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 - 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 - Chasman, Daniel I 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 - Demerath, Ellen W 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 D 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 - Haiman, Christopher A A1 - Hall, Per A1 - Hamann, Ute A1 - Henderson, Brian E A1 - Hocking, Lynne J 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 - Kooperberg, Charles 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 - Nordestgaard, Børge G 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 N 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 - Tim D 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 D 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 - Grabe, Hans J 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.