%0 Journal Article %J N Engl J Med %D 2011 %T Diabetes mellitus, fasting glucose, and risk of cause-specific death. %A Rao Kondapally Seshasai, Sreenivasa %A Kaptoge, Stephen %A Thompson, Alexander %A Di Angelantonio, Emanuele %A Gao, Pei %A Sarwar, Nadeem %A Whincup, Peter H %A Mukamal, Kenneth J %A Gillum, Richard F %A Holme, Ingar %A Njølstad, Inger %A Fletcher, Astrid %A Nilsson, Peter %A Lewington, Sarah %A Collins, Rory %A Gudnason, Vilmundur %A Thompson, Simon G %A Sattar, Naveed %A Selvin, Elizabeth %A Hu, Frank B %A Danesh, John %K Blood Glucose %K Cause of Death %K Diabetes Mellitus %K Female %K Humans %K Hyperglycemia %K Life Expectancy %K Male %K Middle Aged %K Risk %K Survival Analysis %X

BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.

CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

%B N Engl J Med %V 364 %P 829-841 %8 2011 Mar 03 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21366474?dopt=Abstract %R 10.1056/NEJMoa1008862 %0 Journal Article %J Nature %D 2011 %T Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. %A Ehret, Georg B %A Munroe, Patricia B %A Rice, Kenneth M %A Bochud, Murielle %A Johnson, Andrew D %A Chasman, Daniel I %A Smith, Albert V %A Tobin, Martin D %A Verwoert, Germaine C %A Hwang, Shih-Jen %A Pihur, Vasyl %A Vollenweider, Peter %A O'Reilly, Paul F %A Amin, Najaf %A Bragg-Gresham, Jennifer L %A Teumer, Alexander %A Glazer, Nicole L %A Launer, Lenore %A Zhao, Jing Hua %A Aulchenko, Yurii %A Heath, Simon %A Sõber, Siim %A Parsa, Afshin %A Luan, Jian'an %A Arora, Pankaj %A Dehghan, Abbas %A Zhang, Feng %A Lucas, Gavin %A Hicks, Andrew A %A Jackson, Anne U %A Peden, John F %A Tanaka, Toshiko %A Wild, Sarah H %A Rudan, Igor %A Igl, Wilmar %A Milaneschi, Yuri %A Parker, Alex N %A Fava, Cristiano %A Chambers, John C %A Fox, Ervin R %A Kumari, Meena %A Go, Min Jin %A van der Harst, Pim %A Kao, Wen Hong Linda %A Sjögren, Marketa %A Vinay, D G %A Alexander, Myriam %A Tabara, Yasuharu %A Shaw-Hawkins, Sue %A Whincup, Peter H %A Liu, Yongmei %A Shi, Gang %A Kuusisto, Johanna %A Tayo, Bamidele %A Seielstad, Mark %A Sim, Xueling %A Nguyen, Khanh-Dung Hoang %A Lehtimäki, Terho %A Matullo, Giuseppe %A Wu, Ying %A Gaunt, Tom R %A Onland-Moret, N Charlotte %A Cooper, Matthew N %A Platou, Carl G P %A Org, Elin %A Hardy, Rebecca %A Dahgam, Santosh %A Palmen, Jutta %A Vitart, Veronique %A Braund, Peter S %A Kuznetsova, Tatiana %A Uiterwaal, Cuno S P M %A Adeyemo, Adebowale %A Palmas, Walter %A Campbell, Harry %A Ludwig, Barbara %A Tomaszewski, Maciej %A Tzoulaki, Ioanna %A Palmer, Nicholette D %A Aspelund, Thor %A Garcia, Melissa %A Chang, Yen-Pei C %A O'Connell, Jeffrey R %A Steinle, Nanette I %A Grobbee, Diederick E %A Arking, Dan E %A Kardia, Sharon L %A Morrison, Alanna C %A Hernandez, Dena 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Tetsuro %A Saleheen, Danish %A Chandak, Giriraj R %A Coresh, Josef %A Navis, Gerjan %A Salomaa, Veikko %A Han, Bok-Ghee %A Zhu, Xiaofeng %A Kooner, Jaspal S %A Melander, Olle %A Ridker, Paul M %A Bandinelli, Stefania %A Gyllensten, Ulf B %A Wright, Alan F %A Wilson, James F %A Ferrucci, Luigi %A Farrall, Martin %A Tuomilehto, Jaakko %A Pramstaller, Peter P %A Elosua, Roberto %A Soranzo, Nicole %A Sijbrands, Eric J G %A Altshuler, David %A Loos, Ruth J F %A Shuldiner, Alan R %A Gieger, Christian %A Meneton, Pierre %A Uitterlinden, André G %A Wareham, Nicholas J %A Gudnason, Vilmundur %A Rotter, Jerome I %A Rettig, Rainer %A Uda, Manuela %A Strachan, David P %A Witteman, Jacqueline C M %A Hartikainen, Anna-Liisa %A Beckmann, Jacques S %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Boehnke, Michael %A Larson, Martin G %A Jarvelin, Marjo-Riitta %A Psaty, Bruce M %A Abecasis, Goncalo R %A Chakravarti, Aravinda %A Elliott, Paul %A van Duijn, Cornelia M %A Newton-Cheh, Christopher %A Levy, Daniel %A Caulfield, Mark J %A Johnson, Toby %K Africa %K Asia %K Blood Pressure %K Cardiovascular Diseases %K Coronary Artery Disease %K Europe %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Kidney Diseases %K Polymorphism, Single Nucleotide %K Stroke %X

