TY - JOUR T1 - Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. JF - JAMA Y1 - 2009 A1 - Vasan, Ramachandran S A1 - Glazer, Nicole L A1 - Felix, Janine F A1 - Lieb, Wolfgang A1 - Wild, Philipp S A1 - Felix, Stephan B A1 - Watzinger, Norbert A1 - Larson, Martin G A1 - Smith, Nicholas L A1 - Dehghan, Abbas A1 - Grosshennig, Anika A1 - Schillert, Arne A1 - Teumer, Alexander A1 - Schmidt, Reinhold A1 - Kathiresan, Sekar A1 - Lumley, Thomas A1 - Aulchenko, Yurii S A1 - König, Inke R A1 - Zeller, Tanja A1 - Homuth, Georg A1 - Struchalin, Maksim A1 - Aragam, Jayashri A1 - Bis, Joshua C A1 - Rivadeneira, Fernando A1 - Erdmann, Jeanette A1 - Schnabel, Renate B A1 - Dörr, Marcus A1 - Zweiker, Robert A1 - Lind, Lars A1 - Rodeheffer, Richard J A1 - Greiser, Karin Halina A1 - Levy, Daniel A1 - Haritunians, Talin A1 - Deckers, Jaap W A1 - Stritzke, Jan A1 - Lackner, Karl J A1 - Völker, Uwe A1 - Ingelsson, Erik A1 - Kullo, Iftikhar A1 - Haerting, Johannes A1 - O'Donnell, Christopher J A1 - Heckbert, Susan R A1 - Stricker, Bruno H A1 - Ziegler, Andreas A1 - Reffelmann, Thorsten A1 - Redfield, Margaret M A1 - Werdan, Karl A1 - Mitchell, Gary F A1 - Rice, Kenneth A1 - Arnett, Donna K A1 - Hofman, Albert A1 - Gottdiener, John S A1 - Uitterlinden, André G A1 - Meitinger, Thomas A1 - Blettner, Maria A1 - Friedrich, Nele A1 - Wang, Thomas J A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Wichmann, H-Erich A1 - Munzel, Thomas F A1 - Kroemer, Heyo K A1 - Benjamin, Emelia J A1 - Rotter, Jerome I A1 - Witteman, Jacqueline C A1 - Schunkert, Heribert A1 - Schmidt, Helena A1 - Völzke, Henry A1 - Blankenberg, Stefan KW - Adult KW - Aged KW - Aged, 80 and over KW - Aorta KW - Cardiovascular Diseases KW - Echocardiography KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart Atria KW - Heart Ventricles KW - Humans KW - Male KW - Middle Aged KW - Organ Size KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Ventricular Dysfunction, Left KW - Ventricular Function, Left AB -

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

VL - 302 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19584346?dopt=Abstract ER - TY - JOUR T1 - Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. JF - PLoS One Y1 - 2010 A1 - Gkrania-Klotsas, Effrossyni A1 - Ye, Zheng A1 - Cooper, Andrew J A1 - Sharp, Stephen J A1 - Luben, Robert A1 - Biggs, Mary L A1 - Chen, Liang-Kung A1 - Gokulakrishnan, Kuppan A1 - Hanefeld, Markolf A1 - Ingelsson, Erik A1 - Lai, Wen-An A1 - Lin, Shih-Yi A1 - Lind, Lars A1 - Lohsoonthorn, Vitool A1 - Mohan, Viswanathan A1 - Muscari, Antonio A1 - Nilsson, Goran A1 - Ohrvik, John A1 - Chao Qiang, Jiang A1 - Jenny, Nancy Swords A1 - Tamakoshi, Koji A1 - Temelkova-Kurktschiev, Theodora A1 - Wang, Ya-Yu A1 - Yajnik, Chittaranjan Sakerlal A1 - Zoli, Marco A1 - Khaw, Kay-Tee A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Langenberg, Claudia KW - Adult KW - Aged KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Leukocyte Count KW - Male KW - Middle Aged KW - Prospective Studies AB -

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

VL - 5 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20976133?dopt=Abstract ER - TY - JOUR T1 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. JF - Nat Genet Y1 - 2010 A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Prokopenko, Inga A1 - Saxena, Richa A1 - Soranzo, Nicole A1 - Jackson, Anne U A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Gloyn, Anna L A1 - Lindgren, Cecilia M A1 - Mägi, Reedik A1 - Morris, Andrew P A1 - Randall, Joshua A1 - Johnson, Toby A1 - Elliott, Paul A1 - Rybin, Denis A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Henneman, Peter A1 - Grallert, Harald A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Franklin, Christopher S A1 - Navarro, Pau A1 - Song, Kijoung A1 - Goel, Anuj A1 - Perry, John R B A1 - Egan, Josephine M A1 - Lajunen, Taina A1 - Grarup, Niels A1 - Sparsø, Thomas A1 - Doney, Alex A1 - Voight, Benjamin F A1 - Stringham, Heather M A1 - Li, Man A1 - Kanoni, Stavroula A1 - Shrader, Peter A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Qi, Lu A1 - Timpson, Nicholas J A1 - Gieger, Christian A1 - Zabena, Carina A1 - Rocheleau, Ghislain A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Payne, Felicity A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ardlie, Kristin A1 - Ariyurek, Yavuz A1 - Balkau, Beverley A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bonnefond, Amélie A1 - Bonnycastle, Lori L A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Charpentier, Guillaume A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Dina, Christian A1 - Erdos, Michael R A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Fox, Caroline S A1 - Frants, Rune A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Groves, Christopher J A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Gyllensten, Ulf A1 - Hadjadj, Samy A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Herder, Christian A1 - Hicks, Andrew A A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Hui, Jennie A1 - Hung, Joe A1 - Isomaa, Bo A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Lyssenko, Valeriya A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Manning, Alisa K A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McCulloch, Laura J A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Morken, Mario A A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Narisu, Narisu A1 - Neville, Matthew J A1 - Oostra, Ben A A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Palmer, Colin N A A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Rathmann, Wolfgang A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Roden, Michael A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Scott, Laura J A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurethsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tanaka, Toshiko A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - van Hoek, Mandy A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Walters, G Bragi A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Weedon, Michael N A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zeggini, Eleftheria A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Loos, Ruth J F A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Hattersley, Andrew T A1 - Silander, Kaisa A1 - Salomaa, Veikko A1 - Smith, George Davey A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Serrano-Ríos, Manuel A1 - Morris, Andrew D A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pankow, James S A1 - Sampson, Michael J A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Pramstaller, Peter Paul A1 - Wichmann, H Erich A1 - Illig, Thomas A1 - Rudan, Igor A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Campbell, Harry A1 - Wilson, James F A1 - Bergman, Richard N A1 - Buchanan, Thomas A A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Altshuler, David A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Deloukas, Panos A1 - Spector, Timothy D A1 - Frayling, Timothy M A1 - Ferrucci, Luigi A1 - Kong, Augustine A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Aulchenko, Yurii S A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Waterworth, Dawn M A1 - Vollenweider, Peter A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Abecasis, Goncalo R A1 - Wareham, Nicholas J A1 - Sladek, Robert A1 - Froguel, Philippe A1 - Watanabe, Richard M A1 - Meigs, James B A1 - Groop, Leif A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Florez, Jose C A1 - Barroso, Inês KW - Adolescent KW - Adult KW - Alleles KW - Blood Glucose KW - Child KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - DNA Copy Number Variations KW - Fasting KW - Gene Expression Regulation KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Reproducibility of Results AB -

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract ER - TY - JOUR T1 - Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis. JF - Diabetes Y1 - 2011 A1 - Kanoni, Stavroula A1 - Nettleton, Jennifer A A1 - Hivert, Marie-France A1 - Ye, Zheng A1 - van Rooij, Frank J A A1 - Shungin, Dmitry A1 - Sonestedt, Emily A1 - Ngwa, Julius S A1 - Wojczynski, Mary K A1 - Lemaitre, Rozenn N A1 - Gustafsson, Stefan A1 - Anderson, Jennifer S A1 - Tanaka, Toshiko A1 - Hindy, George A1 - Saylor, Georgia A1 - Renstrom, Frida A1 - Bennett, Amanda J A1 - van Duijn, Cornelia M A1 - Florez, Jose C A1 - Fox, Caroline S A1 - Hofman, Albert A1 - Hoogeveen, Ron C A1 - Houston, Denise K A1 - Hu, Frank B A1 - Jacques, Paul F A1 - Johansson, Ingegerd A1 - Lind, Lars A1 - Liu, Yongmei A1 - McKeown, Nicola A1 - Ordovas, Jose A1 - Pankow, James S A1 - Sijbrands, Eric J G A1 - Syvänen, Ann-Christine A1 - Uitterlinden, André G A1 - Yannakoulia, Mary A1 - Zillikens, M Carola A1 - Wareham, Nick J A1 - Prokopenko, Inga A1 - Bandinelli, Stefania A1 - Forouhi, Nita G A1 - Cupples, L Adrienne A1 - Loos, Ruth J A1 - Hallmans, Göran A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Ferrucci, Luigi A1 - Kritchevsky, Stephen B A1 - McCarthy, Mark I A1 - Ingelsson, Erik A1 - Borecki, Ingrid B A1 - Witteman, Jacqueline C M A1 - Orho-Melander, Marju A1 - Siscovick, David S A1 - Meigs, James B A1 - Franks, Paul W A1 - Dedoussis, George V KW - Blood Glucose KW - Cation Transport Proteins KW - Cohort Studies KW - Humans KW - Polymorphism, Single Nucleotide KW - Zinc KW - Zinc Transporter 8 AB -

OBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

VL - 60 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21810599?dopt=Abstract ER - TY - JOUR T1 - Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. JF - Lancet Y1 - 2012 A1 - Lorenz, Matthias W A1 - Polak, Joseph F A1 - Kavousi, Maryam A1 - Mathiesen, Ellisiv B A1 - Völzke, Henry A1 - Tuomainen, Tomi-Pekka A1 - Sander, Dirk A1 - Plichart, Matthieu A1 - Catapano, Alberico L A1 - Robertson, Christine M A1 - Kiechl, Stefan A1 - Rundek, Tatjana A1 - Desvarieux, Moïse A1 - Lind, Lars A1 - Schmid, Caroline A1 - DasMahapatra, Pronabesh A1 - Gao, Lu A1 - Ziegelbauer, Kathrin A1 - Bots, Michiel L A1 - Thompson, Simon G KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Disease Progression KW - Follow-Up Studies KW - Humans KW - Myocardial Infarction KW - Prognosis KW - Risk Assessment KW - Stroke AB -

BACKGROUND: Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association.

METHODS: We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis.

FINDINGS: Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02).

INTERPRETATION: The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.

FUNDING: Deutsche Forschungsgemeinschaft.

VL - 379 IS - 9831 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22541275?dopt=Abstract ER - TY - JOUR T1 - Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. JF - Nat Genet Y1 - 2012 A1 - Scott, Robert A A1 - Lagou, Vasiliki A1 - Welch, Ryan P A1 - Wheeler, Eleanor A1 - Montasser, May E A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Strawbridge, Rona J A1 - Rehnberg, Emil A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Rasmussen-Torvik, Laura J A1 - Yengo, Loic A1 - Lecoeur, Cécile A1 - Shungin, Dmitry A1 - Sanna, Serena A1 - Sidore, Carlo A1 - Johnson, Paul C D A1 - Jukema, J Wouter A1 - Johnson, Toby A1 - Mahajan, Anubha A1 - Verweij, Niek A1 - Thorleifsson, Gudmar A1 - Hottenga, Jouke-Jan A1 - Shah, Sonia A1 - Smith, Albert V A1 - Sennblad, Bengt A1 - Gieger, Christian A1 - Salo, Perttu A1 - Perola, Markus A1 - Timpson, Nicholas J A1 - Evans, David M A1 - Pourcain, Beate St A1 - Wu, Ying A1 - Andrews, Jeanette S A1 - Hui, Jennie A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Horikoshi, Momoko A1 - Navarro, Pau A1 - Isaacs, Aaron A1 - O'Connell, Jeffrey R A1 - Stirrups, Kathleen A1 - Vitart, Veronique A1 - Hayward, Caroline A1 - Esko, Tõnu A1 - Mihailov, Evelin A1 - Fraser, Ross M A1 - Fall, Tove A1 - Voight, Benjamin F A1 - Raychaudhuri, Soumya A1 - Chen, Han A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Rayner, Nigel W A1 - Robertson, Neil A1 - Rybin, Denis A1 - Liu, Ching-Ti A1 - Beckmann, Jacques S A1 - Willems, Sara M A1 - Chines, Peter S A1 - Jackson, Anne U A1 - Kang, Hyun Min A1 - Stringham, Heather M A1 - Song, Kijoung A1 - Tanaka, Toshiko A1 - Peden, John F A1 - Goel, Anuj A1 - Hicks, Andrew A A1 - An, Ping A1 - Müller-Nurasyid, Martina A1 - Franco-Cereceda, Anders A1 - Folkersen, Lasse A1 - Marullo, Letizia A1 - Jansen, Hanneke A1 - Oldehinkel, Albertine J A1 - Bruinenberg, Marcel A1 - Pankow, James S A1 - North, Kari E A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Edkins, Sarah A1 - Varga, Tibor V A1 - Hallmans, Göran A1 - Oksa, Heikki A1 - Antonella, Mulas A1 - Nagaraja, Ramaiah A1 - Trompet, Stella A1 - Ford, Ian A1 - Bakker, Stephan J L A1 - Kong, Augustine A1 - Kumari, Meena A1 - Gigante, Bruna A1 - Herder, Christian A1 - Munroe, Patricia B A1 - Caulfield, Mark A1 - Antti, Jula A1 - Mangino, Massimo A1 - Small, Kerrin A1 - Miljkovic, Iva A1 - Liu, Yongmei A1 - Atalay, Mustafa A1 - Kiess, Wieland A1 - James, Alan L A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Palmer, Colin N A A1 - Doney, Alex S F A1 - Willemsen, Gonneke A1 - Smit, Johannes H A1 - Campbell, Susan A1 - Polasek, Ozren A1 - Bonnycastle, Lori L A1 - Hercberg, Serge A1 - Dimitriou, Maria A1 - Bolton, Jennifer L A1 - Fowkes, Gerard R A1 - Kovacs, Peter A1 - Lindström, Jaana A1 - Zemunik, Tatijana A1 - Bandinelli, Stefania A1 - Wild, Sarah H A1 - Basart, Hanneke V A1 - Rathmann, Wolfgang A1 - Grallert, Harald A1 - Maerz, Winfried A1 - Kleber, Marcus E A1 - Boehm, Bernhard O A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Province, Michael A A1 - Borecki, Ingrid B A1 - Hastie, Nicholas D A1 - Rudan, Igor A1 - Campbell, Harry A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Stumvoll, Michael A1 - Ferrucci, Luigi A1 - Waterworth, Dawn M A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Tuomilehto, Jaakko A1 - Watanabe, Richard M A1 - de Geus, Eco J C A1 - Penninx, Brenda W A1 - Hofman, Albert A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Wright, Alan F A1 - Hovingh, G Kees A1 - Metspalu, Andres A1 - Uusitupa, Matti A1 - Magnusson, Patrik K E A1 - Kyvik, Kirsten O A1 - Kaprio, Jaakko A1 - Price, Jackie F A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Meneton, Pierre A1 - Lind, Lars A1 - Boehnke, Michael A1 - Shuldiner, Alan R A1 - van Duijn, Cornelia M A1 - Morris, Andrew D A1 - Toenjes, Anke A1 - Peyser, Patricia A A1 - Beilby, John P A1 - Körner, Antje A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Adair, Linda S A1 - Smith, George Davey A1 - Spector, Tim D A1 - Illig, Thomas A1 - de Faire, Ulf A1 - Hamsten, Anders A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Hingorani, Aroon A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Boomsma, Dorret I A1 - Stefansson, Kari A1 - van der Harst, Pim A1 - Dupuis, Josée A1 - Pedersen, Nancy L A1 - Sattar, Naveed A1 - Harris, Tamara B A1 - Cucca, Francesco A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Mohlke, Karen L A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Pouta, Anneli A1 - Jarvelin, Marjo-Riitta A1 - Wareham, Nicholas J A1 - Bouatia-Naji, Nabila A1 - McCarthy, Mark I A1 - Franks, Paul W A1 - Meigs, James B A1 - Teslovich, Tanya M A1 - Florez, Jose C A1 - Langenberg, Claudia A1 - Ingelsson, Erik A1 - Prokopenko, Inga A1 - Barroso, Inês KW - Adult KW - Animals KW - Blood Glucose KW - Fasting KW - Female KW - Gene Frequency KW - Genome-Wide Association Study KW - Humans KW - Insulin KW - Male KW - Metabolic Networks and Pathways KW - Mice KW - Osmolar Concentration KW - Quantitative Trait Loci AB -

