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Nicola Pirastu A1 - Pirie, Ailith A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - David J Porteous A1 - Psaty, Bruce M A1 - Pylkäs, Katri A1 - Radice, Paolo A1 - Raffel, Leslie J A1 - Fernando Rivadeneira A1 - Rudan, Igor A1 - Rudolph, Anja A1 - Ruggiero, Daniela A1 - Cinzia Felicita Sala A1 - Sanna, Serena A1 - Sawyer, Elinor J A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Schmidt, Frank A1 - Schmutzler, Rita K A1 - Schoemaker, Minouk J A1 - Scott, Robert A A1 - Seynaeve, Caroline M A1 - Simard, Jacques A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Stöckl, Doris A1 - Strauch, Konstantin A1 - Swerdlow, Anthony A1 - Kent D Taylor A1 - Thorsteinsdottir, Unnur A1 - Toland, Amanda E A1 - Tomlinson, Ian A1 - Truong, Thérèse A1 - Tryggvadottir, Laufey A1 - Stephen T Turner A1 - Vozzi, Diego A1 - Wang, Qin A1 - Wellons, Melissa A1 - Gonneke Willemsen A1 - James F Wilson A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce B H R A1 - Alan F Wright A1 - Yannoukakos, Drakoulis A1 - Zemunik, Tatijana A1 - Wei Zhang A1 - Zygmunt, Marek A1 - Bergmann, Sven A1 - Dorret I Boomsma A1 - Buring, Julie E A1 - Luigi Ferrucci A1 - Grant W Montgomery A1 - Gudnason, Vilmundur A1 - Timothy Spector A1 - Cornelia M van Duijn A1 - Alizadeh, Behrooz Z A1 - Ciullo, Marina A1 - Crisponi, Laura A1 - Easton, Douglas F A1 - Paolo P. Gasparini A1 - Gieger, Christian A1 - Tamara B Harris A1 - Caroline Hayward A1 - Sharon L R Kardia A1 - Kraft, Peter A1 - McKnight, Barbara A1 - Andres Metspalu A1 - Alanna C Morrison A1 - Reiner, Alex P A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Toniolo, Daniela A1 - André G Uitterlinden A1 - Ulivi, Sheila A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - David R Weir A1 - Laura M Yerges-Armstrong A1 - Price, Alkes L A1 - Stefansson, Kari A1 - Visser, Jenny A A1 - Ong, Ken K A1 - Chang-Claude, Jenny A1 - Joanne M Murabito A1 - Perry, John R B A1 - Murray, Anna KW - Age Factors KW - Aging KW - BRCA1 Protein KW - Breast Neoplasms KW - DNA Repair KW - Female KW - Genome KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Hypothalamus KW - Menopause KW - Middle Aged KW - Models, Genetic KW - Older Adults KW - Phenotype KW - Reproduction KW - Signal Transduction AB -

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

VL - 47 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract ER - TY - JOUR T1 - Genetic diversity is a predictor of mortality in humans. JF - BMC Genet Y1 - 2014 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Albert Vernon Smith A1 - Kathryn L Lunetta A1 - Michael A Nalls A1 - Jennifer A Smith A1 - Toshiko Tanaka A1 - Gail Davies A1 - Lei Yu A1 - Saira S Mirza A1 - Teumer, Alexander A1 - Coresh, Josef A1 - Pankow, James S A1 - Franceschini, Nora A1 - Scaria, Anish A1 - Oshima, Junko A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Guðny Eiríksdóttir A1 - Tamara B Harris A1 - Li, Hanyue A1 - Karasik, David A1 - Douglas P Kiel A1 - Melissa E Garcia A1 - Yongmei Liu A1 - Jessica Faul A1 - Sharon L R Kardia A1 - Wei Zhao A1 - Luigi Ferrucci A1 - Allerhand, Michael A1 - David C Liewald A1 - Redmond, Paul A1 - John M Starr A1 - Philip L de Jager A1 - Nese Direk A1 - Mohammed Arfan Ikram A1 - André G Uitterlinden A1 - Homuth, Georg A1 - Lorbeer, Roberto A1 - Hans-Jörgen Grabe A1 - Lenore J Launer A1 - Joanne M Murabito A1 - Andrew B Singleton A1 - David R Weir A1 - Bandinelli, Stefania A1 - Ian J Deary A1 - David A Bennett A1 - Henning Tiemeier A1 - Kocher, Thomas A1 - Lumley, Thomas A1 - Dan E Arking KW - Genome-Wide Association Study KW - Heterozygote KW - Humans KW - Mortality KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models AB -