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

%B Nature %V 478 %P 103-9 %8 2011 Sep 11 %G eng %N 7367 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract %R 10.1038/nature10405 %0 Journal Article %J PLoS Genet %D 2012 %T Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. %A Dastani, Zari %A Hivert, Marie-France %A Timpson, Nicholas %A Perry, John R B %A Yuan, Xin %A Scott, Robert A %A Henneman, Peter %A Heid, Iris M %A Kizer, Jorge R %A Lyytikäinen, Leo-Pekka %A Fuchsberger, Christian %A Tanaka, Toshiko %A Morris, Andrew P %A Small, Kerrin %A Isaacs, Aaron %A Beekman, Marian %A Coassin, Stefan %A Lohman, Kurt %A Qi, Lu %A Kanoni, Stavroula %A Pankow, James S %A Uh, Hae-Won %A Wu, Ying %A Bidulescu, Aurelian %A Rasmussen-Torvik, Laura J %A Greenwood, Celia M T %A Ladouceur, Martin %A Grimsby, Jonna %A Manning, Alisa K %A Liu, Ching-Ti %A Kooner, Jaspal %A Mooser, Vincent E %A Vollenweider, Peter %A Kapur, Karen A %A Chambers, 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Schlessinger, David %A Uda, Manuela %A Ruokonen, Aimo %A Jarvelin, Marjo-Riitta %A Peltonen, Leena %A Mooser, Vincent %A Sladek, Robert %A Musunuru, Kiran %A Smith, Albert V %A Edmondson, Andrew C %A Stylianou, Ioannis M %A Koseki, Masahiro %A Pirruccello, James P %A Chasman, Daniel I %A Johansen, Christopher T %A Fouchier, Sigrid W %A Peloso, Gina M %A Barbalic, Maja %A Ricketts, Sally L %A Bis, Joshua C %A Feitosa, Mary F %A Orho-Melander, Marju %A Melander, Olle %A Li, Xiaohui %A Li, Mingyao %A Cho, Yoon Shin %A Go, Min Jin %A Kim, Young Jin %A Lee, Jong-Young %A Park, Taesung %A Kim, Kyunga %A Sim, Xueling %A Ong, Rick Twee-Hee %A Croteau-Chonka, Damien C %A Lange, Leslie A %A Smith, Joshua D %A Ziegler, Andreas %A Zhang, Weihua %A Zee, Robert Y L %A Whitfield, John B %A Thompson, John R %A Surakka, Ida %A Spector, Tim D %A Smit, Johannes H %A Sinisalo, Juha %A Scott, James %A Saharinen, Juha %A Sabatti, Chiara %A Rose, Lynda M %A Roberts, Robert %A Rieder, Mark %A Parker, Alex N %A Paré, Guillaume %A O'Donnell, Christopher J %A Nieminen, Markku S %A Nickerson, Deborah A %A Montgomery, Grant W %A McArdle, Wendy %A Masson, David %A Martin, Nicholas G %A Marroni, Fabio %A Lucas, Gavin %A Luben, Robert %A Lokki, Marja-Liisa %A Lettre, Guillaume %A Launer, Lenore J %A Lakatta, Edward G %A Laaksonen, Reijo %A Kyvik, Kirsten O %A König, Inke R %A Khaw, Kay-Tee %A Kaplan, Lee M %A Johansson, Asa %A Janssens, A Cecile J W %A Igl, Wilmar %A Hovingh, G Kees %A Hengstenberg, Christian %A Havulinna, Aki S %A Hastie, Nicholas D %A Harris, Tamara B %A Haritunians, Talin %A Hall, Alistair S %A Groop, Leif C %A Gonzalez, Elena %A Freimer, Nelson B %A Erdmann, Jeanette %A Ejebe, Kenechi G %A Döring, Angela %A Dominiczak, Anna F %A Demissie, Serkalem %A Deloukas, Panagiotis %A de Faire, Ulf %A Crawford, Gabriel %A Chen, Yii-der I %A Caulfield, Mark J %A Boekholdt, S Matthijs %A Assimes, Themistocles L %A Quertermous, Thomas %A Seielstad, Mark %A Wong, Tien Y %A Tai, E-Shyong %A Feranil, Alan B %A Kuzawa, Christopher W %A Taylor, Herman A %A Gabriel, Stacey B %A Holm, Hilma %A Gudnason, Vilmundur %A Krauss, Ronald M %A Ordovas, Jose M %A Munroe, Patricia B %A Kooner, Jaspal S %A Tall, Alan R %A Hegele, Robert A %A Kastelein, John J P %A Schadt, Eric E %A Strachan, David P %A Reilly, Muredach P %A Samani, Nilesh J %A Schunkert, Heribert %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Ridker, Paul M %A Rader, Daniel J %A Kathiresan, Sekar %K Adiponectin %K African Americans %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Gene Expression %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Tolerance Test %K Humans %K Insulin Resistance %K Male %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Waist-Hip Ratio %X