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

VL - 44 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

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.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Common variants associated with plasma triglycerides and risk for coronary artery disease. JF - Nat Genet Y1 - 2013 A1 - Do, Ron A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Gao, Chi A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Eyjolfsson, Gudmundur Ingi A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Altshuler, David A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R A1 - Daly, Mark J A1 - Neale, Benjamin M A1 - Kathiresan, Sekar KW - Biological Transport KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Triglycerides AB -

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

VL - 45 IS - 11 ER - TY - JOUR T1 - Discovery and refinement of loci associated with lipid levels. JF - Nat Genet Y1 - 2013 A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Do, Ron A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Ingi Eyjolfsson, Gudmundur A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Kathiresan, Sekar A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R KW - African Continental Ancestry Group KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipids KW - Triglycerides AB -

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

VL - 45 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. JF - Nat Genet Y1 - 2013 A1 - Berndt, Sonja I A1 - Gustafsson, Stefan A1 - Mägi, Reedik A1 - Ganna, Andrea A1 - Wheeler, Eleanor A1 - Feitosa, Mary F A1 - Justice, Anne E A1 - Monda, Keri L A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Esko, Tõnu A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gentilini, Davide A1 - Jackson, Anne U A1 - Luan, Jian'an A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Willer, Cristen J A1 - Winkler, Thomas W A1 - Wood, Andrew R A1 - Workalemahu, Tsegaselassie A1 - Hu, Yi-Juan A1 - Lee, Sang Hong A1 - Liang, Liming A1 - Lin, Dan-Yu A1 - Min, Josine L A1 - Neale, Benjamin M A1 - Thorleifsson, Gudmar A1 - Yang, Jian A1 - Albrecht, Eva A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - den Heijer, Martin A1 - Eklund, Niina A1 - Fischer, Krista A1 - Goel, Anuj A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Jarick, Ivonne A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kanoni, Stavroula A1 - Kleber, Marcus E A1 - König, Inke R A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Lamina, Claudia A1 - Lecoeur, Cécile A1 - Li, Guo A1 - Mangino, Massimo A1 - McArdle, Wendy L A1 - Medina-Gómez, Carolina A1 - Müller-Nurasyid, Martina A1 - Ngwa, Julius S A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Pechlivanis, Sonali A1 - Perola, Markus A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Rose, Lynda M A1 - Shi, Jianxin A1 - Shungin, Dmitry A1 - Smith, Albert Vernon A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Trip, Mieke D A1 - Tyrer, Jonathan A1 - van Vliet-Ostaptchouk, Jana V A1 - Vandenput, Liesbeth A1 - Waite, Lindsay L A1 - Zhao, Jing Hua A1 - Absher, Devin A1 - Asselbergs, Folkert W A1 - Atalay, Mustafa A1 - Attwood, Antony P A1 - Balmforth, Anthony J A1 - Basart, Hanneke A1 - Beilby, John A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Bruinenberg, Marcel A1 - Campbell, Harry A1 - Chasman, Daniel I A1 - Chines, Peter S A1 - Collins, Francis S A1 - Connell, John M A1 - Cookson, William O A1 - de Faire, Ulf A1 - de Vegt, Femmie A1 - Dei, Mariano A1 - Dimitriou, Maria A1 - Edkins, Sarah A1 - Estrada, Karol A1 - Evans, David M A1 - Farrall, Martin A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Franke, Lude A1 - Frau, Francesca A1 - Gejman, Pablo V A1 - Grallert, Harald A1 - Grönberg, Henrik A1 - Gudnason, Vilmundur A1 - Hall, Alistair S A1 - Hall, Per A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Heath, Andrew C A1 - Hebebrand, Johannes A1 - Homuth, Georg A1 - Hu, Frank B A1 - Hunt, Sarah E A1 - Hyppönen, Elina A1 - Iribarren, Carlos A1 - Jacobs, Kevin B A1 - Jansson, John-Olov A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Khaw, Kay-Tee A1 - Kivimaki, Mika A1 - Koenig, Wolfgang A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laitinen, Jaana H A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lind, Lars A1 - Lindström, Jaana A1 - Liu, Jianjun A1 - Liuzzi, Antonio A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Madden, Pamela A A1 - Magnusson, Patrik K A1 - Manunta, Paolo A1 - Marek, Diana A1 - März, Winfried A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Montgomery, Grant W A1 - Mooser, Vincent A1 - Mühleisen, Thomas W A1 - Munroe, Patricia B A1 - Musk, Arthur W A1 - Narisu, Narisu A1 - Navis, Gerjan A1 - Nicholson, George A1 - Nohr, Ellen A A1 - Ong, Ken K A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Palotie, Aarno A1 - Peden, John F A1 - Pedersen, Nancy A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Prokopenko, Inga A1 - Pütter, Carolin A1 - Radhakrishnan, Aparna A1 - Raitakari, Olli A1 - Rendon, Augusto A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Saaristo, Timo E A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Shin, So-Youn A1 - Signorini, Stefano A1 - Sinisalo, Juha A1 - Skrobek, Boris A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Stark, Klaus A1 - Stephens, Jonathan C A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Stumvoll, Michael A1 - Swift, Amy J A1 - Theodoraki, Eirini V A1 - Thorand, Barbara A1 - Trégouët, David-Alexandre A1 - Tremoli, Elena A1 - van der Klauw, Melanie M A1 - van Meurs, Joyce B J A1 - Vermeulen, Sita H A1 - Viikari, Jorma A1 - Virtamo, Jarmo A1 - Vitart, Veronique A1 - Waeber, Gérard A1 - Wang, Zhaoming A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Winkelmann, Bernhard R A1 - Witteman, Jacqueline C M A1 - Wolffenbuttel, Bruce H R A1 - Wong, Andrew A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Amouyel, Philippe A1 - Boehm, Bernhard O A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Cupples, L Adrienne A1 - Cusi, Daniele A1 - Dedoussis, George V A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hingorani, Aroon A1 - Hinney, Anke A1 - Hofman, Albert A1 - Hovingh, Kees G A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kiemeney, Lambertus A A1 - Kuh, Diana A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Levinson, Douglas F A1 - Martin, Nicholas G A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nieminen, Markku S A1 - Njølstad, Inger A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ouwehand, Willem H A1 - Palmer, Lyle J A1 - Penninx, Brenda A1 - Power, Chris A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Rauramaa, Rainer A1 - Ridker, Paul M A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Vollenweider, Peter A1 - Wallaschofski, Henri A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Abecasis, Goncalo R A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunian, Talin A1 - Heid, Iris M A1 - Hunter, David A1 - Kaplan, Robert C A1 - Karpe, Fredrik A1 - Moffatt, Miriam F A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Pawitan, Yudi A1 - Schadt, Eric E A1 - Schlessinger, David A1 - Steinthorsdottir, Valgerdur A1 - Strachan, David P A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Visscher, Peter M A1 - Di Blasio, Anna Maria A1 - Hirschhorn, Joel N A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Meyre, David A1 - Scherag, Andre A1 - McCarthy, Mark I A1 - Speliotes, Elizabeth K A1 - North, Kari E A1 - Loos, Ruth J F A1 - Ingelsson, Erik KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Case-Control Studies KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Meta-Analysis as Topic KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Waist-Hip Ratio AB -

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

VL - 45 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract ER - TY - JOUR T1 - Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies. JF - J Nutr Y1 - 2013 A1 - Hruby, Adela A1 - Ngwa, Julius S A1 - Renstrom, Frida A1 - Wojczynski, Mary K A1 - Ganna, Andrea A1 - Hallmans, Göran A1 - Houston, Denise K A1 - Jacques, Paul F A1 - Kanoni, Stavroula A1 - Lehtimäki, Terho A1 - Lemaitre, Rozenn N A1 - Manichaikul, Ani A1 - North, Kari E A1 - Ntalla, Ioanna A1 - Sonestedt, Emily A1 - Tanaka, Toshiko A1 - van Rooij, Frank J A A1 - Bandinelli, Stefania A1 - Djoussé, Luc A1 - Grigoriou, Efi A1 - Johansson, Ingegerd A1 - Lohman, Kurt K A1 - Pankow, James S A1 - Raitakari, Olli T A1 - Riserus, Ulf A1 - Yannakoulia, Mary A1 - Zillikens, M Carola A1 - Hassanali, Neelam A1 - Liu, Yongmei A1 - Mozaffarian, Dariush A1 - Papoutsakis, Constantina A1 - Syvänen, Ann-Christine A1 - Uitterlinden, André G A1 - Viikari, Jorma A1 - Groves, Christopher J A1 - Hofman, Albert A1 - Lind, Lars A1 - McCarthy, Mark I A1 - Mikkilä, Vera A1 - Mukamal, Kenneth A1 - Franco, Oscar H A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Dedoussis, George V A1 - Ferrucci, Luigi A1 - Hu, Frank B A1 - Ingelsson, Erik A1 - Kähönen, Mika A1 - Kao, W H Linda A1 - Kritchevsky, Stephen B A1 - Orho-Melander, Marju A1 - Prokopenko, Inga A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Witteman, Jacqueline C M A1 - Franks, Paul W A1 - Meigs, James B A1 - McKeown, Nicola M A1 - Nettleton, Jennifer A KW - Blood Glucose KW - Female KW - Genetic Loci KW - Humans KW - Insulin KW - Magnesium KW - Male KW - Polymorphism, Single Nucleotide KW - Trace Elements KW - TRPM Cation Channels AB -

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.

VL - 143 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23343670?dopt=Abstract ER - TY - JOUR T1 - Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. JF - Nat Genet Y1 - 2013 A1 - den Hoed, Marcel A1 - Eijgelsheim, Mark A1 - Esko, Tõnu A1 - Brundel, Bianca J J M A1 - Peal, David S A1 - Evans, David M A1 - Nolte, Ilja M A1 - Segrè, Ayellet V A1 - Holm, Hilma A1 - Handsaker, Robert E A1 - Westra, Harm-Jan A1 - Johnson, Toby A1 - Isaacs, Aaron A1 - Yang, Jian A1 - Lundby, Alicia A1 - Zhao, Jing Hua A1 - Kim, Young Jin A1 - Go, Min Jin A1 - Almgren, Peter A1 - Bochud, Murielle A1 - Boucher, Gabrielle A1 - Cornelis, Marilyn C A1 - Gudbjartsson, Daniel A1 - Hadley, David A1 - van der Harst, Pim A1 - Hayward, Caroline A1 - den Heijer, Martin A1 - Igl, Wilmar A1 - Jackson, Anne U A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Kemp, John P A1 - Kristiansson, Kati A1 - Ladenvall, Claes A1 - Lorentzon, Mattias A1 - Montasser, May E A1 - Njajou, Omer T A1 - O'Reilly, Paul F A1 - Padmanabhan, Sandosh A1 - St Pourcain, Beate A1 - Rankinen, Tuomo A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - Timpson, Nicholas J A1 - Vitart, Veronique A1 - Waite, Lindsay A1 - Wheeler, William A1 - Zhang, Weihua A1 - Draisma, Harmen H M A1 - Feitosa, Mary F A1 - Kerr, Kathleen F A1 - Lind, Penelope A A1 - Mihailov, Evelin A1 - Onland-Moret, N Charlotte A1 - Song, Ci A1 - Weedon, Michael N A1 - Xie, Weijia A1 - Yengo, Loic A1 - Absher, Devin A1 - Albert, Christine M A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - de Bakker, Paul I W A1 - Balkau, Beverley A1 - Barlassina, Cristina A1 - Benaglio, Paola A1 - Bis, Joshua C A1 - Bouatia-Naji, Nabila A1 - Brage, Søren A1 - Chanock, Stephen J A1 - Chines, Peter S A1 - Chung, Mina A1 - Darbar, Dawood A1 - Dina, Christian A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Felix, Stephan B A1 - Fischer, Krista A1 - Fuchsberger, Christian A1 - de Geus, Eco J C A1 - Goyette, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Hofman, Albert A1 - Holewijn, Suzanne A1 - Hoogstra-Berends, Femke A1 - Hottenga, Jouke-Jan A1 - Jensen, Majken K A1 - Johansson, Asa A1 - Junttila, Juhani A1 - Kääb, Stefan A1 - Kanon, Bart A1 - Ketkar, Shamika A1 - Khaw, Kay-Tee A1 - Knowles, Joshua W A1 - Kooner, Angrad S A1 - Kors, Jan A A1 - Kumari, Meena A1 - Milani, Lili A1 - Laiho, Päivi A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Leusink, Maarten A1 - Liu, Yongmei A1 - Luben, Robert N A1 - Lunetta, Kathryn L A1 - Lynch, Stacey N A1 - Markus, Marcello R P A1 - Marques-Vidal, Pedro A1 - Mateo Leach, Irene A1 - McArdle, Wendy L A1 - McCarroll, Steven A A1 - Medland, Sarah E A1 - Miller, Kathryn A A1 - Montgomery, Grant W A1 - Morrison, Alanna C A1 - Müller-Nurasyid, Martina A1 - Navarro, Pau A1 - Nelis, Mari A1 - O'Connell, Jeffrey R A1 - O'Donnell, Christopher J A1 - Ong, Ken K A1 - Newman, Anne B A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Rao, Dabeeru C A1 - Ring, Susan M A1 - Rossin, Elizabeth J A1 - Rudan, Diana A1 - Sanna, Serena A1 - Scott, Robert A A1 - Sehmi, Jaban S A1 - Sharp, Stephen A1 - Shin, Jordan T A1 - Singleton, Andrew B A1 - Smith, Albert V A1 - Soranzo, Nicole A1 - Spector, Tim D A1 - Stewart, Chip A1 - Stringham, Heather M A1 - Tarasov, Kirill V A1 - Uitterlinden, André G A1 - Vandenput, Liesbeth A1 - Hwang, Shih-Jen A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Wong, Andrew A1 - Wong, Quenna A1 - Jamshidi, Yalda A1 - Zitting, Paavo A1 - Boer, Jolanda M A A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Ekelund, Ulf A1 - Forouhi, Nita G A1 - Froguel, Philippe A1 - Hingorani, Aroon A1 - Ingelsson, Erik A1 - Kivimaki, Mika A1 - Kronmal, Richard A A1 - Kuh, Diana A1 - Lind, Lars A1 - Martin, Nicholas G A1 - Oostra, Ben A A1 - Pedersen, Nancy L A1 - Quertermous, Thomas A1 - Rotter, Jerome I A1 - van der Schouw, Yvonne T A1 - Verschuren, W M Monique A1 - Walker, Mark A1 - Albanes, Demetrius A1 - Arnar, David O A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Boehnke, Michael A1 - de Boer, Rudolf A A1 - Bouchard, Claude A1 - Caulfield, W L Mark A1 - Chambers, John C A1 - Curhan, Gary A1 - Cusi, Daniele A1 - Eriksson, Johan A1 - Ferrucci, Luigi A1 - van Gilst, Wiek H A1 - Glorioso, Nicola A1 - de Graaf, Jacqueline A1 - Groop, Leif A1 - Gyllensten, Ulf A1 - Hsueh, Wen-Chi A1 - Hu, Frank B A1 - Huikuri, Heikki V A1 - Hunter, David J A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kiemeney, Lambertus A A1 - van der Klauw, Melanie M A1 - Kooner, Jaspal S A1 - Kraft, Peter A1 - Iacoviello, Licia A1 - Lehtimäki, Terho A1 - Lokki, Marja-Liisa L A1 - Mitchell, Braxton D A1 - Navis, Gerjan A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Poulter, Neil R A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Rimm, Eric B A1 - Rioux, John D A1 - Rizzi, Federica A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Sever, Peter S A1 - Shields, Denis C A1 - Shuldiner, Alan R A1 - Sinisalo, Juha A1 - Stanton, Alice V A1 - Stolk, Ronald P A1 - Strachan, David P A1 - Tardif, Jean-Claude A1 - Thorsteinsdottir, Unnur A1 - Tuomilehto, Jaako A1 - van Veldhuisen, Dirk J A1 - Virtamo, Jarmo A1 - Viikari, Jorma A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Widen, Elisabeth A1 - Cho, Yoon Shin A1 - Olsen, Jesper V A1 - Visscher, Peter M A1 - Willer, Cristen A1 - Franke, Lude A1 - Erdmann, Jeanette A1 - Thompson, John R A1 - Pfeufer, Arne A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Ellinor, Patrick T A1 - Stricker, Bruno H Ch A1 - Metspalu, Andres A1 - Perola, Markus A1 - Beckmann, Jacques S A1 - Smith, George Davey A1 - Stefansson, Kari A1 - Wareham, Nicholas J A1 - Munroe, Patricia B A1 - Sibon, Ody C M A1 - Milan, David J A1 - Snieder, Harold A1 - Samani, Nilesh J A1 - Loos, Ruth J F KW - Animals KW - Arrhythmias, Cardiac KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Heart Rate KW - Humans KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

