TY - JOUR T1 - NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. JF - PLoS Genet Y1 - 2009 A1 - Heard-Costa, Nancy L A1 - Zillikens, M Carola A1 - Monda, Keri L A1 - Johansson, Asa A1 - Harris, Tamara B A1 - Fu, Mao A1 - Haritunians, Talin A1 - Feitosa, Mary F A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Garcia, Melissa A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Mitchell, Braxton D A1 - McArdle, Patrick F A1 - Shuldiner, Alan R A1 - Bielinski, Suzette J A1 - Boerwinkle, Eric A1 - Brancati, Fred A1 - Demerath, Ellen W A1 - Pankow, James S A1 - Arnold, Alice M A1 - Chen, Yii-Der Ida A1 - Glazer, Nicole L A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Amin, Najaf A1 - Campbell, Harry A1 - Gyllensten, Ulf A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Rudan, Igor A1 - Struchalin, Maksim A1 - Vitart, Veronique A1 - Gao, Xiaoyi A1 - Kraja, Aldi A1 - Province, Michael A A1 - Zhang, Qunyuan A1 - Atwood, Larry D A1 - Dupuis, Josée A1 - Hirschhorn, Joel N A1 - Jaquish, Cashell E A1 - O'Donnell, Christopher J A1 - Vasan, Ramachandran S A1 - White, Charles C A1 - Aulchenko, Yurii S A1 - Estrada, Karol A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Oostra, Ben A A1 - Kaplan, Robert C A1 - Gudnason, Vilmundur A1 - O'Connell, Jeffrey R A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - North, Kari E KW - Aged KW - Body Mass Index KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist Circumference AB -

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19557197?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of aging. JF - Neurobiol Aging Y1 - 2011 A1 - Walter, Stefan A1 - Atzmon, Gil A1 - Demerath, Ellen W A1 - Garcia, Melissa E A1 - Kaplan, Robert C A1 - Kumari, Meena A1 - Lunetta, Kathryn L A1 - Milaneschi, Yuri A1 - Tanaka, Toshiko A1 - Tranah, Gregory J A1 - Völker, Uwe A1 - Yu, Lei A1 - Arnold, Alice A1 - Benjamin, Emelia J A1 - Biffar, Reiner A1 - Buchman, Aron S A1 - Boerwinkle, Eric A1 - Couper, David A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Harris, Tamara B A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Karasik, David A1 - Kiel, Douglas P A1 - Kocher, Thomas A1 - Kuningas, Maris A1 - Launer, Lenore J A1 - Lohman, Kurt K A1 - Lutsey, Pamela L A1 - Mackenbach, Johan A1 - Marciante, Kristin A1 - Psaty, Bruce M A1 - Reiman, Eric M A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Shardell, Michelle D A1 - Smith, Albert V A1 - van Duijn, Cornelia A1 - Walston, Jeremy A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Baumeister, Sebastian E A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Liu, Yongmei A1 - Murabito, Joanne M A1 - Newman, Anne B A1 - Tiemeier, Henning A1 - Franceschini, Nora KW - Aging KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity AB -

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

VL - 32 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gérard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Polymerase gamma KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms. JF - Genetics Y1 - 2012 A1 - Chiang, Charleston W K A1 - Liu, Ching-Ti A1 - Lettre, Guillaume A1 - Lange, Leslie A A1 - Jorgensen, Neal W A1 - Keating, Brendan J A1 - Vedantam, Sailaja A1 - Nock, Nora L A1 - Franceschini, Nora A1 - Reiner, Alex P A1 - Demerath, Ellen W A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Wilson, James G A1 - North, Kari E A1 - Papanicolaou, George J A1 - Cupples, L Adrienne A1 - Murabito, Joanne M A1 - Hirschhorn, Joel N KW - Alleles KW - Animals KW - Body Height KW - Body Mass Index KW - Child KW - Conserved Sequence KW - Dogs KW - Evolution, Molecular KW - Female KW - Genetic Fitness KW - Genetic Variation KW - Genome, Human KW - Genotype KW - Humans KW - Inheritance Patterns KW - Male KW - Mice KW - Pedigree KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Rats KW - Reproduction KW - Young Adult AB -

Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.