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

%B PLoS Genet %V 8 %P e1002607 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract %R 10.1371/journal.pgen.1002607 %0 Journal Article %J Exp Gerontol %D 2014 %T Gender and telomere length: systematic review and meta-analysis. %A Gardner, Michael %A Bann, David %A Wiley, Laura %A Cooper, Rachel %A Hardy, Rebecca %A Nitsch, Dorothea %A Martin-Ruiz, Carmen %A Shiels, Paul %A Sayer, Avan Aihie %A Barbieri, Michelangela %A Bekaert, Sofie %A Bischoff, Claus %A Brooks-Wilson, Angela %A Chen, Wei %A Cooper, Cyrus %A Christensen, Kaare %A De Meyer, Tim %A Deary, Ian %A Der, Geoff %A Diez Roux, Ana %A Fitzpatrick, Annette %A Hajat, Anjum %A Halaschek-Wiener, Julius %A Harris, Sarah %A Hunt, Steven C %A Jagger, Carol %A Jeon, Hyo-Sung %A Kaplan, Robert %A Kimura, Masayuki %A Lansdorp, Peter %A Li, Changyong %A Maeda, Toyoki %A Mangino, Massimo %A Nawrot, Tim S %A Nilsson, Peter %A Nordfjall, Katarina %A Paolisso, Giuseppe %A Ren, Fu %A Riabowol, Karl %A Robertson, Tony %A Roos, Goran %A Staessen, Jan A %A Spector, Tim %A Tang, Nelson %A Unryn, Brad %A van der Harst, Pim %A Woo, Jean %A Xing, Chao %A Yadegarfar, Mohammad E %A Park, Jae Yong %A Young, Neal %A Kuh, Diana %A von Zglinicki, Thomas %A Ben-Shlomo, Yoav %K Adult %K Aged %K Aged, 80 and over %K Aging %K Female %K Humans %K Male %K Middle Aged %K Sex Factors %K Telomere %X

BACKGROUND: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.

METHODS: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.

RESULTS: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error.