VL - 45 IS - 6 ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. JF - PLoS Genet Y1 - 2013 A1 - O'Seaghdha, Conall M A1 - Wu, Hongsheng A1 - Yang, Qiong A1 - Kapur, Karen A1 - Guessous, Idris A1 - Zuber, Annie Mercier A1 - Köttgen, Anna A1 - Stoudmann, Candice A1 - Teumer, Alexander A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Dehghan, Abbas A1 - Zhang, Weihua A1 - Eiriksdottir, Gudny A1 - Li, Guo A1 - Tanaka, Toshiko A1 - Portas, Laura A1 - Lopez, Lorna M A1 - Hayward, Caroline A1 - Lohman, Kurt A1 - Matsuda, Koichi A1 - Padmanabhan, Sandosh A1 - Firsov, Dmitri A1 - Sorice, Rossella A1 - Ulivi, Sheila A1 - Brockhaus, A Catharina A1 - Kleber, Marcus E A1 - Mahajan, Anubha A1 - Ernst, Florian D A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Mace, Aurelien A1 - Boerwinckle, Eric A1 - Arking, Dan E A1 - Tanikawa, Chizu A1 - Nakamura, Yusuke A1 - Brown, Morris J A1 - Gaspoz, Jean-Michel A1 - Theler, Jean-Marc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Vitart, Veronique A1 - Wright, Alan F A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Brown, Edward M A1 - Estrada, Karol A1 - Ding, Jingzhong A1 - Harris, Tamara B A1 - Bandinelli, Stefania A1 - Hernandez, Dena A1 - Singleton, Andrew B A1 - Girotto, Giorgia A1 - Ruggiero, Daniela A1 - d'Adamo, Adamo Pio A1 - Robino, Antonietta A1 - Meitinger, Thomas A1 - Meisinger, Christa A1 - Davies, Gail A1 - Starr, John M A1 - Chambers, John C A1 - Boehm, Bernhard O A1 - Winkelmann, Bernhard R A1 - Huang, Jie A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Völker, Uwe A1 - Hannemann, Anke A1 - Biffar, Reiner A1 - Hoffmann, Wolfgang A1 - Shin, So-Youn A1 - Lescuyer, Pierre A1 - Henry, Hughes A1 - Schurmann, Claudia A1 - Munroe, Patricia B A1 - Gasparini, Paolo A1 - Pirastu, Nicola A1 - Ciullo, Marina A1 - Gieger, Christian A1 - März, Winfried A1 - Lind, Lars A1 - Spector, Tim D A1 - Smith, Albert V A1 - Rudan, Igor A1 - Wilson, James F A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Pirastu, Mario A1 - Ferrucci, Luigi A1 - Liu, Yongmei A1 - Kestenbaum, Bryan A1 - Kooner, Jaspal S A1 - Witteman, Jacqueline C M A1 - Nauck, Matthias A1 - Kao, W H Linda A1 - Wallaschofski, Henri A1 - Bonny, Olivier A1 - Fox, Caroline S A1 - Bochud, Murielle KW - Animals KW - Bone and Bones KW - Bone Density KW - Calcium KW - European Continental Ancestry Group KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Kidney KW - Mice KW - Polymorphism, Single Nucleotide AB -

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

VL - 9 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract ER - TY - JOUR T1 - Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. JF - PLoS Genet Y1 - 2013 A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Kutalik, Zoltán A1 - Berndt, Sonja I A1 - Jackson, Anne U A1 - Monda, Keri L A1 - Kilpeläinen, Tuomas O A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Li, Shengxu A1 - Workalemahu, Tsegaselassie A1 - Feitosa, Mary F A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gustafsson, Stefan A1 - Locke, Adam E A1 - Mathieson, Iain A1 - Scherag, Andre A1 - Vedantam, Sailaja A1 - Wood, Andrew R A1 - Liang, Liming A1 - Steinthorsdottir, Valgerdur A1 - Thorleifsson, Gudmar A1 - Dermitzakis, Emmanouil T A1 - Dimas, Antigone S A1 - Karpe, Fredrik A1 - Min, Josine L A1 - Nicholson, George A1 - Clegg, Deborah J A1 - Person, Thomas A1 - Krohn, Jon P A1 - Bauer, Sabrina A1 - Buechler, Christa A1 - Eisinger, Kristina A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Hottenga, Jouke-Jan A1 - Prokopenko, Inga A1 - Waite, Lindsay L A1 - Harris, Tamara B A1 - Smith, Albert Vernon A1 - Shuldiner, Alan R A1 - McArdle, Wendy L A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Grönberg, Henrik A1 - Chen, Yii-Der Ida A1 - Li, Guo A1 - Beckmann, Jacques S A1 - Johnson, Toby A1 - Thorsteinsdottir, Unnur A1 - Teder-Laving, Maris A1 - Khaw, Kay-Tee A1 - Wareham, Nicholas J A1 - Zhao, Jing Hua A1 - Amin, Najaf A1 - Oostra, Ben A A1 - Kraja, Aldi T A1 - Province, Michael A A1 - Cupples, L Adrienne A1 - Heard-Costa, Nancy L A1 - Kaprio, Jaakko A1 - Ripatti, Samuli A1 - Surakka, Ida A1 - Collins, Francis S A1 - Saramies, Jouko A1 - Tuomilehto, Jaakko A1 - Jula, Antti A1 - Salomaa, Veikko A1 - Erdmann, Jeanette A1 - Hengstenberg, Christian A1 - Loley, Christina A1 - Schunkert, Heribert A1 - Lamina, Claudia A1 - Wichmann, H Erich A1 - Albrecht, Eva A1 - Gieger, Christian A1 - Hicks, Andrew A A1 - Johansson, Asa A1 - Pramstaller, Peter P A1 - Kathiresan, Sekar A1 - Speliotes, Elizabeth K A1 - Penninx, Brenda A1 - Hartikainen, Anna-Liisa A1 - Jarvelin, Marjo-Riitta A1 - Gyllensten, Ulf A1 - Boomsma, Dorret I A1 - Campbell, Harry A1 - Wilson, James F A1 - Chanock, Stephen J A1 - Farrall, Martin A1 - Goel, Anuj A1 - Medina-Gómez, Carolina A1 - Rivadeneira, Fernando A1 - Estrada, Karol A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Zillikens, M Carola A1 - den Heijer, Martin A1 - Kiemeney, Lambertus A A1 - Maschio, Andrea A1 - Hall, Per A1 - Tyrer, Jonathan A1 - Teumer, Alexander A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Tönjes, Anke A1 - Mangino, Massimo A1 - Spector, Tim D A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Attwood, Antony Paul A1 - Sambrook, Jennifer G A1 - Hung, Joseph A1 - Palmer, Lyle J A1 - Lokki, Marja-Liisa A1 - Sinisalo, Juha A1 - Boucher, Gabrielle A1 - Huikuri, Heikki A1 - Lorentzon, Mattias A1 - Ohlsson, Claes A1 - Eklund, Niina A1 - Eriksson, Johan G A1 - Barlassina, Cristina A1 - Rivolta, Carlo A1 - Nolte, Ilja M A1 - Snieder, Harold A1 - van der Klauw, Melanie M A1 - van Vliet-Ostaptchouk, Jana V A1 - Gejman, Pablo V A1 - Shi, Jianxin A1 - Jacobs, Kevin B A1 - Wang, Zhaoming A1 - Bakker, Stephan J L A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van der Harst, Pim A1 - Martin, Nicholas G A1 - Medland, Sarah E A1 - Montgomery, Grant W A1 - Yang, Jian A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Raitakari, Olli A1 - Absher, Devin A1 - Iribarren, Carlos A1 - Basart, Hanneke A1 - Hovingh, Kees G A1 - Hyppönen, Elina A1 - Power, Chris A1 - Anderson, Denise A1 - Beilby, John P A1 - Hui, Jennie A1 - Jolley, Jennifer A1 - Sager, Hendrik A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Kristiansson, Kati A1 - Perola, Markus A1 - Lindström, Jaana A1 - Swift, Amy J A1 - Uusitupa, Matti A1 - Atalay, Mustafa A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Bolton, Jennifer L A1 - Fowkes, Gerry A1 - Fraser, Ross M A1 - Price, Jackie F A1 - Fischer, Krista A1 - Krjutå Kov, Kaarel A1 - Metspalu, Andres A1 - Mihailov, Evelin A1 - Langenberg, Claudia A1 - Luan, Jian'an A1 - Ong, Ken K A1 - Chines, Peter S A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Edkins, Sarah A1 - Franks, Paul W A1 - Hallmans, Göran A1 - Shungin, Dmitry A1 - Morris, Andrew David A1 - Palmer, Colin N A A1 - Erbel, Raimund A1 - Moebus, Susanne A1 - Nöthen, Markus M A1 - Pechlivanis, Sonali A1 - Hveem, Kristian A1 - Narisu, Narisu A1 - Hamsten, Anders A1 - Humphries, Steve E A1 - Strawbridge, Rona J A1 - Tremoli, Elena A1 - Grallert, Harald A1 - Thorand, Barbara A1 - Illig, Thomas A1 - Koenig, Wolfgang A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Boehm, Bernhard O A1 - Kleber, Marcus E A1 - März, Winfried A1 - Winkelmann, Bernhard R A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Arveiler, Dominique A1 - Cesana, Giancarlo A1 - Kuulasmaa, Kari A1 - Virtamo, Jarmo A1 - Yarnell, John W G A1 - Kuh, Diana A1 - Wong, Andrew A1 - Lind, Lars A1 - de Faire, Ulf A1 - Gigante, Bruna A1 - Magnusson, Patrik K E A1 - Pedersen, Nancy L A1 - Dedoussis, George A1 - Dimitriou, Maria A1 - Kolovou, Genovefa A1 - Kanoni, Stavroula A1 - Stirrups, Kathleen A1 - Bonnycastle, Lori L A1 - Njølstad, Inger A1 - Wilsgaard, Tom A1 - Ganna, Andrea A1 - Rehnberg, Emil A1 - Hingorani, Aroon A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David A1 - Ingelsson, Erik A1 - Kaplan, Robert A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Schlessinger, David A1 - Strachan, David P A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Abecasis, Goncalo R A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Qi, Lu A1 - Loos, Ruth J F A1 - Lindgren, Cecilia M A1 - North, Kari E A1 - Heid, Iris M KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Body Weight KW - Body Weights and Measures KW - Female KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Waist Circumference KW - Waist-Hip Ratio AB -