VL - 192 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22714408?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association of body fat distribution in African ancestry populations suggests new loci. JF - PLoS Genet Y1 - 2013 A1 - Liu, Ching-Ti A1 - Monda, Keri L A1 - Taylor, Kira C A1 - Lange, Leslie A1 - Demerath, Ellen W A1 - Palmas, Walter A1 - Wojczynski, Mary K A1 - Ellis, Jaclyn C A1 - Vitolins, Mara Z A1 - Liu, Simin A1 - Papanicolaou, George J A1 - Irvin, Marguerite R A1 - Xue, Luting A1 - Griffin, Paula J A1 - Nalls, Michael A A1 - Adeyemo, Adebowale A1 - Liu, Jiankang A1 - Li, Guo A1 - Ruiz-Narvaez, Edward A A1 - Chen, Wei-Min A1 - Chen, Fang A1 - Henderson, Brian E A1 - Millikan, Robert C A1 - Ambrosone, Christine B A1 - Strom, Sara S A1 - Guo, Xiuqing A1 - Andrews, Jeanette S A1 - Sun, Yan V A1 - Mosley, Thomas H A1 - Yanek, Lisa R A1 - Shriner, Daniel A1 - Haritunians, Talin A1 - Rotter, Jerome I A1 - Speliotes, Elizabeth K A1 - Smith, Megan A1 - Rosenberg, Lynn A1 - Mychaleckyj, Josyf A1 - Nayak, Uma A1 - Spruill, Ida A1 - Garvey, W Timothy A1 - Pettaway, Curtis A1 - Nyante, Sarah A1 - Bandera, Elisa V A1 - Britton, Angela F A1 - Zonderman, Alan B A1 - Rasmussen-Torvik, Laura J A1 - Chen, Yii-Der Ida A1 - Ding, Jingzhong A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Zhao, Wei A1 - Peyser, Patricia A A1 - Kardia, Sharon L R A1 - Kabagambe, Edmond A1 - Broeckel, Ulrich A1 - Chen, Guanjie A1 - Zhou, Jie A1 - Wassertheil-Smoller, Sylvia A1 - Neuhouser, Marian L A1 - Rampersaud, Evadnie A1 - Psaty, Bruce A1 - Kooperberg, Charles A1 - Manson, JoAnn E A1 - Kuller, Lewis H A1 - Ochs-Balcom, Heather M A1 - Johnson, Karen C A1 - Sucheston, Lara A1 - Ordovas, Jose M A1 - Palmer, Julie R A1 - Haiman, Christopher A A1 - McKnight, Barbara A1 - Howard, Barbara V A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Liu, Yongmei A1 - Allison, Matthew A A1 - Grant, Struan F A A1 - Burke, Gregory L A1 - Patel, Sanjay R A1 - Schreiner, Pamela J A1 - Borecki, Ingrid B A1 - Evans, Michele K A1 - Taylor, Herman A1 - Sale, Michèle M A1 - Howard, Virginia A1 - Carlson, Christopher S A1 - Rotimi, Charles N A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Reiner, Alexander P A1 - Cupples, L Adrienne A1 - North, Kari E A1 - Fox, Caroline S KW - Adiposity KW - African Continental Ancestry Group KW - Body Fat Distribution KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

VL - 9 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23966867?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of early menopause and the combined impact of identified variants. JF - Hum Mol Genet Y1 - 2013 A1 - Perry, John R B A1 - Corre, Tanguy A1 - Esko, Tõnu A1 - Chasman, Daniel I A1 - Fischer, Krista A1 - Franceschini, Nora A1 - He, Chunyan A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Vernon Smith, Albert A1 - Stolk, Lisette A1 - Sulem, Patrick A1 - Weedon, Michael N A1 - Zhuang, Wei V A1 - Arnold, Alice A1 - Ashworth, Alan A1 - Bergmann, Sven A1 - Buring, Julie E A1 - Burri, Andrea A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Couper, David J A1 - Goodarzi, Mark O A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Hofman, Albert A1 - Jones, Michael A1 - Kraft, Peter A1 - Launer, Lenore A1 - Laven, Joop S E A1 - Li, Guo A1 - McKnight, Barbara A1 - Masciullo, Corrado A1 - Milani, Lili A1 - Orr, Nicholas A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Schoemaker, Minouk A1 - Traglia, Michela A1 - Waeber, Gérard A1 - Chanock, Stephen J A1 - Demerath, Ellen W A1 - Garcia, Melissa A1 - Hankinson, Susan E A1 - Hu, Frank B A1 - Hunter, David J A1 - Lunetta, Kathryn L A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Murabito, Joanne M A1 - Newman, Anne B A1 - Ong, Ken K A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Swerdlow, Anthony J A1 - Thorsteinsdottir, Unnur A1 - van Dam, Rob M A1 - Uitterlinden, André G A1 - Visser, Jenny A A1 - Vollenweider, Peter A1 - Toniolo, Daniela A1 - Murray, Anna KW - Case-Control Studies KW - Female KW - Gene Frequency KW - Genome-Wide Association Study KW - Humans KW - Menopause, Premature KW - Polymorphism, Single Nucleotide KW - Primary Ovarian Insufficiency KW - Quantitative Trait Loci KW - Risk AB -