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

VL - 15 UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301661/ U1 - http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations. JF - Am J Hum Genet Y1 - 2013 A1 - Franceschini, Nora A1 - Fox, Ervin A1 - Zhang, Zhaogong A1 - Edwards, Todd L A1 - Michael A Nalls A1 - Yun Ju Sung A1 - Bamidele O Tayo A1 - Yan V Sun A1 - Gottesman, Omri A1 - Adebawole Adeyemo A1 - Andrew D Johnson A1 - Young, J Hunter A1 - Kenneth Rice A1 - Duan, Qing A1 - Chen, Fang A1 - Yun Li A1 - Tang, Hua A1 - Myriam Fornage A1 - Keene, Keith L A1 - Andrews, Jeanette S A1 - Jennifer A Smith A1 - Jessica Faul A1 - Guangfa, Zhang A1 - Guo, Wei A1 - Liu, Yu A1 - Murray, Sarah S A1 - Musani, Solomon K A1 - Srinivasan, Sathanur A1 - Digna R Velez Edwards A1 - Wang, Heming A1 - Becker, Lewis C A1 - Bovet, Pascal A1 - Bochud, Murielle A1 - Broeckel, Ulrich A1 - Burnier, Michel A1 - Carty, Cara A1 - Daniel I Chasman A1 - Georg B Ehret A1 - Chen, Wei-Min A1 - Chen, Guanjie A1 - Wei Chen A1 - Ding, Jingzhong A1 - Dreisbach, Albert W A1 - Michele K Evans A1 - Guo, Xiuqing A1 - Melissa E Garcia A1 - Jensen, Rich A1 - Keller, Margaux F A1 - Lettre, Guillaume A1 - Lotay, Vaneet A1 - Martin, Lisa W A1 - Moore, Jason H A1 - Alanna C Morrison A1 - Thomas H Mosley A1 - Ogunniyi, Adesola A1 - Walter R Palmas A1 - George J Papanicolaou A1 - Alan Penman A1 - Polak, Joseph F A1 - Ridker, Paul M A1 - Babatunde Salako A1 - Andrew B Singleton A1 - Daniel Shriner A1 - Kent D Taylor A1 - Ramachandran S Vasan A1 - Kerri Wiggins A1 - Williams, Scott M A1 - Yanek, Lisa R A1 - Wei Zhao A1 - Alan B Zonderman A1 - Becker, Diane M A1 - Berenson, Gerald A1 - Boerwinkle, Eric A1 - Erwin P Bottinger A1 - Cushman, Mary A1 - Charles B Eaton A1 - Nyberg, Fredrik A1 - Gerardo Heiss A1 - Joel N Hirschhron A1 - Howard, Virginia J A1 - Karczewsk, Konrad J A1 - Lanktree, Matthew B A1 - Liu, Kiang A1 - Yongmei Liu A1 - Ruth J F Loos A1 - Margolis, Karen A1 - Snyder, Michael A1 - Psaty, Bruce M A1 - Schork, Nicholas J A1 - David R Weir A1 - Charles N Rotimi A1 - Sale, Michele M A1 - Tamara B Harris A1 - Sharon L R Kardia A1 - Hunt, Steven C A1 - Donna K Arnett A1 - Redline, Susan A1 - Cooper, Richard S A1 - Neil Risch A1 - Rao, D C A1 - Rotter, Jerome I A1 - Chakravarti, Aravinda A1 - Reiner, Alex P A1 - Levy, Daniel A1 - Keating, Brendan J A1 - Zhu, Xiaofeng KW - Africa KW - African Continental Ancestry Group KW - Blood pressure KW - Cohort Studies KW - Databases, Genetic KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Quantitative Trait, Heritable KW - Reproducibility of Results AB -

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

VL - 93 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23972371?dopt=Abstract ER -