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23754948?dopt=Abstract ER - TY - JOUR T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. JF - Nat Genet Y1 - 2014 A1 - Arking, Dan E A1 - Pulit, Sara L A1 - Crotti, Lia A1 - van der Harst, Pim A1 - Munroe, Patricia B A1 - Koopmann, Tamara T A1 - Sotoodehnia, Nona A1 - Rossin, Elizabeth J A1 - Morley, Michael A1 - Wang, Xinchen A1 - Johnson, Andrew D A1 - Lundby, Alicia A1 - Gudbjartsson, Daniel F A1 - Noseworthy, Peter A A1 - Eijgelsheim, Mark A1 - Bradford, Yuki A1 - Tarasov, Kirill V A1 - Dörr, Marcus A1 - Müller-Nurasyid, Martina A1 - Lahtinen, Annukka M A1 - Nolte, Ilja M A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Isaacs, Aaron A1 - Newhouse, Stephen J A1 - Evans, Daniel S A1 - Post, Wendy S A1 - Waggott, Daryl A1 - Lyytikäinen, Leo-Pekka A1 - Hicks, Andrew A A1 - Eisele, Lewin A1 - Ellinghaus, David A1 - Hayward, Caroline A1 - Navarro, Pau A1 - Ulivi, Sheila A1 - Tanaka, Toshiko A1 - Tester, David J A1 - Chatel, Stéphanie A1 - Gustafsson, Stefan A1 - Kumari, Meena A1 - Morris, Richard W A1 - Naluai, Åsa T A1 - Padmanabhan, Sandosh A1 - Kluttig, Alexander A1 - Strohmer, Bernhard A1 - Panayiotou, Andrie G A1 - Torres, Maria A1 - Knoflach, Michael A1 - Hubacek, Jaroslav A A1 - Slowikowski, Kamil A1 - Raychaudhuri, Soumya A1 - Kumar, Runjun D A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shuldiner, Alan R A1 - Alonso, Alvaro A1 - Bader, Joel S A1 - Ehret, Georg A1 - Huang, Hailiang A1 - Kao, W H Linda A1 - Strait, James B A1 - Macfarlane, Peter W A1 - Brown, Morris A1 - Caulfield, Mark J A1 - Samani, Nilesh J A1 - Kronenberg, Florian A1 - Willeit, Johann A1 - Smith, J Gustav A1 - Greiser, Karin H A1 - Meyer Zu Schwabedissen, Henriette A1 - Werdan, Karl A1 - Carella, Massimo A1 - Zelante, Leopoldo A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wright, Alan F A1 - Griffin, Maura A1 - Daly, Mark J A1 - Arnar, David O A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Denny, Joshua C A1 - Roden, Dan M A1 - Zuvich, Rebecca L A1 - Emilsson, Valur A1 - Plump, Andrew S A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Yin, Xiaoyan A1 - Bobbo, Marco A1 - D'Adamo, Adamo P A1 - Iorio, Annamaria A1 - Sinagra, Gianfranco A1 - Carracedo, Angel A1 - Cummings, Steven R A1 - Nalls, Michael A A1 - Jula, Antti A1 - Kontula, Kimmo K A1 - Marjamaa, Annukka A1 - Oikarinen, Lasse A1 - Perola, Markus A1 - Porthan, Kimmo A1 - Erbel, Raimund A1 - Hoffmann, Per A1 - Jöckel, Karl-Heinz A1 - Kälsch, Hagen A1 - Nöthen, Markus M A1 - den Hoed, Marcel A1 - Loos, Ruth J F A1 - Thelle, Dag S A1 - Gieger, Christian A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Peters, Annette A1 - Prucha, Hanna A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - de Boer, Rudolf A A1 - Franke, Lude A1 - van der Vleuten, Pieter A A1 - Beckmann, Britt Maria A1 - Martens, Eimo A1 - Bardai, Abdennasser A1 - Hofman, Nynke A1 - Wilde, Arthur A M A1 - Behr, Elijah R A1 - Dalageorgou, Chrysoula A1 - Giudicessi, John R A1 - Medeiros-Domingo, Argelia A1 - Barc, Julien A1 - Kyndt, Florence A1 - Probst, Vincent A1 - Ghidoni, Alice A1 - Insolia, Roberto A1 - Hamilton, Robert M A1 - Scherer, Stephen W A1 - Brandimarto, Jeffrey A1 - Margulies, Kenneth A1 - Moravec, Christine E A1 - del Greco M, Fabiola A1 - Fuchsberger, Christian A1 - O'Connell, Jeffrey R A1 - Lee, Wai K A1 - Watt, Graham C M A1 - Campbell, Harry A1 - Wild, Sarah H A1 - El Mokhtari, Nour E A1 - Frey, Norbert A1 - Asselbergs, Folkert W A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van den Berg, Maarten P A1 - van Veldhuisen, Dirk J A1 - Kellis, Manolis A1 - Krijthe, Bouwe P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Kors, Jan A A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Kedenko, Lyudmyla A1 - Lamina, Claudia A1 - Oostra, Ben A A1 - Abecasis, Goncalo R A1 - Lakatta, Edward G A1 - Mulas, Antonella A1 - Orrù, Marco A1 - Schlessinger, David A1 - Uda, Manuela A1 - Markus, Marcello R P A1 - Völker, Uwe A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Arnlöv, Johan A1 - Lind, Lars A1 - Sundström, Johan A1 - Syvänen, Ann-Christine A1 - Kivimaki, Mika A1 - Kähönen, Mika A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Viikari, Jorma S A1 - Adamkova, Vera A1 - Kiechl, Stefan A1 - Brion, Maria A1 - Nicolaides, Andrew N A1 - Paulweber, Bernhard A1 - Haerting, Johannes A1 - Dominiczak, Anna F A1 - Nyberg, Fredrik A1 - Whincup, Peter H A1 - Hingorani, Aroon D A1 - Schott, Jean-Jacques A1 - Bezzina, Connie R A1 - Ingelsson, Erik A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Wilson, James F A1 - Rudan, Igor A1 - Franke, Andre A1 - Mühleisen, Thomas W A1 - Pramstaller, Peter P A1 - Lehtimäki, Terho J A1 - Paterson, Andrew D A1 - Parsa, Afshin A1 - Liu, Yongmei A1 - van Duijn, Cornelia M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Jamshidi, Yalda A1 - Salomaa, Veikko A1 - Felix, Stephan B A1 - Sanna, Serena A1 - Ritchie, Marylyn D A1 - Stricker, Bruno H A1 - Stefansson, Kari A1 - Boyer, Laurie A A1 - Cappola, Thomas P A1 - Olsen, Jesper V A1 - Lage, Kasper A1 - Schwartz, Peter J A1 - Kääb, Stefan A1 - Chakravarti, Aravinda A1 - Ackerman, Michael J A1 - Pfeufer, Arne A1 - de Bakker, Paul I W A1 - Newton-Cheh, Christopher KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Calcium Signaling KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Heart Ventricles KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Myocardium KW - Polymorphism, Single Nucleotide AB -

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies six new loci associated with forced vital capacity. JF - Nat Genet Y1 - 2014 A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Wain, Louise V A1 - Franceschini, Nora A1 - Koch, Beate A1 - Pottinger, Tess D A1 - Smith, Albert Vernon A1 - Duan, Qing A1 - Oldmeadow, Chris A1 - Lee, Mi Kyeong A1 - Strachan, David P A1 - James, Alan L A1 - Huffman, Jennifer E A1 - Vitart, Veronique A1 - Ramasamy, Adaikalavan A1 - Wareham, Nicholas J A1 - Kaprio, Jaakko A1 - Wang, Xin-Qun A1 - Trochet, Holly A1 - Kähönen, Mika A1 - Flexeder, Claudia A1 - Albrecht, Eva A1 - Lopez, Lorna M A1 - de Jong, Kim A1 - Thyagarajan, Bharat A1 - Alves, Alexessander Couto A1 - Enroth, Stefan A1 - Omenaas, Ernst A1 - Joshi, Peter K A1 - Fall, Tove A1 - Viñuela, Ana A1 - Launer, Lenore J A1 - Loehr, Laura R A1 - Fornage, Myriam A1 - Li, Guo A1 - Wilk, Jemma B A1 - Tang, Wenbo A1 - Manichaikul, Ani A1 - Lahousse, Lies A1 - Harris, Tamara B A1 - North, Kari E A1 - Rudnicka, Alicja R A1 - Hui, Jennie A1 - Gu, Xiangjun A1 - Lumley, Thomas A1 - Wright, Alan F A1 - Hastie, Nicholas D A1 - Campbell, Susan A1 - Kumar, Rajesh A1 - Pin, Isabelle A1 - Scott, Robert A A1 - Pietiläinen, Kirsi H A1 - Surakka, Ida A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Schulz, Holger A1 - Heinrich, Joachim A1 - Davies, Gail A1 - Vonk, Judith M A1 - Wojczynski, Mary A1 - Pouta, Anneli A1 - Johansson, Asa A1 - Wild, Sarah H A1 - Ingelsson, Erik A1 - Rivadeneira, Fernando A1 - Völzke, Henry A1 - Hysi, Pirro G A1 - Eiriksdottir, Gudny A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Gao, Wei A1 - Postma, Dirkje S A1 - White, Wendy B A1 - Rich, Stephen S A1 - Hofman, Albert A1 - Aspelund, Thor A1 - Couper, David A1 - Smith, Lewis J A1 - Psaty, Bruce M A1 - Lohman, Kurt A1 - Burchard, Esteban G A1 - Uitterlinden, André G A1 - Garcia, Melissa A1 - Joubert, Bonnie R A1 - McArdle, Wendy L A1 - Musk, A Bill A1 - Hansel, Nadia A1 - Heckbert, Susan R A1 - Zgaga, Lina A1 - van Meurs, Joyce B J A1 - Navarro, Pau A1 - Rudan, Igor A1 - Oh, Yeon-Mok A1 - Redline, Susan A1 - Jarvis, Deborah L A1 - Zhao, Jing Hua A1 - Rantanen, Taina A1 - O'Connor, George T A1 - Ripatti, Samuli A1 - Scott, Rodney J A1 - Karrasch, Stefan A1 - Grallert, Harald A1 - Gaddis, Nathan C A1 - Starr, John M A1 - Wijmenga, Cisca A1 - Minster, Ryan L A1 - Lederer, David J A1 - Pekkanen, Juha A1 - Gyllensten, Ulf A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Gläser, Sven A1 - Hammond, Christopher J A1 - Burkart, Kristin M A1 - Beilby, John A1 - Kritchevsky, Stephen B A1 - Gudnason, Vilmundur A1 - Hancock, Dana B A1 - Williams, O Dale A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Petrini, Marcy F A1 - Wjst, Matthias A1 - Kim, Woo Jin A1 - Porteous, David J A1 - Scotland, Generation A1 - Smith, Blair H A1 - Viljanen, Anne A1 - Heliövaara, Markku A1 - Attia, John R A1 - Sayers, Ian A1 - Hampel, Regina A1 - Gieger, Christian A1 - Deary, Ian J A1 - Boezen, H Marike A1 - Newman, Anne A1 - Jarvelin, Marjo-Riitta A1 - Wilson, James F A1 - Lind, Lars A1 - Stricker, Bruno H A1 - Teumer, Alexander A1 - Spector, Timothy D A1 - Melén, Erik A1 - Peters, Marjolein J A1 - Lange, Leslie A A1 - Barr, R Graham A1 - Bracke, Ken R A1 - Verhamme, Fien M A1 - Sung, Joohon A1 - Hiemstra, Pieter S A1 - Cassano, Patricia A A1 - Sood, Akshay A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Hall, Ian P A1 - Brusselle, Guy G A1 - Tobin, Martin D A1 - London, Stephanie J KW - Cohort Studies KW - Databases, Genetic KW - Follow-Up Studies KW - Forced Expiratory Volume KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung Diseases KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Quantitative Trait Loci KW - Respiratory Function Tests KW - Spirometry KW - Vital Capacity AB -

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

VL - 46 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract ER - TY - JOUR T1 - Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. JF - PLoS One Y1 - 2014 A1 - Tang, Wenbo A1 - Kowgier, Matthew A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Joubert, Bonnie R A1 - Hodge, Emily A1 - Gharib, Sina A A1 - Smith, Albert V A1 - Ruczinski, Ingo A1 - Gudnason, Vilmundur A1 - Mathias, Rasika A A1 - Harris, Tamara B A1 - Hansel, Nadia N A1 - Launer, Lenore J A1 - Barnes, Kathleen C A1 - Hansen, Joyanna G A1 - Albrecht, Eva A1 - Aldrich, Melinda C A1 - Allerhand, Michael A1 - Barr, R Graham A1 - Brusselle, Guy G A1 - Couper, David J A1 - Curjuric, Ivan A1 - Davies, Gail A1 - Deary, Ian J A1 - Dupuis, Josée A1 - Fall, Tove A1 - Foy, Millennia A1 - Franceschini, Nora A1 - Gao, Wei A1 - Gläser, Sven A1 - Gu, Xiangjun A1 - Hancock, Dana B A1 - Heinrich, Joachim A1 - Hofman, Albert A1 - Imboden, Medea A1 - Ingelsson, Erik A1 - James, Alan A1 - Karrasch, Stefan A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Kumar, Ashish A1 - Lahousse, Lies A1 - Li, Guo A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Lumley, Thomas A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Musk, Bill A1 - North, Kari E A1 - Palmer, Lyle J A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schulz, Holger A1 - Smith, Lewis J A1 - Sood, Akshay A1 - Starr, John M A1 - Strachan, David P A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Voorman, Arend A1 - Wain, Louise V A1 - Wells, Martin T A1 - Wilk, Jemma B A1 - Williams, O Dale A1 - Heckbert, Susan R A1 - Stricker, Bruno H A1 - London, Stephanie J A1 - Fornage, Myriam A1 - Tobin, Martin D A1 - O'Connor, George T A1 - Hall, Ian P A1 - Cassano, Patricia A KW - Adult KW - Chromosomes, Human, Pair 11 KW - Female KW - Gene Expression Regulation KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Male KW - Respiration AB -

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

VL - 9 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract ER - TY - JOUR T1 - Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci. JF - Diabetes Y1 - 2016 A1 - Walford, Geoffrey A A1 - Gustafsson, Stefan A1 - Rybin, Denis A1 - Stančáková, Alena A1 - Chen, Han A1 - Liu, Ching-Ti A1 - Hong, Jaeyoung A1 - Jensen, Richard A A1 - Rice, Ken A1 - Morris, Andrew P A1 - Mägi, Reedik A1 - Tönjes, Anke A1 - Prokopenko, Inga A1 - Kleber, Marcus E A1 - Delgado, Graciela A1 - Silbernagel, Günther A1 - Jackson, Anne U A1 - Appel, Emil V A1 - Grarup, Niels A1 - Lewis, Joshua P A1 - Montasser, May E A1 - Landenvall, Claes A1 - Staiger, Harald A1 - Luan, Jian'an A1 - Frayling, Timothy M A1 - Weedon, Michael N A1 - Xie, Weijia A1 - Morcillo, Sonsoles A1 - Martínez-Larrad, María Teresa A1 - Biggs, Mary L A1 - Chen, Yii-Der Ida A1 - Corbaton-Anchuelo, Arturo A1 - Færch, Kristine A1 - Gómez-Zumaquero, Juan Miguel A1 - Goodarzi, Mark O A1 - Kizer, Jorge R A1 - Koistinen, Heikki A A1 - Leong, Aaron A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Machicao, Fausto A1 - Manning, Alisa K A1 - Martín-Núñez, Gracia María A1 - Rojo-Martínez, Gemma A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Zmuda, Joseph M A1 - Zhang, Zhongyang A1 - Serrano-Ríos, Manuel A1 - Smith, Ulf A1 - Soriguer, Federico A1 - Hansen, Torben A1 - Jørgensen, Torben J A1 - Linnenberg, Allan A1 - Pedersen, Oluf A1 - Walker, Mark A1 - Langenberg, Claudia A1 - Scott, Robert A A1 - Wareham, Nicholas J A1 - Fritsche, Andreas A1 - Häring, Hans-Ulrich A1 - Stefan, Norbert A1 - Groop, Leif A1 - O'Connell, Jeff R A1 - Boehnke, Michael A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - März, Winfried A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Psaty, Bruce M A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Meigs, James B A1 - Dupuis, Josée A1 - Ingelsson, Erik A1 - Florez, Jose C AB -

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

VL - 65 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27416945?dopt=Abstract ER - TY - JOUR T1 - Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration. JF - Eur J Prev Cardiol Y1 - 2016 A1 - Willeit, Peter A1 - Thompson, Simon G A1 - Agewall, Stefan A1 - Bergström, Göran A1 - Bickel, Horst A1 - Catapano, Alberico L A1 - Chien, Kuo-Liong A1 - de Groot, Eric A1 - Empana, Jean-Philippe A1 - Etgen, Thorleif A1 - Franco, Oscar H A1 - Iglseder, Bernhard A1 - Johnsen, Stein H A1 - Kavousi, Maryam A1 - Lind, Lars A1 - Liu, Jing A1 - Mathiesen, Ellisiv B A1 - Norata, Giuseppe D A1 - Olsen, Michael H A1 - Papagianni, Aikaterini A1 - Poppert, Holger A1 - Price, Jackie F A1 - Sacco, Ralph L A1 - Yanez, David N A1 - Zhao, Dong A1 - Schminke, Ulf A1 - Bülbül, Alpaslan A1 - Polak, Joseph F A1 - Sitzer, Matthias A1 - Hofman, Albert A1 - Grigore, Liliana A1 - Dörr, Marcus A1 - Su, Ta-Chen A1 - Ducimetiere, Pierre A1 - Xie, Wuxiang A1 - Ronkainen, Kimmo A1 - Kiechl, Stefan A1 - Rundek, Tatjana A1 - Robertson, Christine A1 - Fagerberg, Björn A1 - Bokemark, Lena A1 - Steinmetz, Helmuth A1 - Ikram, M Arfan A1 - Völzke, Henry A1 - Lin, Hung-Ju A1 - Plichart, Matthieu A1 - Tuomainen, Tomi-Pekka A1 - Desvarieux, Moïse A1 - McLachlan, Stela A1 - Schmidt, Caroline A1 - Kauhanen, Jussi A1 - Willeit, Johann A1 - Lorenz, Matthias W A1 - Sander, Dirk AB -

BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.

METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.

RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015).

CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.

VL - 23 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25416041?dopt=Abstract ER - TY - JOUR T1 - Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis. JF - Lancet Diabetes Endocrinol Y1 - 2016 A1 - Willeit, Peter A1 - Kaptoge, Stephen A1 - Welsh, Paul A1 - Butterworth, Adam A1 - Chowdhury, Rajiv A1 - Spackman, Sarah A1 - Pennells, Lisa A1 - Gao, Pei A1 - Burgess, Stephen A1 - Freitag, Daniel A1 - Sweeting, Michael A1 - Wood, Angela A1 - Cook, Nancy A1 - Judd, Suzanne A1 - Trompet, Stella A1 - Nambi, Vijay A1 - Olsen, Michael A1 - Everett, Brendan A1 - Kee, Frank A1 - Arnlöv, Johan A1 - Salomaa, Veikko A1 - Levy, Daniel A1 - Kauhanen, Jussi A1 - Laukkanen, Jari A1 - Kavousi, Maryam A1 - Ninomiya, Toshiharu A1 - Casas, Juan-Pablo A1 - Daniels, Lori A1 - Lind, Lars A1 - Kistorp, Caroline A1 - Rosenberg, Jens A1 - Mueller, Thomas A1 - Rubattu, Speranza A1 - Panagiotakos, Demosthenes A1 - Franco, Oscar A1 - de Lemos, James A1 - Luchner, Andreas A1 - Kizer, Jorge A1 - Kiechl, Stefan A1 - Salonen, Jukka A1 - Goya Wannamethee, S A1 - de Boer, Rudolf A1 - Nordestgaard, Børge A1 - Andersson, Jonas A1 - Jørgensen, Torben A1 - Melander, Olle A1 - Ballantyne, Christie A1 - DeFilippi, Christopher A1 - Ridker, Paul A1 - Cushman, Mary A1 - Rosamond, Wayne A1 - Thompson, Simon A1 - Gudnason, Vilmundur A1 - Sattar, Naveed A1 - Danesh, John A1 - Di Angelantonio, Emanuele KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Female KW - Humans KW - Male KW - Middle Aged KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Prospective Studies KW - Risk Assessment AB -

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.

METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.

FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure.

INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.

FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.

VL - 4 IS - 10 ER - TY - JOUR T1 - Genetic loci associated with heart rate variability and their effects on cardiac disease risk. JF - Nat Commun Y1 - 2017 A1 - Nolte, Ilja M A1 - Munoz, M Loretto A1 - Tragante, Vinicius A1 - Amare, Azmeraw T A1 - Jansen, Rick A1 - Vaez, Ahmad A1 - von der Heyde, Benedikt A1 - Avery, Christy L A1 - Bis, Joshua C A1 - Dierckx, Bram A1 - van Dongen, Jenny A1 - Gogarten, Stephanie M A1 - Goyette, Philippe A1 - Hernesniemi, Jussi A1 - Huikari, Ville A1 - Hwang, Shih-Jen A1 - Jaju, Deepali A1 - Kerr, Kathleen F A1 - Kluttig, Alexander A1 - Krijthe, Bouwe P A1 - Kumar, Jitender A1 - van der Laan, Sander W A1 - Lyytikäinen, Leo-Pekka A1 - Maihofer, Adam X A1 - Minassian, Arpi A1 - van der Most, Peter J A1 - Müller-Nurasyid, Martina A1 - Nivard, Michel A1 - Salvi, Erika A1 - Stewart, James D A1 - Thayer, Julian F A1 - Verweij, Niek A1 - Wong, Andrew A1 - Zabaneh, Delilah A1 - Zafarmand, Mohammad H A1 - Abdellaoui, Abdel A1 - Albarwani, Sulayma A1 - Albert, Christine A1 - Alonso, Alvaro A1 - Ashar, Foram A1 - Auvinen, Juha A1 - Axelsson, Tomas A1 - Baker, Dewleen G A1 - de Bakker, Paul I W A1 - Barcella, Matteo A1 - Bayoumi, Riad A1 - Bieringa, Rob J A1 - Boomsma, Dorret A1 - Boucher, Gabrielle A1 - Britton, Annie R A1 - Christophersen, Ingrid A1 - Dietrich, Andrea A1 - Ehret, George B A1 - Ellinor, Patrick T A1 - Eskola, Markku A1 - Felix, Janine F A1 - Floras, John S A1 - Franco, Oscar H A1 - Friberg, Peter A1 - Gademan, Maaike G J A1 - Geyer, Mark A A1 - Giedraitis, Vilmantas A1 - Hartman, Catharina A A1 - Hemerich, Daiane A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huikuri, Heikki A1 - Hutri-Kähönen, Nina A1 - Jouven, Xavier A1 - Junttila, Juhani A1 - Juonala, Markus A1 - Kiviniemi, Antti M A1 - Kors, Jan A A1 - Kumari, Meena A1 - Kuznetsova, Tatiana A1 - Laurie, Cathy C A1 - Lefrandt, Joop D A1 - Li, Yong A1 - Li, Yun A1 - Liao, Duanping A1 - Limacher, Marian C A1 - Lin, Henry J A1 - Lindgren, Cecilia M A1 - Lubitz, Steven A A1 - Mahajan, Anubha A1 - McKnight, Barbara A1 - Zu Schwabedissen, Henriette Meyer A1 - Milaneschi, Yuri A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Nalls, Mike A A1 - Navis, Gerjan A1 - Neijts, Melanie A1 - Nikus, Kjell A1 - North, Kari E A1 - O'Connor, Daniel T A1 - Ormel, Johan A1 - Perz, Siegfried A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Risbrough, Victoria B A1 - Sinner, Moritz F A1 - Siscovick, David A1 - Smit, Johannes H A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Staessen, Jan A A1 - Stein, Phyllis K A1 - Stilp, Adrienne M A1 - Stolarz-Skrzypek, Katarzyna A1 - Strauch, Konstantin A1 - Sundström, Johan A1 - Swenne, Cees A A1 - Syvänen, Ann-Christine A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thornton, Timothy A A1 - Tinker, Lesley E A1 - Uitterlinden, André G A1 - van Setten, Jessica A1 - Voss, Andreas A1 - Waldenberger, Melanie A1 - Wilhelmsen, Kirk C A1 - Willemsen, Gonneke A1 - Wong, Quenna A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Cusi, Daniele A1 - Evans, Michele K A1 - Greiser, Halina K A1 - van der Harst, Pim A1 - Hassan, Mohammad A1 - Ingelsson, Erik A1 - Jarvelin, Marjo-Riitta A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kivimaki, Mika A1 - Kooperberg, Charles A1 - Kuh, Diana A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Nievergelt, Caroline M A1 - O'Donnell, Chris J A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda A1 - Reiner, Alexander P A1 - Riese, Harriëtte A1 - van Roon, Arie M A1 - Rioux, John D A1 - Rotter, Jerome I A1 - Sofer, Tamar A1 - Stricker, Bruno H A1 - Tiemeier, Henning A1 - Vrijkotte, Tanja G M A1 - Asselbergs, Folkert W A1 - Brundel, Bianca J J M A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - den Hoed, Marcel A1 - Snieder, Harold A1 - de Geus, Eco J C AB -

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 VL - 8 ER - TY - JOUR T1 - Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. JF - Nat Commun Y1 - 2017 A1 - Zillikens, M Carola A1 - Demissie, Serkalem A1 - Hsu, Yi-Hsiang A1 - Yerges-Armstrong, Laura M A1 - Chou, Wen-Chi A1 - Stolk, Lisette A1 - Livshits, Gregory A1 - Broer, Linda A1 - Johnson, Toby A1 - Koller, Daniel L A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Malkin, Ida A1 - Ried, Janina S A1 - Smith, Albert V A1 - Thorleifsson, Gudmar A1 - Vandenput, Liesbeth A1 - Hua Zhao, Jing A1 - Zhang, Weihua A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Baier, Leslie J A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Biffar, Rainer A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos Obanda, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Cederberg, Henna A1 - Chen, Zhao A1 - Cho, Nam H A1 - Jin Choi, Hyung A1 - Claussnitzer, Melina A1 - Collins, Francis A1 - Cummings, Steven R A1 - De Jager, Philip L A1 - Demuth, Ilja A1 - Dhonukshe-Rutten, Rosalie A M A1 - Diatchenko, Luda A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Erdos, Mike A1 - Eriksson, Johan G A1 - Eriksson, Joel A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Girke, Thomas A1 - Glazer, Nicole L A1 - Grallert, Harald A1 - Grewal, Jagvir A1 - Han, Bok-Ghee A1 - Hanson, Robert L A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Hoffman, Eric P A1 - Homuth, Georg A1 - Hsueh, Wen-Chi A1 - Hubal, Monica J A1 - Hubbard, Alan A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koistinen, Heikki A A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Launer, Lenore J A1 - Lee, Jong-Young A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Liu, Tian A1 - Liu, Youfang A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Maixner, William A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Melov, Simon A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Newman, Anne A1 - Nielson, Carrie M A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Parker, Stephen C J A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Prince, Richard L A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schadt, Eric E A1 - Schipf, Sabine A1 - Scott, Laura A1 - Sehmi, Joban A1 - Shen, Jian A1 - Soo Shin, Chan A1 - Sigurdsson, Gunnar A1 - Smith, Shad A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Steinhagen-Thiessen, Elisabeth A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Tan, Sian-Tsung A1 - Tarnopolsky, Mark A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Tuomilehto, Jaakko A1 - van Schoor, Natasja M A1 - Verma, Arjun A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - Weedon, Michael N A1 - Welch, Ryan A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Xie, Weijia A1 - Yu, Lei A1 - Zhou, Yanhua A1 - Chambers, John C A1 - Döring, Angela A1 - van Duijn, Cornelia M A1 - Econs, Michael J A1 - Gudnason, Vilmundur A1 - Kooner, Jaspal S A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Ossowski, Vicky A1 - Waterworth, Dawn A1 - Loos, Ruth J F A1 - Karasik, David A1 - Harris, Tamara B A1 - Ohlsson, Claes A1 - Kiel, Douglas P AB -

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

VL - 8 IS - 1 ER - TY - JOUR T1 - Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. JF - Nat Genet Y1 - 2017 A1 - Christophersen, Ingrid E A1 - Rienstra, Michiel A1 - Roselli, Carolina A1 - Yin, Xiaoyan A1 - Geelhoed, Bastiaan A1 - Barnard, John A1 - Lin, Honghuang A1 - Arking, Dan E A1 - Smith, Albert V A1 - Albert, Christine M A1 - Chaffin, Mark A1 - Tucker, Nathan R A1 - Li, Molong A1 - Klarin, Derek A1 - Bihlmeyer, Nathan A A1 - Low, Siew-Kee A1 - Weeke, Peter E A1 - Müller-Nurasyid, Martina A1 - Smith, J Gustav A1 - Brody, Jennifer A A1 - Niemeijer, Maartje N A1 - Dörr, Marcus A1 - Trompet, Stella A1 - Huffman, Jennifer A1 - Gustafsson, Stefan A1 - Schurmann, Claudia A1 - Kleber, Marcus E A1 - Lyytikäinen, Leo-Pekka A1 - Seppälä, Ilkka A1 - Malik, Rainer A1 - Horimoto, Andrea R V R A1 - Perez, Marco A1 - Sinisalo, Juha A1 - Aeschbacher, Stefanie A1 - Thériault, Sébastien A1 - Yao, Jie A1 - Radmanesh, Farid A1 - Weiss, Stefan A1 - Teumer, Alexander A1 - Choi, Seung Hoan A1 - Weng, Lu-Chen A1 - Clauss, Sebastian A1 - Deo, Rajat A1 - Rader, Daniel J A1 - Shah, Svati H A1 - Sun, Albert A1 - Hopewell, Jemma C A1 - Debette, Stephanie A1 - Chauhan, Ganesh A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Paré, Guillaume A1 - Kamatani, Yoichiro A1 - Hagemeijer, Yanick P A1 - Verweij, Niek A1 - Siland, Joylene E A1 - Kubo, Michiaki A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Bis, Joshua C A1 - Perz, Siegfried A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Magnani, Jared W A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shoemaker, M Benjamin A1 - Padmanabhan, Sandosh A1 - Haessler, Jeffrey A1 - Bartz, Traci M A1 - Waldenberger, Melanie A1 - Lichtner, Peter A1 - Arendt, Marina A1 - Krieger, Jose E A1 - Kähönen, Mika A1 - Risch, Lorenz A1 - Mansur, Alfredo J A1 - Peters, Annette A1 - Smith, Blair H A1 - Lind, Lars A1 - Scott, Stuart A A1 - Lu, Yingchang A1 - Bottinger, Erwin B A1 - Hernesniemi, Jussi A1 - Lindgren, Cecilia M A1 - Wong, Jorge A A1 - Huang, Jie A1 - Eskola, Markku A1 - Morris, Andrew P A1 - Ford, Ian A1 - Reiner, Alex P A1 - Delgado, Graciela A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Sandhu, Roopinder K A1 - Li, Man A1 - Boerwinkle, Eric A1 - Eisele, Lewin A1 - Lannfelt, Lars A1 - Rost, Natalia A1 - Anderson, Christopher D A1 - Taylor, Kent D A1 - Campbell, Archie A1 - Magnusson, Patrik K A1 - Porteous, David A1 - Hocking, Lynne J A1 - Vlachopoulou, Efthymia A1 - Pedersen, Nancy L A1 - Nikus, Kjell A1 - Orho-Melander, Marju A1 - Hamsten, Anders A1 - Heeringa, Jan A1 - Denny, Joshua C A1 - Kriebel, Jennifer A1 - Darbar, Dawood A1 - Newton-Cheh, Christopher A1 - Shaffer, Christian A1 - Macfarlane, Peter W A1 - Heilmann-Heimbach, Stefanie A1 - Almgren, Peter A1 - Huang, Paul L A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Völker, Uwe A1 - Jöckel, Karl-Heinz A1 - Sinner, Moritz F A1 - Lin, Henry J A1 - Guo, Xiuqing A1 - Dichgans, Martin A1 - Ingelsson, Erik A1 - Kooperberg, Charles A1 - Melander, Olle A1 - Loos, Ruth J F A1 - Laurikka, Jari A1 - Conen, David A1 - Rosand, Jonathan A1 - van der Harst, Pim A1 - Lokki, Marja-Liisa A1 - Kathiresan, Sekar A1 - Pereira, Alexandre A1 - Jukema, J Wouter A1 - Hayward, Caroline A1 - Rotter, Jerome I A1 - März, Winfried A1 - Lehtimäki, Terho A1 - Stricker, Bruno H A1 - Chung, Mina K A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Roden, Dan M A1 - Kääb, Stefan A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Tanaka, Toshihiro A1 - Lunetta, Kathryn L A1 - Lubitz, Steven A A1 - Ellinor, Patrick T AB -