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

VL - 22 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23307926?dopt=Abstract ER - TY - JOUR T1 - Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. JF - Hum Mol Genet Y1 - 2014 A1 - Yoneyama, Sachiko A1 - Guo, Yiran A1 - Lanktree, Matthew B A1 - Barnes, Michael R A1 - Elbers, Clara C A1 - Karczewski, Konrad J A1 - Padmanabhan, Sandosh A1 - Bauer, Florianne A1 - Baumert, Jens A1 - Beitelshees, Amber A1 - Berenson, Gerald S A1 - Boer, Jolanda M A A1 - Burke, Gregory A1 - Cade, Brian A1 - Chen, Wei A1 - Cooper-Dehoff, Rhonda M A1 - Gaunt, Tom R A1 - Gieger, Christian A1 - Gong, Yan A1 - Gorski, Mathias A1 - Heard-Costa, Nancy A1 - Johnson, Toby A1 - Lamonte, Michael J A1 - McDonough, Caitrin A1 - Monda, Keri L A1 - Onland-Moret, N Charlotte A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Ordovas, Jose A1 - Peter, Inga A1 - Peters, Annette A1 - Shaffer, Jonathan A1 - Shen, Haiqinq A1 - Smith, Erin A1 - Speilotes, Liz A1 - Thomas, Fridtjof A1 - Thorand, Barbara A1 - Monique Verschuren, W M A1 - Anand, Sonia S A1 - Dominiczak, Anna A1 - Davidson, Karina W A1 - Hegele, Robert A A1 - Heid, Iris A1 - Hofker, Marten H A1 - Huggins, Gordon S A1 - Illig, Thomas A1 - Johnson, Julie A A1 - Kirkland, Susan A1 - König, Wolfgang A1 - Langaee, Taimour Y A1 - McCaffery, Jeanne A1 - Melander, Olle A1 - Mitchell, Braxton D A1 - Munroe, Patricia A1 - Murray, Sarah S A1 - Papanicolaou, George A1 - Redline, Susan A1 - Reilly, Muredach A1 - Samani, Nilesh J A1 - Schork, Nicholas J A1 - van der Schouw, Yvonne T A1 - Shimbo, Daichi A1 - Shuldiner, Alan R A1 - Tobin, Martin D A1 - Wijmenga, Cisca A1 - Yusuf, Salim A1 - Hakonarson, Hakon A1 - Lange, Leslie A A1 - Demerath, Ellen W A1 - Fox, Caroline S A1 - North, Kari E A1 - Reiner, Alex P A1 - Keating, Brendan A1 - Taylor, Kira C KW - Adiposity KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Waist Circumference KW - Waist-Hip Ratio KW - Young Adult AB -