CONCLUSIONS: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

%B Exp Gerontol %V 51 %P 15-27 %8 2014 Mar %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24365661?dopt=Abstract %R 10.1016/j.exger.2013.12.004 %0 Journal Article %J Nat Genet %D 2018 %T Multi-ethnic genome-wide association study for atrial fibrillation. %A Roselli, Carolina %A Chaffin, Mark D %A Weng, Lu-Chen %A Aeschbacher, Stefanie %A Ahlberg, Gustav %A Albert, Christine M %A Almgren, Peter %A Alonso, Alvaro %A Anderson, Christopher D %A Aragam, Krishna G %A Arking, Dan E %A Barnard, John %A Bartz, Traci M %A Benjamin, Emelia J %A Bihlmeyer, Nathan A %A Bis, Joshua C %A Bloom, Heather L %A Boerwinkle, Eric %A Bottinger, Erwin B %A Brody, Jennifer A %A Calkins, Hugh %A Campbell, Archie %A Cappola, Thomas P %A Carlquist, John %A Chasman, Daniel I %A Chen, Lin Y %A Chen, Yii-Der Ida %A Choi, Eue-Keun %A Choi, Seung Hoan %A Christophersen, Ingrid E %A Chung, Mina K %A Cole, John W %A Conen, David %A Cook, James %A Crijns, Harry J %A Cutler, Michael J %A Damrauer, Scott M %A Daniels, Brian R %A Darbar, Dawood %A Delgado, Graciela %A Denny, Joshua C %A Dichgans, Martin %A Dörr, Marcus %A Dudink, Elton A %A Dudley, Samuel C %A Esa, Nada %A Esko, Tõnu %A Eskola, Markku %A Fatkin, Diane %A Felix, Stephan B %A Ford, Ian %A Franco, Oscar H %A Geelhoed, Bastiaan %A Grewal, Raji P %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gupta, Namrata %A Gustafsson, Stefan %A Gutmann, Rebecca %A Hamsten, Anders %A Harris, Tamara B %A Hayward, Caroline %A Heckbert, Susan R %A Hernesniemi, Jussi %A Hocking, Lynne J %A Hofman, Albert %A Horimoto, Andrea R V R %A Huang, Jie %A Huang, Paul L %A Huffman, Jennifer %A Ingelsson, Erik %A Ipek, Esra Gucuk %A Ito, Kaoru %A Jimenez-Conde, Jordi %A Johnson, Renee %A Jukema, J Wouter %A Kääb, Stefan %A Kähönen, Mika %A Kamatani, Yoichiro %A Kane, John P %A Kastrati, Adnan %A Kathiresan, Sekar %A Katschnig-Winter, Petra %A Kavousi, Maryam %A Kessler, Thorsten %A Kietselaer, Bas L %A Kirchhof, Paulus %A Kleber, Marcus E %A Knight, Stacey %A Krieger, Jose E %A Kubo, Michiaki %A Launer, Lenore J %A Laurikka, Jari %A Lehtimäki, Terho %A Leineweber, Kirsten %A Lemaitre, Rozenn N %A Li, Man %A Lim, Hong Euy %A Lin, Henry J %A Lin, Honghuang %A Lind, Lars %A Lindgren, Cecilia M %A Lokki, Marja-Liisa %A London, Barry %A Loos, Ruth J F %A Low, Siew-Kee %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Macfarlane, Peter W %A Magnusson, Patrik K %A Mahajan, Anubha %A Malik, Rainer %A Mansur, Alfredo J %A Marcus, Gregory M %A Margolin, Lauren %A Margulies, Kenneth B %A März, Winfried %A McManus, David D %A Melander, Olle %A Mohanty, Sanghamitra %A Montgomery, Jay A %A Morley, Michael P %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Natale, Andrea %A Nazarian, Saman %A Neumann, Benjamin %A Newton-Cheh, Christopher %A Niemeijer, Maartje N %A Nikus, Kjell %A Nilsson, Peter %A Noordam, Raymond %A Oellers, Heidi %A Olesen, Morten S %A Orho-Melander, Marju %A Padmanabhan, Sandosh %A Pak, Hui-Nam %A Paré, Guillaume %A Pedersen, Nancy L %A Pera, Joanna %A Pereira, Alexandre %A Porteous, David %A Psaty, Bruce M %A Pulit, Sara L %A Pullinger, Clive R %A Rader, Daniel J %A Refsgaard, Lena %A Ribasés, Marta %A Ridker, Paul M %A Rienstra, Michiel %A Risch, Lorenz %A Roden, Dan M %A Rosand, Jonathan %A Rosenberg, Michael A %A Rost, Natalia %A Rotter, Jerome I %A Saba, Samir %A Sandhu, Roopinder K %A Schnabel, Renate B %A Schramm, Katharina %A Schunkert, Heribert %A Schurman, Claudia %A Scott, Stuart A %A Seppälä, Ilkka %A Shaffer, Christian %A Shah, Svati %A Shalaby, Alaa A %A Shim, Jaemin %A Shoemaker, M Benjamin %A Siland, Joylene E %A Sinisalo, Juha %A Sinner, Moritz F %A Slowik, Agnieszka %A Smith, Albert V %A Smith, Blair H %A Smith, J Gustav %A Smith, Jonathan D %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stricker, Bruno H %A Sun, Albert %A Sun, Han %A Svendsen, Jesper H %A Tanaka, Toshihiro %A Tanriverdi, Kahraman %A Taylor, Kent D %A Teder-Laving, Maris %A Teumer, Alexander %A Thériault, Sébastien %A Trompet, Stella %A Tucker, Nathan R %A Tveit, Arnljot %A Uitterlinden, André G %A van der Harst, Pim %A Van Gelder, Isabelle C %A Van Wagoner, David R %A Verweij, Niek %A Vlachopoulou, Efthymia %A Völker, Uwe %A Wang, Biqi %A Weeke, Peter E %A Weijs, Bob %A Weiss, Raul %A Weiss, Stefan %A Wells, Quinn S %A Wiggins, Kerri L %A Wong, Jorge A %A Woo, Daniel %A Worrall, Bradford B %A Yang, Pil-Sung %A Yao, Jie %A Yoneda, Zachary T %A Zeller, Tanja %A Zeng, Lingyao %A Lubitz, Steven A %A Lunetta, Kathryn L %A Ellinor, Patrick T %X

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

%B Nat Genet %V 50 %P 1225-1233 %8 2018 Sep %G eng %N 9 %R 10.1038/s41588-018-0133-9