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

VL - 49 IS - 6 ER - TY - JOUR T1 - Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. JF - J Clin Invest Y1 - 2017 A1 - Wild, Philipp S A1 - Felix, Janine F A1 - Schillert, Arne A1 - Teumer, Alexander A1 - Chen, Ming-Huei A1 - Leening, Maarten J G A1 - Völker, Uwe A1 - Großmann, Vera A1 - Brody, Jennifer A A1 - Irvin, Marguerite R A1 - Shah, Sanjiv J A1 - Pramana, Setia A1 - Lieb, Wolfgang A1 - Schmidt, Reinhold A1 - Stanton, Alice V A1 - Malzahn, Dörthe A1 - Smith, Albert Vernon A1 - Sundström, Johan A1 - Minelli, Cosetta A1 - Ruggiero, Daniela A1 - Lyytikäinen, Leo-Pekka A1 - Tiller, Daniel A1 - Smith, J Gustav A1 - Monnereau, Claire A1 - Di Tullio, Marco R A1 - Musani, Solomon K A1 - Morrison, Alanna C A1 - Pers, Tune H A1 - Morley, Michael A1 - Kleber, Marcus E A1 - Aragam, Jayashri A1 - Benjamin, Emelia J A1 - Bis, Joshua C A1 - Bisping, Egbert A1 - Broeckel, Ulrich A1 - Cheng, Susan A1 - Deckers, Jaap W A1 - del Greco M, Fabiola A1 - Edelmann, Frank A1 - Fornage, Myriam A1 - Franke, Lude A1 - Friedrich, Nele A1 - Harris, Tamara B A1 - Hofer, Edith A1 - Hofman, Albert A1 - Huang, Jie A1 - Hughes, Alun D A1 - Kähönen, Mika A1 - Investigators, Knhi A1 - Kruppa, Jochen A1 - Lackner, Karl J A1 - Lannfelt, Lars A1 - Laskowski, Rafael A1 - Launer, Lenore J A1 - Leosdottir, Margrét A1 - Lin, Honghuang A1 - Lindgren, Cecilia M A1 - Loley, Christina A1 - MacRae, Calum A A1 - Mascalzoni, Deborah A1 - Mayet, Jamil A1 - Medenwald, Daniel A1 - Morris, Andrew P A1 - Müller, Christian A1 - Müller-Nurasyid, Martina A1 - Nappo, Stefania A1 - Nilsson, Peter M A1 - Nuding, Sebastian A1 - Nutile, Teresa A1 - Peters, Annette A1 - Pfeufer, Arne A1 - Pietzner, Diana A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rice, Kenneth M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Ruohonen, Saku T A1 - Sacco, Ralph L A1 - Samdarshi, Tandaw E A1 - Schmidt, Helena A1 - Sharp, Andrew S P A1 - Shields, Denis C A1 - Sorice, Rossella A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Surendran, Praveen A1 - Thom, Simon A1 - Töglhofer, Anna M A1 - Uitterlinden, André G A1 - Wachter, Rolf A1 - Völzke, Henry A1 - Ziegler, Andreas A1 - Münzel, Thomas A1 - März, Winfried A1 - Cappola, Thomas P A1 - Hirschhorn, Joel N A1 - Mitchell, Gary F A1 - Smith, Nicholas L A1 - Fox, Ervin R A1 - Dueker, Nicole D A1 - Jaddoe, Vincent W V A1 - Melander, Olle A1 - Russ, Martin A1 - Lehtimäki, Terho A1 - Ciullo, Marina A1 - Hicks, Andrew A A1 - Lind, Lars A1 - Gudnason, Vilmundur A1 - Pieske, Burkert A1 - Barron, Anthony J A1 - Zweiker, Robert A1 - Schunkert, Heribert A1 - Ingelsson, Erik A1 - Liu, Kiang A1 - Arnett, Donna K A1 - Psaty, Bruce M A1 - Blankenberg, Stefan A1 - Larson, Martin G A1 - Felix, Stephan B A1 - Franco, Oscar H A1 - Zeller, Tanja A1 - Vasan, Ramachandran S A1 - Dörr, Marcus AB -

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

FUNDING: For detailed information per study, see Acknowledgments.

VL - 127 IS - 5 ER - TY - JOUR T1 - Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. JF - Am J Hum Genet Y1 - 2017 A1 - Manousaki, Despoina A1 - Dudding, Tom A1 - Haworth, Simon A1 - Hsu, Yi-Hsiang A1 - Liu, Ching-Ti A1 - Medina-Gómez, Carolina A1 - Voortman, Trudy A1 - van der Velde, Nathalie A1 - Melhus, Håkan A1 - Robinson-Cohen, Cassianne A1 - Cousminer, Diana L A1 - Nethander, Maria A1 - Vandenput, Liesbeth A1 - Noordam, Raymond A1 - Forgetta, Vincenzo A1 - Greenwood, Celia M T A1 - Biggs, Mary L A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Zemel, Babette S A1 - Mitchell, Jonathan A A1 - Taylor, Bruce A1 - Lorentzon, Mattias A1 - Karlsson, Magnus A1 - Jaddoe, Vincent V W A1 - Tiemeier, Henning A1 - Campos-Obando, Natalia A1 - Franco, Oscar H A1 - Utterlinden, Andre G A1 - Broer, Linda A1 - van Schoor, Natasja M A1 - Ham, Annelies C A1 - Ikram, M Arfan A1 - Karasik, David A1 - de Mutsert, Renée A1 - Rosendaal, Frits R A1 - den Heijer, Martin A1 - Wang, Thomas J A1 - Lind, Lars A1 - Orwoll, Eric S A1 - Mook-Kanamori, Dennis O A1 - Michaëlsson, Karl A1 - Kestenbaum, Bryan A1 - Ohlsson, Claes A1 - Mellström, Dan A1 - de Groot, Lisette C P G M A1 - Grant, Struan F A A1 - Kiel, Douglas P A1 - Zillikens, M Carola A1 - Rivadeneira, Fernando A1 - Sawcer, Stephen A1 - Timpson, Nicholas J A1 - Richards, J Brent KW - Cholestanetriol 26-Monooxygenase KW - Cytochrome P450 Family 2 KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Multiple Sclerosis KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Vitamin D KW - Vitamin D Deficiency AB -

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

VL - 101 IS - 2 ER - TY - JOUR T1 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kraja, Aldi T A1 - Cook, James P A1 - Warren, Helen R A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Evangelou, Evangelos A1 - Manning, Alisa K A1 - Grarup, Niels A1 - Drenos, Fotios A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Amin, Najaf A1 - Blakemore, Alexandra I F 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 - Harris, Sarah E A1 - Have, Christian T A1 - Havulinna, Aki S A1 - Zhang, He A1 - Jørgensen, Marit E A1 - Käräjämäki, AnneMari A1 - Kooperberg, Charles 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 - Marioni, Riccardo E A1 - Mei, Hao A1 - Menni, Cristina A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Rayner, Nigel William A1 - Riaz, Muhammad A1 - Rice, Ken A1 - Richard, Melissa A A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Stančáková, Alena A1 - Stirrups, Kathleen E 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 - Christensen, Cramer K A1 - de Boer, Rudolf A A1 - Deary, Ian J A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Dominiczak, Anna F A1 - Dörr, Marcus A1 - Joehanes, Roby A1 - Edwards, Todd L A1 - Esko, Tõnu A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Franks, Paul W A1 - Gambaro, Giovanni A1 - Groop, Leif A1 - Hallmans, Göran A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Heikki, Oksa A1 - Ingelsson, Erik A1 - Tuomilehto, Jaakko A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal S A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Lind, Lars A1 - Loos, Ruth J F 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 - Poulter, Neil R A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sever, Peter J A1 - Skaaby, Tea A1 - Stafford, Jeanette M A1 - Starr, John M A1 - van der Harst, Pim A1 - van der Meer, Peter A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Gudnason, Vilmundur A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Willer, Cristen J A1 - Witte, Daniel R A1 - Zeggini, Eleftheria A1 - Saleheen, Danish A1 - Butterworth, Adam S A1 - Danesh, John A1 - Asselbergs, Folkert W A1 - Wain, Louise V A1 - Ehret, Georg B A1 - Chasman, Daniel I 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 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 (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) 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 DBH) 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 - Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. JF - Hypertension Y1 - 2017 A1 - Wain, Louise V A1 - Vaez, Ahmad A1 - Jansen, Rick A1 - Joehanes, Roby A1 - van der Most, Peter J A1 - Erzurumluoglu, A Mesut A1 - O'Reilly, Paul F A1 - Cabrera, Claudia P A1 - Warren, Helen R A1 - Rose, Lynda M A1 - Verwoert, Germaine C A1 - Hottenga, Jouke-Jan A1 - Strawbridge, Rona J A1 - Esko, Tõnu A1 - Arking, Dan E A1 - Hwang, Shih-Jen A1 - Guo, Xiuqing A1 - Kutalik, Zoltán A1 - Trompet, Stella A1 - Shrine, Nick A1 - Teumer, Alexander A1 - Ried, Janina S A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Amin, Najaf A1 - Nolte, Ilja M A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Wareham, Nicholas J A1 - Hofer, Edith A1 - Joshi, Peter K A1 - Kristiansson, Kati A1 - Traglia, Michela A1 - Havulinna, Aki S A1 - Goel, Anuj A1 - Nalls, Mike A A1 - Sõber, Siim A1 - Vuckovic, Dragana A1 - Luan, Jian'an A1 - del Greco M, Fabiola A1 - Ayers, Kristin L A1 - Marrugat, Jaume A1 - Ruggiero, Daniela A1 - Lopez, Lorna M A1 - Niiranen, Teemu A1 - Enroth, Stefan A1 - Jackson, Anne U A1 - Nelson, Christopher P A1 - Huffman, Jennifer E A1 - Zhang, Weihua A1 - Marten, Jonathan A1 - Gandin, Ilaria A1 - Harris, Sarah E A1 - Zemunik, Tatijana A1 - Lu, Yingchang A1 - Evangelou, Evangelos A1 - Shah, Nabi A1 - de Borst, Martin H A1 - Mangino, Massimo A1 - Prins, Bram P A1 - Campbell, Archie A1 - Li-Gao, Ruifang A1 - Chauhan, Ganesh A1 - Oldmeadow, Christopher A1 - Abecasis, Goncalo A1 - Abedi, Maryam A1 - Barbieri, Caterina M A1 - Barnes, Michael R A1 - Batini, Chiara A1 - Beilby, John A1 - Blake, Tineka A1 - Boehnke, Michael A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brown, Morris A1 - Brumat, Marco A1 - Campbell, Harry A1 - Chambers, John C A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Connell, John A1 - Cordell, Heather J A1 - Damman, Jeffrey J A1 - Davies, Gail A1 - de Geus, Eco J A1 - de Mutsert, Renée A1 - Deelen, Joris A1 - Demirkale, Yusuf A1 - Doney, Alex S F A1 - Dörr, Marcus A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Gao, He A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Gow, Alan J A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Hui, Jennie A1 - Jarvelin, Marjo-Riitta A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Khaw, Kay-Tee A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Langenberg, Claudia A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Mach, François A1 - Mamasoula, Chrysovalanto A1 - Menni, Cristina A1 - Mifsud, Borbala A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nandakumar, Priyanka A1 - Nguyen, Quang Tri A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Saba, Yasaman A1 - Saint Pierre, Aude A1 - Sala, Cinzia F A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Scott, Rodney A1 - Seelen, Marc A A1 - Shields, Denis C A1 - Siscovick, David A1 - Sorice, Rossella A1 - Stanton, Alice A1 - Stott, David J A1 - Sundström, Johan A1 - Swertz, Morris A1 - Taylor, Kent D A1 - Thom, Simon A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Wright, Alan F A1 - Yao, Jie A1 - Thériault, Sébastien A1 - Conen, David A1 - Attia, John A1 - Sever, Peter A1 - Debette, Stephanie A1 - Mook-Kanamori, Dennis O A1 - Zeggini, Eleftheria A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Palmer, Colin N A A1 - Vergnaud, Anne-Claire A1 - Loos, Ruth J F A1 - Polasek, Ozren A1 - Starr, John M A1 - Girotto, Giorgia A1 - Hayward, Caroline A1 - Kooner, Jaspal S A1 - Lindgren, Cecila M A1 - Vitart, Veronique A1 - Samani, Nilesh J A1 - Tuomilehto, Jaakko A1 - Gyllensten, Ulf A1 - Knekt, Paul A1 - Deary, Ian J A1 - Ciullo, Marina A1 - Elosua, Roberto A1 - Keavney, Bernard D A1 - Hicks, Andrew A A1 - Scott, Robert A A1 - Gasparini, Paolo A1 - Laan, Maris A1 - Liu, Yongmei A1 - Watkins, Hugh A1 - Hartman, Catharina A A1 - Salomaa, Veikko A1 - Toniolo, Daniela A1 - Perola, Markus A1 - Wilson, James F A1 - Schmidt, Helena A1 - Zhao, Jing Hua A1 - Lehtimäki, Terho A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Rettig, Rainer A1 - James, Alan A1 - Jukema, J Wouter A1 - Strachan, David P A1 - Palmas, Walter A1 - Metspalu, Andres A1 - Ingelsson, Erik A1 - Boomsma, Dorret I A1 - Franco, Oscar H A1 - Bochud, Murielle A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Elliott, Paul A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Knight, Joanne A1 - Morris, Andrew P A1 - Levy, Daniel A1 - Tobin, Martin D A1 - Snieder, Harold A1 - Caulfield, Mark J A1 - Ehret, Georg B AB -

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

ER - TY - JOUR T1 - Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. JF - PLoS Med Y1 - 2018 A1 - Imamura, Fumiaki A1 - Fretts, Amanda A1 - Marklund, Matti A1 - Ardisson Korat, Andres V A1 - Yang, Wei-Sin A1 - Lankinen, Maria A1 - Qureshi, Waqas A1 - Helmer, Catherine A1 - Chen, Tzu-An A1 - Wong, Kerry A1 - Bassett, Julie K A1 - Murphy, Rachel A1 - Tintle, Nathan A1 - Yu, Chaoyu Ian A1 - Brouwer, Ingeborg A A1 - Chien, Kuo-Liong A1 - Frazier-Wood, Alexis C A1 - Del Gobbo, Liana C A1 - Djoussé, Luc A1 - Geleijnse, Johanna M A1 - Giles, Graham G A1 - de Goede, Janette A1 - Gudnason, Vilmundur A1 - Harris, William S A1 - Hodge, Allison A1 - Hu, Frank A1 - Koulman, Albert A1 - Laakso, Markku A1 - Lind, Lars A1 - Lin, Hung-Ju A1 - McKnight, Barbara A1 - Rajaobelina, Kalina A1 - Riserus, Ulf A1 - Robinson, Jennifer G A1 - Samieri, Cecilia A1 - Siscovick, David S A1 - Soedamah-Muthu, Sabita S A1 - Sotoodehnia, Nona A1 - Sun, Qi A1 - Tsai, Michael Y A1 - Uusitupa, Matti A1 - Wagenknecht, Lynne E A1 - Wareham, Nick J A1 - Wu, Jason HY A1 - Micha, Renata A1 - Forouhi, Nita G A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Aged KW - Australia KW - Biomarkers KW - Dairy Products KW - Diabetes Mellitus, Type 2 KW - Dietary Fats KW - Europe KW - Fatty Acids KW - Fatty Acids, Monounsaturated KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Prospective Studies KW - Sex Factors KW - Taiwan KW - United States AB -

BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D).

METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.

CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

VL - 15 IS - 10 ER - TY - JOUR T1 - Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. JF - Nat Genet Y1 - 2018 A1 - Evangelou, Evangelos A1 - Warren, Helen R A1 - Mosen-Ansorena, David A1 - Mifsud, Borbala A1 - Pazoki, Raha A1 - Gao, He A1 - Ntritsos, Georgios A1 - Dimou, Niki A1 - Cabrera, Claudia P A1 - Karaman, Ibrahim A1 - Ng, Fu Liang A1 - Evangelou, Marina A1 - Witkowska, Katarzyna A1 - Tzanis, Evan A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - Velez Edwards, Digna R A1 - Sun, Yan V A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Wilson, Peter W F A1 - Tsao, Philip S A1 - Kovesdy, Csaba P A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Milani, Lili A1 - Almgren, Peter A1 - Boutin, Thibaud A1 - Debette, Stephanie A1 - Ding, Jun A1 - Giulianini, Franco A1 - Holliday, Elizabeth G A1 - Jackson, Anne U A1 - Li-Gao, Ruifang A1 - Lin, Wei-Yu A1 - Luan, Jian'an A1 - Mangino, Massimo A1 - Oldmeadow, Christopher A1 - Prins, Bram Peter A1 - Qian, Yong A1 - Sargurupremraj, Muralidharan A1 - Shah, Nabi A1 - Surendran, Praveen A1 - Thériault, Sébastien A1 - Verweij, Niek A1 - Willems, Sara M A1 - Zhao, Jing-Hua A1 - Amouyel, Philippe A1 - Connell, John A1 - de Mutsert, Renée A1 - Doney, Alex S F A1 - Farrall, Martin A1 - Menni, Cristina A1 - Morris, Andrew D A1 - Noordam, Raymond A1 - Paré, Guillaume A1 - Poulter, Neil R A1 - Shields, Denis C A1 - Stanton, Alice A1 - Thom, Simon A1 - Abecasis, Goncalo A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ayers, Kristin L A1 - Barbieri, Caterina M A1 - Batini, Chiara A1 - Bis, Joshua C A1 - Blake, Tineka A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brumat, Marco A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chauhan, Ganesh A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Cordell, Heather J A1 - Davies, Gail A1 - Borst, Martin H de A1 - Geus, Eco J de A1 - Deary, Ian J A1 - Deelen, Joris A1 - del Greco M, Fabiola A1 - Demirkale, Cumhur Yusuf A1 - Dörr, Marcus A1 - Ehret, Georg B A1 - Elosua, Roberto A1 - Enroth, Stefan A1 - Erzurumluoglu, A Mesut A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Franco, Oscar H A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gow, Alan J A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Harris, Sarah E A1 - Hartman, Catharina A A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Ingelsson, Erik A1 - James, Alan A1 - Jansen, Rick A1 - Jarvelin, Marjo-Riitta A1 - Joehanes, Roby A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Joshi, Peter K A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Keavney, Bernard D A1 - Khaw, Kay-Tee A1 - Knekt, Paul A1 - Knight, Joanne A1 - Kolcic, Ivana A1 - Kooner, Jaspal S A1 - Koskinen, Seppo A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Laan, Maris A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lopez, Lorna M A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Mamasoula, Chrysovalanto A1 - Marrugat, Jaume A1 - Marten, Jonathan A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nalls, Mike A A1 - Nandakumar, Priyanka A1 - Nelson, Christopher P A1 - Niiranen, Teemu A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - O'Reilly, Paul F A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Palotie, Aarno A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Nguyen, Quang Tri A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rettig, Rainer A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Ried, Janina S A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia F A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Shrine, Nick A1 - Siscovick, David A1 - Smith, Albert V A1 - Snieder, Harold A1 - Sõber, Siim A1 - Sorice, Rossella A1 - Starr, John M A1 - Stott, David J A1 - Strachan, David P A1 - Strawbridge, Rona J A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Tobin, Martin D A1 - Tomaszewski, Maciej A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Trompet, Stella A1 - Tuomilehto, Jaakko A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Vaez, Ahmad A1 - van der Most, Peter J A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Verwoert, Germaine C A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wright, Alan F A1 - Yao, Jie A1 - Zemunik, Tatijana A1 - Zhang, Weihua A1 - Attia, John R A1 - Butterworth, Adam S A1 - Chasman, Daniel I A1 - Conen, David A1 - Cucca, Francesco A1 - Danesh, John A1 - Hayward, Caroline A1 - Howson, Joanna M M A1 - Laakso, Markku A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Melander, Olle A1 - Mook-Kanamori, Dennis O A1 - Palmer, Colin N A A1 - Risch, Lorenz A1 - Scott, Robert A A1 - Scott, Rodney J A1 - Sever, Peter A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Zeggini, Eleftheria A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Newton-Cheh, Christopher A1 - Brown, Morris J A1 - Metspalu, Andres A1 - Hung, Adriana M A1 - O'Donnell, Christopher J A1 - Edwards, Todd L A1 - Psaty, Bruce M A1 - Tzoulaki, Ioanna A1 - Barnes, Michael R A1 - Wain, Louise V A1 - Elliott, Paul A1 - Caulfield, Mark J AB -

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

VL - 50 IS - 10 ER - TY - JOUR T1 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. JF - Am J Hum Genet Y1 - 2018 A1 - Ligthart, Symen A1 - Vaez, Ahmad A1 - Võsa, Urmo A1 - Stathopoulou, Maria G A1 - de Vries, Paul S A1 - Prins, Bram P A1 - van der Most, Peter J A1 - Tanaka, Toshiko A1 - Naderi, Elnaz A1 - Rose, Lynda M A1 - Wu, Ying A1 - Karlsson, Robert A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Pool, Rene A1 - Zhu, Gu A1 - Mace, Aurelien A1 - Sidore, Carlo A1 - Trompet, Stella A1 - Mangino, Massimo A1 - Sabater-Lleal, Maria A1 - Kemp, John P A1 - Abbasi, Ali A1 - Kacprowski, Tim A1 - Verweij, Niek A1 - Smith, Albert V A1 - Huang, Tao A1 - Marzi, Carola A1 - Feitosa, Mary F A1 - Lohman, Kurt K A1 - Kleber, Marcus E A1 - Milaneschi, Yuri A1 - Mueller, Christian A1 - Huq, Mahmudul A1 - Vlachopoulou, Efthymia A1 - Lyytikäinen, Leo-Pekka A1 - Oldmeadow, Christopher A1 - Deelen, Joris A1 - Perola, Markus A1 - Zhao, Jing Hua A1 - Feenstra, Bjarke A1 - Amini, Marzyeh A1 - Lahti, Jari A1 - Schraut, Katharina E A1 - Fornage, Myriam A1 - Suktitipat, Bhoom A1 - Chen, Wei-Min A1 - Li, Xiaohui A1 - Nutile, Teresa A1 - Malerba, Giovanni A1 - Luan, Jian'an A1 - Bak, Tom A1 - Schork, Nicholas A1 - del Greco M, Fabiola A1 - Thiering, Elisabeth A1 - Mahajan, Anubha A1 - Marioni, Riccardo E A1 - Mihailov, Evelin A1 - Eriksson, Joel A1 - Ozel, Ayse Bilge A1 - Zhang, Weihua A1 - Nethander, Maria A1 - Cheng, Yu-Ching A1 - Aslibekyan, Stella A1 - Ang, Wei A1 - Gandin, Ilaria A1 - Yengo, Loic A1 - Portas, Laura A1 - Kooperberg, Charles A1 - Hofer, Edith A1 - Rajan, Kumar B A1 - Schurmann, Claudia A1 - den Hollander, Wouter A1 - Ahluwalia, Tarunveer S A1 - Zhao, Jing A1 - Draisma, Harmen H M A1 - Ford, Ian A1 - Timpson, Nicholas A1 - Teumer, Alexander A1 - Huang, Hongyan A1 - Wahl, Simone A1 - Liu, Yongmei A1 - Huang, Jie A1 - Uh, Hae-Won A1 - Geller, Frank A1 - Joshi, Peter K A1 - Yanek, Lisa R A1 - Trabetti, Elisabetta A1 - Lehne, Benjamin A1 - Vozzi, Diego A1 - Verbanck, Marie A1 - Biino, Ginevra A1 - Saba, Yasaman A1 - Meulenbelt, Ingrid A1 - O'Connell, Jeff R A1 - Laakso, Markku A1 - Giulianini, Franco A1 - Magnusson, Patrik K E A1 - Ballantyne, Christie M A1 - Hottenga, Jouke Jan A1 - Montgomery, Grant W A1 - Rivadineira, Fernando A1 - Rueedi, Rico A1 - Steri, Maristella A1 - Herzig, Karl-Heinz A1 - Stott, David J A1 - Menni, Cristina A1 - Frånberg, Mattias A1 - St Pourcain, Beate A1 - Felix, Stephan B A1 - Pers, Tune H A1 - Bakker, Stephan J L A1 - Kraft, Peter A1 - Peters, Annette A1 - Vaidya, Dhananjay A1 - Delgado, Graciela A1 - Smit, Johannes H A1 - Großmann, Vera A1 - Sinisalo, Juha A1 - Seppälä, Ilkka A1 - Williams, Stephen R A1 - Holliday, Elizabeth G A1 - Moed, Matthijs A1 - Langenberg, Claudia A1 - Räikkönen, Katri A1 - Ding, Jingzhong A1 - Campbell, Harry A1 - Sale, Michèle M A1 - Chen, Yii-der I A1 - James, Alan L A1 - Ruggiero, Daniela A1 - Soranzo, Nicole A1 - Hartman, Catharina A A1 - Smith, Erin N A1 - Berenson, Gerald S A1 - Fuchsberger, Christian A1 - Hernandez, Dena A1 - Tiesler, Carla M T A1 - Giedraitis, Vilmantas A1 - Liewald, David A1 - Fischer, Krista A1 - Mellström, Dan A1 - Larsson, Anders A1 - Wang, Yunmei A1 - Scott, William R A1 - Lorentzon, Matthias A1 - Beilby, John A1 - Ryan, Kathleen A A1 - Pennell, Craig E A1 - Vuckovic, Dragana A1 - Balkau, Beverly A1 - Concas, Maria Pina A1 - Schmidt, Reinhold A1 - Mendes de Leon, Carlos F A1 - Bottinger, Erwin P A1 - Kloppenburg, Margreet A1 - Paternoster, Lavinia A1 - Boehnke, Michael A1 - Musk, A W A1 - Willemsen, Gonneke A1 - Evans, David M A1 - Madden, Pamela A F A1 - Kähönen, Mika A1 - Kutalik, Zoltán A1 - Zoledziewska, Magdalena A1 - Karhunen, Ville A1 - Kritchevsky, Stephen B A1 - Sattar, Naveed A1 - Lachance, Genevieve A1 - Clarke, Robert A1 - Harris, Tamara B A1 - Raitakari, Olli T A1 - Attia, John R A1 - van Heemst, Diana A1 - Kajantie, Eero A1 - Sorice, Rossella A1 - Gambaro, Giovanni A1 - Scott, Robert A A1 - Hicks, Andrew A A1 - Ferrucci, Luigi A1 - Standl, Marie A1 - Lindgren, Cecilia M A1 - Starr, John M A1 - Karlsson, Magnus A1 - Lind, Lars A1 - Li, Jun Z A1 - Chambers, John C A1 - Mori, Trevor A A1 - de Geus, Eco J C N A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Auvinen, Juha A1 - Buckley, Brendan M A1 - de Craen, Anton J M A1 - Waldenberger, Melanie A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Scott, Rodney J A1 - McEvoy, Mark A1 - Beekman, Marian A1 - Bombieri, Cristina A1 - Ridker, Paul M A1 - Mohlke, Karen L A1 - Pedersen, Nancy L A1 - Morrison, Alanna C A1 - Boomsma, Dorret I A1 - Whitfield, John B A1 - Strachan, David P A1 - Hofman, Albert A1 - Vollenweider, Peter A1 - Cucca, Francesco A1 - Jarvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Spector, Tim D A1 - Hamsten, Anders A1 - Zeller, Tanja A1 - Uitterlinden, André G A1 - Nauck, Matthias A1 - Gudnason, Vilmundur A1 - Qi, Lu A1 - Grallert, Harald A1 - Borecki, Ingrid B A1 - Rotter, Jerome I A1 - März, Winfried A1 - Wild, Philipp S A1 - Lokki, Marja-Liisa A1 - Boyle, Michael A1 - Salomaa, Veikko A1 - Melbye, Mads A1 - Eriksson, Johan G A1 - Wilson, James F A1 - Penninx, Brenda W J H A1 - Becker, Diane M A1 - Worrall, Bradford B A1 - Gibson, Greg A1 - Krauss, Ronald M A1 - Ciullo, Marina A1 - Zaza, Gianluigi A1 - Wareham, Nicholas J A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Murray, Sarah S A1 - Pramstaller, Peter P A1 - Bandinelli, Stefania A1 - Heinrich, Joachim A1 - Ingelsson, Erik A1 - Deary, Ian J A1 - Mägi, Reedik A1 - Vandenput, Liesbeth A1 - van der Harst, Pim A1 - Desch, Karl C A1 - Kooner, Jaspal S A1 - Ohlsson, Claes A1 - Hayward, Caroline A1 - Lehtimäki, Terho A1 - Shuldiner, Alan R A1 - Arnett, Donna K A1 - Beilin, Lawrence J A1 - Robino, Antonietta A1 - Froguel, Philippe A1 - Pirastu, Mario A1 - Jess, Tine A1 - Koenig, Wolfgang A1 - Loos, Ruth J F A1 - Evans, Denis A A1 - Schmidt, Helena A1 - Smith, George Davey A1 - Slagboom, P Eline A1 - Eiriksdottir, Gudny A1 - Morris, Andrew P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Nolte, Ilja M A1 - Boerwinkle, Eric A1 - Visvikis-Siest, Sophie A1 - Reiner, Alex P A1 - Gross, Myron A1 - Bis, Joshua C A1 - Franke, Lude A1 - Franco, Oscar H A1 - Benjamin, Emelia J A1 - Chasman, Daniel I A1 - Dupuis, Josée A1 - Snieder, Harold A1 - Dehghan, Abbas A1 - Alizadeh, Behrooz Z AB -

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

VL - 103 IS - 5 ER - TY - JOUR T1 - Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium. JF - PLoS One Y1 - 2018 A1 - de Oliveira Otto, Marcia C A1 - Lemaitre, Rozenn N A1 - Sun, Qi A1 - King, Irena B A1 - Wu, Jason H Y A1 - Manichaikul, Ani A1 - Rich, Stephen S A1 - Tsai, Michael Y A1 - Chen, Y D A1 - Fornage, Myriam A1 - Weihua, Guan A1 - Aslibekyan, Stella A1 - Irvin, Marguerite R A1 - Kabagambe, Edmond K A1 - Arnett, Donna K A1 - Jensen, Majken K A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Steffen, Lyn M A1 - Smith, Caren E A1 - Riserus, Ulf A1 - Lind, Lars A1 - Hu, Frank B A1 - Rimm, Eric B A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Fatty Acids KW - Genome-Wide Association Study KW - Humans KW - Introns KW - Lactase KW - Myosins KW - Polymorphism, Single Nucleotide KW - Sphingomyelins KW - Sphingosine N-Acyltransferase KW - Tumor Suppressor Proteins AB -

BACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.

OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.

DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.

RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37×10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07×10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4×10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5×10-2).

CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.