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

VL - 23 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of loci associated with age at natural menopause in African-American women. JF - Hum Mol Genet Y1 - 2014 A1 - Chen, Christina T L A1 - Liu, Ching-Ti A1 - Chen, Gary K A1 - Andrews, Jeanette S A1 - Arnold, Alice M A1 - Dreyfus, Jill A1 - Franceschini, Nora A1 - Garcia, Melissa E A1 - Kerr, Kathleen F A1 - Li, Guo A1 - Lohman, Kurt K A1 - Musani, Solomon K A1 - Nalls, Michael A A1 - Raffel, Leslie J A1 - Smith, Jennifer A1 - Ambrosone, Christine B A1 - Bandera, Elisa V A1 - Bernstein, Leslie A1 - Britton, Angela A1 - Brzyski, Robert G A1 - Cappola, Anne A1 - Carlson, Christopher S A1 - Couper, David A1 - Deming, Sandra L A1 - Goodarzi, Mark O A1 - Heiss, Gerardo A1 - John, Esther M A1 - Lu, Xiaoning A1 - Le Marchand, Loïc A1 - Marciante, Kristin A1 - McKnight, Barbara A1 - Millikan, Robert A1 - Nock, Nora L A1 - Olshan, Andrew F A1 - Press, Michael F A1 - Vaiyda, Dhananjay A1 - Woods, Nancy F A1 - Taylor, Herman A A1 - Zhao, Wei A1 - Zheng, Wei A1 - Evans, Michele K A1 - Harris, Tamara B A1 - Henderson, Brian E A1 - Kardia, Sharon L R A1 - Kooperberg, Charles A1 - Liu, Yongmei A1 - Mosley, Thomas H A1 - Psaty, Bruce A1 - Wellons, Melissa A1 - Windham, Beverly G A1 - Zonderman, Alan B A1 - Cupples, L Adrienne A1 - Demerath, Ellen W A1 - Haiman, Christopher A1 - Murabito, Joanne M A1 - Rajkovic, Aleksandar KW - African Americans KW - Age Factors KW - Chromosomes, Human KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Menopause KW - United States AB -

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.

VL - 23 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24493794?dopt=Abstract ER - TY - JOUR T1 - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. JF - Genome Biol Y1 - 2016 A1 - Ligthart, Symen A1 - Marzi, Carola A1 - Aslibekyan, Stella A1 - Mendelson, Michael M A1 - Conneely, Karen N A1 - Tanaka, Toshiko A1 - Colicino, Elena A1 - Waite, Lindsay L A1 - Joehanes, Roby A1 - Guan, Weihua A1 - Brody, Jennifer A A1 - Elks, Cathy A1 - Marioni, Riccardo A1 - Jhun, Min A A1 - Agha, Golareh A1 - Bressler, Jan A1 - Ward-Caviness, Cavin K A1 - Chen, Brian H A1 - Huan, Tianxiao A1 - Bakulski, Kelly A1 - Salfati, Elias L A1 - Fiorito, Giovanni A1 - Wahl, Simone A1 - Schramm, Katharina A1 - Sha, Jin A1 - Hernandez, Dena G A1 - Just, Allan C A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Pilling, Luke C A1 - Pankow, James S A1 - Tsao, Phil S A1 - Liu, Chunyu A1 - Zhao, Wei A1 - Guarrera, Simonetta A1 - Michopoulos, Vasiliki J A1 - Smith, Alicia K A1 - Peters, Marjolein J A1 - Melzer, David A1 - Vokonas, Pantel A1 - Fornage, Myriam A1 - Prokisch, Holger A1 - Bis, Joshua C A1 - Chu, Audrey Y A1 - Herder, Christian A1 - Grallert, Harald A1 - Yao, Chen A1 - Shah, Sonia A1 - McRae, Allan F A1 - Lin, Honghuang A1 - Horvath, Steve A1 - Fallin, Daniele A1 - Hofman, Albert A1 - Wareham, Nicholas J A1 - Wiggins, Kerri L A1 - Feinberg, Andrew P A1 - Starr, John M A1 - Visscher, Peter M A1 - Murabito, Joanne M A1 - Kardia, Sharon L R A1 - Absher, Devin M A1 - Binder, Elisabeth B A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Matullo, Giuseppe A1 - Schwartz, Joel D A1 - Demerath, Ellen W A1 - Uitterlinden, André G A1 - van Meurs, Joyce B J A1 - Franco, Oscar H A1 - Chen, Yii-Der Ida A1 - Levy, Daniel A1 - Turner, Stephen T A1 - Deary, Ian J A1 - Ressler, Kerry J A1 - Dupuis, Josée A1 - Ferrucci, Luigi A1 - Ong, Ken K A1 - Assimes, Themistocles L A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Arnett, Donna K A1 - Baccarelli, Andrea A A1 - Benjamin, Emelia J A1 - Dehghan, Abbas AB -

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

VL - 17 IS - 1 ER - TY - JOUR T1 - Epigenetic Signatures of Cigarette Smoking. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Joehanes, Roby A1 - Just, Allan C A1 - Marioni, Riccardo E A1 - Pilling, Luke C A1 - Reynolds, Lindsay M A1 - Mandaviya, Pooja R A1 - Guan, Weihua A1 - Xu, Tao A1 - Elks, Cathy E A1 - Aslibekyan, Stella A1 - Moreno-Macias, Hortensia A1 - Smith, Jennifer A A1 - Brody, Jennifer A A1 - Dhingra, Radhika A1 - Yousefi, Paul A1 - Pankow, James S A1 - Kunze, Sonja A1 - Shah, Sonia H A1 - McRae, Allan F A1 - Lohman, Kurt A1 - Sha, Jin A1 - Absher, Devin M A1 - Ferrucci, Luigi A1 - Zhao, Wei A1 - Demerath, Ellen W A1 - Bressler, Jan A1 - Grove, Megan L A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Yao, Chen A1 - Kiel, Douglas P A1 - Peters, Annette A1 - Wang-Sattler, Rui A1 - Visscher, Peter M A1 - Wray, Naomi R A1 - Starr, John M A1 - Ding, Jingzhong A1 - Rodriguez, Carlos J A1 - Wareham, Nicholas J A1 - Irvin, Marguerite R A1 - Zhi, Degui A1 - Barrdahl, Myrto A1 - Vineis, Paolo A1 - Ambatipudi, Srikant A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Schwartz, Joel A1 - Colicino, Elena A1 - Hou, Lifang A1 - Vokonas, Pantel S A1 - Hernandez, Dena G A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Turner, Stephen T A1 - Ware, Erin B A1 - Smith, Alicia K A1 - Klengel, Torsten A1 - Binder, Elisabeth B A1 - Psaty, Bruce M A1 - Taylor, Kent D A1 - Gharib, Sina A A1 - Swenson, Brenton R A1 - Liang, Liming A1 - DeMeo, Dawn L A1 - O'Connor, George T A1 - Herceg, Zdenko A1 - Ressler, Kerry J A1 - Conneely, Karen N A1 - Sotoodehnia, Nona A1 - Kardia, Sharon L R A1 - Melzer, David A1 - Baccarelli, Andrea A A1 - van Meurs, Joyce B J A1 - Romieu, Isabelle A1 - Arnett, Donna K A1 - Ong, Ken K A1 - Liu, Yongmei A1 - Waldenberger, Melanie A1 - Deary, Ian J A1 - Fornage, Myriam A1 - Levy, Daniel A1 - London, Stephanie J AB -

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

VL - 9 IS - 5 ER - TY - JOUR T1 - Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. JF - Nat Commun Y1 - 2017 A1 - Joshi, Peter K A1 - Pirastu, Nicola A1 - Kentistou, Katherine A A1 - Fischer, Krista A1 - Hofer, Edith A1 - Schraut, Katharina E A1 - Clark, David W A1 - Nutile, Teresa A1 - Barnes, Catriona L K A1 - Timmers, Paul R H J 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-Gómez, Carolina A1 - Bartz, Traci M A1 - Trompet, Stella A1 - Lange, Leslie A 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 - Demerath, Ellen W A1 - Demuth, Ilja A1 - Faul, Jessica D A1 - Ford, Ian A1 - Gialluisi, Alessandro A1 - Gögele, Martin A1 - Graff, Mariaelisa A1 - Hingorani, Aroon A1 - Hottenga, Jouke-Jan 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 - Medland, Sarah E A1 - Milani, Lili A1 - Nagy, Reka A1 - Ollier, William E R A1 - Peyser, Patricia A A1 - Pramstaller, Peter P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando 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 - Zonderman, Alan B A1 - Lehtimäki, Terho A1 - Evans, Michele K A1 - Pirastu, Mario A1 - Fuchsberger, Christian A1 - Bertram, Lars A1 - Pendleton, Neil A1 - Kardia, Sharon L R A1 - Ciullo, Marina A1 - Becker, Diane M A1 - Wong, Andrew A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Wilson, James G A1 - Jukema, J Wouter A1 - Kiemeney, Lambertus A1 - Uitterlinden, André G A1 - Franceschini, Nora A1 - North, Kari E A1 - Weir, David R A1 - Metspalu, Andres A1 - Boomsma, Dorret I A1 - Hayward, Caroline A1 - Chasman, Daniel A1 - Martin, Nicholas G A1 - Sattar, Naveed A1 - Campbell, Harry A1 - Esko, Tõnu A1 - Kutalik, Zoltán A1 - Wilson, James F 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 - Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality. JF - Circ Genom Precis Med Y1 - 2020 A1 - Ma, Jiantao A1 - Rebholz, Casey M A1 - Braun, Kim V E A1 - Reynolds, Lindsay M A1 - Aslibekyan, Stella A1 - Xia, Rui A1 - Biligowda, Niranjan G A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Joehanes, Roby A1 - Hu, Emily A A1 - Vitolins, Mara Z A1 - Wood, Alexis C A1 - Lohman, Kurt A1 - Ochoa-Rosales, Carolina A1 - van Meurs, Joyce A1 - Uitterlinden, Andre A1 - Liu, Yongmei A1 - Elhadad, Mohamed A A1 - Heier, Margit A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Colicino, Elena A1 - Whitsel, Eric A A1 - Baldassari, Antoine A1 - Gharib, Sina A A1 - Sotoodehnia, Nona A1 - Brody, Jennifer A A1 - Sitlani, Colleen M A1 - Tanaka, Toshiko A1 - Hill, W David A1 - Corley, Janie A1 - Deary, Ian J A1 - Zhang, Yan A1 - Schöttker, Ben A1 - Brenner, Hermann A1 - Walker, Maura E A1 - Ye, Shumao A1 - Nguyen, Steve A1 - Pankow, Jim A1 - Demerath, Ellen W A1 - Zheng, Yinan A1 - Hou, Lifang A1 - Liang, Liming A1 - Lichtenstein, Alice H A1 - Hu, Frank B A1 - Fornage, Myriam A1 - Voortman, Trudy A1 - Levy, Daniel AB -

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied.

METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.

RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10).

CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

VL - 13 IS - 4 ER - TY - JOUR T1 - Genetic insights into biological mechanisms governing human ovarian ageing. JF - Nature Y1 - 2021 A1 - Ruth, Katherine S A1 - Day, Felix R A1 - Hussain, Jazib A1 - Martínez-Marchal, Ana A1 - Aiken, Catherine E A1 - Azad, Ajuna A1 - Thompson, Deborah J A1 - Knoblochova, Lucie A1 - Abe, Hironori A1 - Tarry-Adkins, Jane L A1 - Gonzalez, Javier Martin A1 - Fontanillas, Pierre A1 - Claringbould, Annique A1 - Bakker, Olivier B A1 - Sulem, Patrick A1 - Walters, Robin G A1 - Terao, Chikashi A1 - Turon, Sandra A1 - Horikoshi, Momoko A1 - Lin, Kuang A1 - Onland-Moret, N Charlotte A1 - Sankar, Aditya A1 - Hertz, Emil Peter Thrane A1 - Timshel, Pascal N A1 - Shukla, Vallari A1 - Borup, Rehannah A1 - Olsen, Kristina W A1 - Aguilera, Paula A1 - Ferrer-Roda, Mònica A1 - Huang, Yan A1 - Stankovic, Stasa A1 - Timmers, Paul R H J A1 - Ahearn, Thomas U A1 - Alizadeh, Behrooz Z A1 - Naderi, Elnaz A1 - Andrulis, Irene L A1 - Arnold, Alice M A1 - Aronson, Kristan J A1 - Augustinsson, Annelie A1 - Bandinelli, Stefania A1 - Barbieri, Caterina M A1 - Beaumont, Robin N A1 - Becher, Heiko A1 - Beckmann, Matthias W A1 - Benonisdottir, Stefania A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Boomsma, Dorret I A1 - Bowker, Nicholas A1 - Brody, Jennifer A A1 - Broer, Linda A1 - Buring, Julie E A1 - Campbell, Archie A1 - Campbell, Harry A1 - Castelao, Jose E A1 - Catamo, Eulalia A1 - Chanock, Stephen J A1 - Chenevix-Trench, Georgia A1 - Ciullo, Marina A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cox, Angela A1 - Crisponi, Laura A1 - Cross, Simon S A1 - Cucca, Francesco A1 - Czene, Kamila A1 - Smith, George Davey A1 - de Geus, Eco J C N A1 - de Mutsert, Renée A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Dunning, Alison M A1 - Dwek, Miriam A1 - Eriksson, Mikael A1 - Esko, Tõnu A1 - Fasching, Peter A A1 - Faul, Jessica D A1 - Ferrucci, Luigi A1 - Franceschini, Nora A1 - Frayling, Timothy M A1 - Gago-Dominguez, Manuela A1 - Mezzavilla, Massimo A1 - García-Closas, Montserrat A1 - Gieger, Christian A1 - Giles, Graham G A1 - Grallert, Harald A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Guénel, Pascal A1 - Haiman, Christopher A A1 - Håkansson, Niclas A1 - Hall, Per A1 - Hayward, Caroline A1 - He, Chunyan A1 - He, Wei A1 - Heiss, Gerardo A1 - Høffding, Miya K A1 - Hopper, John L A1 - Hottenga, Jouke J A1 - Hu, Frank A1 - Hunter, David A1 - Ikram, Mohammad A A1 - Jackson, Rebecca D A1 - Joaquim, Micaella D R A1 - John, Esther M A1 - Joshi, Peter K A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Kartsonaki, Christiana A1 - Karlsson, Robert A1 - Kitahara, Cari M A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Kraft, Peter A1 - Kurian, Allison W A1 - Kutalik, Zoltán A1 - La Bianca, Martina A1 - Lachance, Genevieve A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Lawlor, Deborah A A1 - Le Marchand, Loïc A1 - Li, Jingmei A1 - Lindblom, Annika A1 - Lindström, Sara A1 - Lindstrom, Tricia A1 - Linet, Martha A1 - Liu, Yongmei A1 - Liu, Simin A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mannermaa, Arto A1 - Marco, Brumat A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Mbarek, Hamdi A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Metspalu, Andres A1 - Milani, Lili A1 - Milne, Roger L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mulas, Antonella A1 - Mulligan, Anna M A1 - Murray, Alison A1 - Nalls, Mike A A1 - Newman, Anne A1 - Noordam, Raymond A1 - Nutile, Teresa A1 - Nyholt, Dale R A1 - Olshan, Andrew F A1 - Olsson, Håkan A1 - Painter, Jodie N A1 - Patel, Alpa V A1 - Pedersen, Nancy L A1 - Perjakova, Natalia A1 - Peters, Annette A1 - Peters, Ulrike A1 - Pharoah, Paul D P A1 - Polasek, Ozren A1 - Porcu, Eleonora A1 - Psaty, Bruce M A1 - Rahman, Iffat A1 - Rennert, Gad A1 - Rennert, Hedy S A1 - Ridker, Paul M A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rossouw, Jacques A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Saloustros, Emmanouil A1 - Sandler, Dale P A1 - Sanna, Serena A1 - Sawyer, Elinor J A1 - Sarnowski, Chloe A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Schoemaker, Minouk J A1 - Schraut, Katharina E A1 - Scott, Christopher A1 - Shekari, Saleh A1 - Shrikhande, Amruta A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Spector, Tim D A1 - Spinelli, John J A1 - Stampfer, Meir A1 - Stöckl, Doris A1 - van Meurs, Joyce B J A1 - Strauch, Konstantin A1 - Styrkarsdottir, Unnur A1 - Swerdlow, Anthony J A1 - Tanaka, Toshiko A1 - Teras, Lauren R A1 - Teumer, Alexander A1 - Þorsteinsdottir, Unnur A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Troester, Melissa A A1 - Truong, Thérèse A1 - Tyrrell, Jessica A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Vachon, Celine M A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wang, Qin A1 - Wareham, Nicholas J A1 - Weinberg, Clarice R A1 - Weir, David R A1 - Wilcox, Amber N A1 - van Dijk, Ko Willems A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wolk, Alicja A1 - Wood, Andrew R A1 - Zhao, Wei A1 - Zygmunt, Marek A1 - Chen, Zhengming A1 - Li, Liming A1 - Franke, Lude A1 - Burgess, Stephen A1 - Deelen, Patrick A1 - Pers, Tune H A1 - Grøndahl, Marie Louise A1 - Andersen, Claus Yding A1 - Pujol, Anna A1 - Lopez-Contreras, Andres J A1 - Daniel, Jeremy A A1 - Stefansson, Kari A1 - Chang-Claude, Jenny A1 - van der Schouw, Yvonne T A1 - Lunetta, Kathryn L A1 - Chasman, Daniel I A1 - Easton, Douglas F A1 - Visser, Jenny A A1 - Ozanne, Susan E A1 - Namekawa, Satoshi H A1 - Solc, Petr A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Hoffmann, Eva R A1 - Murray, Anna A1 - Roig, Ignasi A1 - Perry, John R B AB -

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

VL - 596 IS - 7872 ER -