VL - 13 IS - 5 ER - TY - JOUR T1 - Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. JF - Nat Commun Y1 - 2018 A1 - Jiang, Xia A1 - O'Reilly, Paul F A1 - Aschard, Hugues A1 - Hsu, Yi-Hsiang A1 - Richards, J Brent A1 - Dupuis, Josée A1 - Ingelsson, Erik A1 - Karasik, David A1 - Pilz, Stefan A1 - Berry, Diane A1 - Kestenbaum, Bryan A1 - Zheng, Jusheng A1 - Luan, Jianan A1 - Sofianopoulou, Eleni A1 - Streeten, Elizabeth A A1 - Albanes, Demetrius A1 - Lutsey, Pamela L A1 - Yao, Lu A1 - Tang, Weihong A1 - Econs, Michael J A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Zhou, Ang A1 - Power, Chris A1 - McCarthy, Mark I A1 - Michos, Erin D A1 - Boerwinkle, Eric A1 - Weinstein, Stephanie J A1 - Freedman, Neal D A1 - Huang, Wen-Yi A1 - van Schoor, Natasja M A1 - van der Velde, Nathalie A1 - Groot, Lisette C P G M de A1 - Enneman, Anke A1 - Cupples, L Adrienne A1 - Booth, Sarah L A1 - Vasan, Ramachandran S A1 - Liu, Ching-Ti A1 - Zhou, Yanhua A1 - Ripatti, Samuli A1 - Ohlsson, Claes A1 - Vandenput, Liesbeth A1 - Lorentzon, Mattias A1 - Eriksson, Johan G A1 - Shea, M Kyla A1 - Houston, Denise K A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Ferrucci, Luigi A1 - Peacock, Munro A1 - Gieger, Christian A1 - Beekman, Marian A1 - Slagboom, Eline A1 - Deelen, Joris A1 - Heemst, Diana van A1 - Kleber, Marcus E A1 - März, Winfried A1 - de Boer, Ian H A1 - Wood, Alexis C A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Robinson-Cohen, Cassianne A1 - den Heijer, Martin A1 - Jarvelin, Marjo-Riitta A1 - Cavadino, Alana A1 - Joshi, Peter K A1 - Wilson, James F A1 - Hayward, Caroline A1 - Lind, Lars A1 - Michaëlsson, Karl A1 - Trompet, Stella A1 - Zillikens, M Carola A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Broer, Linda A1 - Zgaga, Lina A1 - Campbell, Harry A1 - Theodoratou, Evropi A1 - Farrington, Susan M A1 - Timofeeva, Maria A1 - Dunlop, Malcolm G A1 - Valdes, Ana M A1 - Tikkanen, Emmi A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Raitakari, Olli T A1 - Mikkilä, Vera A1 - Ikram, M Arfan A1 - Sattar, Naveed A1 - Jukema, J Wouter A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Forouhi, Nita G A1 - Gundersen, Thomas E A1 - Khaw, Kay-Tee A1 - Butterworth, Adam S A1 - Danesh, John A1 - Spector, Timothy A1 - Wang, Thomas J A1 - Hyppönen, Elina A1 - Kraft, Peter A1 - Kiel, Douglas P AB -

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

VL - 9 IS - 1 ER - TY - JOUR T1 - GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. JF - Nat Commun Y1 - 2018 A1 - Franceschini, Nora A1 - Giambartolomei, Claudia A1 - de Vries, Paul S A1 - Finan, Chris A1 - Bis, Joshua C A1 - Huntley, Rachael P A1 - Lovering, Ruth C A1 - Tajuddin, Salman M A1 - Winkler, Thomas W A1 - Graff, Misa A1 - Kavousi, Maryam A1 - Dale, Caroline A1 - Smith, Albert V A1 - Hofer, Edith A1 - van Leeuwen, Elisabeth M A1 - Nolte, Ilja M A1 - Lu, Lingyi A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Pitkänen, Niina A1 - Franzén, Oscar A1 - Joshi, Peter K A1 - Noordam, Raymond A1 - Marioni, Riccardo E A1 - Hwang, Shih-Jen A1 - Musani, Solomon K A1 - Schminke, Ulf A1 - Palmas, Walter A1 - Isaacs, Aaron A1 - Correa, Adolfo A1 - Zonderman, Alan B A1 - Hofman, Albert A1 - Teumer, Alexander A1 - Cox, Amanda J A1 - Uitterlinden, André G A1 - Wong, Andrew A1 - Smit, Andries J A1 - Newman, Anne B A1 - Britton, Annie A1 - Ruusalepp, Arno A1 - Sennblad, Bengt A1 - Hedblad, Bo A1 - Pasaniuc, Bogdan A1 - Penninx, Brenda W A1 - Langefeld, Carl D A1 - Wassel, Christina L A1 - Tzourio, Christophe A1 - Fava, Cristiano A1 - Baldassarre, Damiano A1 - O'Leary, Daniel H A1 - Teupser, Daniel A1 - Kuh, Diana A1 - Tremoli, Elena A1 - Mannarino, Elmo A1 - Grossi, Enzo A1 - Boerwinkle, Eric A1 - Schadt, Eric E A1 - Ingelsson, Erik A1 - Veglia, Fabrizio A1 - Rivadeneira, Fernando A1 - Beutner, Frank A1 - Chauhan, Ganesh A1 - Heiss, Gerardo A1 - Snieder, Harold A1 - Campbell, Harry A1 - Völzke, Henry A1 - Markus, Hugh S A1 - Deary, Ian J A1 - Jukema, J Wouter A1 - de Graaf, Jacqueline A1 - Price, Jacqueline A1 - Pott, Janne A1 - Hopewell, Jemma C A1 - Liang, Jingjing A1 - Thiery, Joachim A1 - Engmann, Jorgen A1 - Gertow, Karl A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Dhana, Klodian A1 - Kiemeney, Lambertus A L M A1 - Lind, Lars A1 - Raffield, Laura M A1 - Launer, Lenore J A1 - Holdt, Lesca M A1 - Dörr, Marcus A1 - Dichgans, Martin A1 - Traylor, Matthew A1 - Sitzer, Matthias A1 - Kumari, Meena A1 - Kivimaki, Mika A1 - Nalls, Mike A A1 - Melander, Olle A1 - Raitakari, Olli A1 - Franco, Oscar H A1 - Rueda-Ochoa, Oscar L A1 - Roussos, Panos A1 - Whincup, Peter H A1 - Amouyel, Philippe A1 - Giral, Philippe A1 - Anugu, Pramod A1 - Wong, Quenna A1 - Malik, Rainer A1 - Rauramaa, Rainer A1 - Burkhardt, Ralph A1 - Hardy, Rebecca A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Morris, Richard W A1 - Strawbridge, Rona J A1 - Wannamethee, S Goya A1 - Hägg, Sara A1 - Shah, Sonia A1 - McLachlan, Stela A1 - Trompet, Stella A1 - Seshadri, Sudha A1 - Kurl, Sudhir A1 - Heckbert, Susan R A1 - Ring, Susan A1 - Harris, Tamara B A1 - Lehtimäki, Terho A1 - Galesloot, Tessel E A1 - Shah, Tina A1 - de Faire, Ulf A1 - Plagnol, Vincent A1 - Rosamond, Wayne D A1 - Post, Wendy A1 - Zhu, Xiaofeng A1 - Zhang, Xiaoling A1 - Guo, Xiuqing A1 - Saba, Yasaman A1 - Dehghan, Abbas A1 - Seldenrijk, Adrie A1 - Morrison, Alanna C A1 - Hamsten, Anders A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Lawlor, Deborah A A1 - Mook-Kanamori, Dennis O A1 - Bowden, Donald W A1 - Schmidt, Helena A1 - Wilson, James F A1 - Wilson, James G A1 - Rotter, Jerome I A1 - Wardlaw, Joanna M A1 - Deanfield, John A1 - Halcox, Julian A1 - Lyytikäinen, Leo-Pekka A1 - Loeffler, Markus A1 - Evans, Michele K A1 - Debette, Stephanie A1 - Humphries, Steve E A1 - Völker, Uwe A1 - Gudnason, Vilmundur A1 - Hingorani, Aroon D A1 - Björkegren, Johan L M A1 - Casas, Juan P A1 - O'Donnell, Christopher J KW - ADAMTS9 Protein KW - Amino Acid Oxidoreductases KW - Carotid Intima-Media Thickness KW - Coronary Disease KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Lod Score KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors AB -

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

VL - 9 IS - 1 ER - TY - JOUR T1 - Meta-analysis of exome array data identifies six novel genetic loci for lung function. JF - Wellcome Open Res Y1 - 2018 A1 - Jackson, Victoria E A1 - Latourelle, Jeanne C A1 - Wain, Louise V A1 - Smith, Albert V A1 - Grove, Megan L A1 - Bartz, Traci M A1 - Obeidat, Ma'en A1 - Province, Michael A A1 - Gao, Wei A1 - Qaiser, Beenish A1 - Porteous, David J A1 - Cassano, Patricia A A1 - Ahluwalia, Tarunveer S A1 - Grarup, Niels A1 - Li, Jin A1 - Altmaier, Elisabeth A1 - Marten, Jonathan A1 - Harris, Sarah E A1 - Manichaikul, Ani A1 - Pottinger, Tess D A1 - Li-Gao, Ruifang A1 - Lind-Thomsen, Allan A1 - Mahajan, Anubha A1 - Lahousse, Lies A1 - Imboden, Medea A1 - Teumer, Alexander A1 - Prins, Bram A1 - Lyytikäinen, Leo-Pekka A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Sitlani, Colleen M A1 - Brody, Jennifer A A1 - Bossé, Yohan A1 - Timens, Wim A1 - Kraja, Aldi A1 - Loukola, Anu A1 - Tang, Wenbo A1 - Liu, Yongmei A1 - Bork-Jensen, Jette A1 - Justesen, Johanne M A1 - Linneberg, Allan A1 - Lange, Leslie A A1 - Rawal, Rajesh A1 - Karrasch, Stefan A1 - Huffman, Jennifer E A1 - Smith, Blair H A1 - Davies, Gail A1 - Burkart, Kristin M A1 - Mychaleckyj, Josyf C A1 - Bonten, Tobias N A1 - Enroth, Stefan A1 - Lind, Lars A1 - Brusselle, Guy G A1 - Kumar, Ashish A1 - Stubbe, Beate A1 - Kähönen, Mika A1 - Wyss, Annah B A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Hao, Ke A1 - Rantanen, Taina A1 - Kritchevsky, Stephen B A1 - Lohman, Kurt A1 - Skaaby, Tea A1 - Pisinger, Charlotta A1 - Hansen, Torben A1 - Schulz, Holger A1 - Polasek, Ozren A1 - Campbell, Archie A1 - Starr, John M A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Johansson, Asa A1 - Ingelsson, Erik A1 - Uitterlinden, André G A1 - Weiss, Stefan A1 - Raitakari, Olli T A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Gharib, Sina A A1 - Sin, Don D A1 - Taylor, Kent D A1 - O'Connor, George T A1 - Kaprio, Jaakko A1 - Harris, Tamara B A1 - Pederson, Oluf A1 - Vestergaard, Henrik A1 - Wilson, James G A1 - Strauch, Konstantin A1 - Hayward, Caroline A1 - Kerr, Shona A1 - Deary, Ian J A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Gyllensten, Ulf A1 - Morris, Andrew P A1 - Ikram, M Arfan A1 - Probst-Hensch, Nicole A1 - Gläser, Sven A1 - Zeggini, Eleftheria A1 - Lehtimäki, Terho A1 - Strachan, David P A1 - Dupuis, Josée A1 - Morrison, Alanna C A1 - Hall, Ian P A1 - Tobin, Martin D A1 - London, Stephanie J AB -

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

VL - 3 ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

VL - 50 IS - 4 ER - TY - JOUR T1 - Multi-ethnic genome-wide association study for atrial fibrillation. JF - Nat Genet Y1 - 2018 A1 - Roselli, Carolina A1 - Chaffin, Mark D A1 - Weng, Lu-Chen A1 - Aeschbacher, Stefanie A1 - Ahlberg, Gustav A1 - Albert, Christine M A1 - Almgren, Peter A1 - Alonso, Alvaro A1 - Anderson, Christopher D A1 - Aragam, Krishna G A1 - Arking, Dan E A1 - Barnard, John A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Bihlmeyer, Nathan A A1 - Bis, Joshua C A1 - Bloom, Heather L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin B A1 - Brody, Jennifer A A1 - Calkins, Hugh A1 - Campbell, Archie A1 - Cappola, Thomas P A1 - Carlquist, John A1 - Chasman, Daniel I A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Choi, Eue-Keun A1 - Choi, Seung Hoan A1 - Christophersen, Ingrid E A1 - Chung, Mina K A1 - Cole, John W A1 - Conen, David A1 - Cook, James A1 - Crijns, Harry J A1 - Cutler, Michael J A1 - Damrauer, Scott M A1 - Daniels, Brian R A1 - Darbar, Dawood A1 - Delgado, Graciela A1 - Denny, Joshua C A1 - Dichgans, Martin A1 - Dörr, Marcus A1 - Dudink, Elton A A1 - Dudley, Samuel C A1 - Esa, Nada A1 - Esko, Tõnu A1 - Eskola, Markku A1 - Fatkin, Diane A1 - Felix, Stephan B A1 - Ford, Ian A1 - Franco, Oscar H A1 - Geelhoed, Bastiaan A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Gustafsson, Stefan A1 - Gutmann, Rebecca A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hernesniemi, Jussi A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Horimoto, Andrea R V R A1 - Huang, Jie A1 - Huang, Paul L A1 - Huffman, Jennifer A1 - Ingelsson, Erik A1 - Ipek, Esra Gucuk A1 - Ito, Kaoru A1 - Jimenez-Conde, Jordi A1 - Johnson, Renee A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kane, John P A1 - Kastrati, Adnan A1 - Kathiresan, Sekar A1 - Katschnig-Winter, Petra A1 - Kavousi, Maryam A1 - Kessler, Thorsten A1 - Kietselaer, Bas L A1 - Kirchhof, Paulus A1 - Kleber, Marcus E A1 - Knight, Stacey A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Laurikka, Jari A1 - Lehtimäki, Terho A1 - Leineweber, Kirsten A1 - Lemaitre, Rozenn N A1 - Li, Man A1 - Lim, Hong Euy A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lokki, Marja-Liisa A1 - London, Barry A1 - Loos, Ruth J F A1 - Low, Siew-Kee A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Macfarlane, Peter W A1 - Magnusson, Patrik K A1 - Mahajan, Anubha A1 - Malik, Rainer A1 - Mansur, Alfredo J A1 - Marcus, Gregory M A1 - Margolin, Lauren A1 - Margulies, Kenneth B A1 - März, Winfried A1 - McManus, David D A1 - Melander, Olle A1 - Mohanty, Sanghamitra A1 - Montgomery, Jay A A1 - Morley, Michael P A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Natale, Andrea A1 - Nazarian, Saman A1 - Neumann, Benjamin A1 - Newton-Cheh, Christopher A1 - Niemeijer, Maartje N A1 - Nikus, Kjell A1 - Nilsson, Peter A1 - Noordam, Raymond A1 - Oellers, Heidi A1 - Olesen, Morten S A1 - Orho-Melander, Marju A1 - Padmanabhan, Sandosh A1 - Pak, Hui-Nam A1 - Paré, Guillaume A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Pereira, Alexandre A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Pullinger, Clive R A1 - Rader, Daniel J A1 - Refsgaard, Lena A1 - Ribasés, Marta A1 - Ridker, Paul M A1 - Rienstra, Michiel A1 - Risch, Lorenz A1 - Roden, Dan M A1 - Rosand, Jonathan A1 - Rosenberg, Michael A A1 - Rost, Natalia A1 - Rotter, Jerome I A1 - Saba, Samir A1 - Sandhu, Roopinder K A1 - Schnabel, Renate B A1 - Schramm, Katharina A1 - Schunkert, Heribert A1 - Schurman, Claudia A1 - Scott, Stuart A A1 - Seppälä, Ilkka A1 - Shaffer, Christian A1 - Shah, Svati A1 - Shalaby, Alaa A A1 - Shim, Jaemin A1 - Shoemaker, M Benjamin A1 - Siland, Joylene E A1 - Sinisalo, Juha A1 - Sinner, Moritz F A1 - Slowik, Agnieszka A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, J Gustav A1 - Smith, Jonathan D A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Sun, Albert A1 - Sun, Han A1 - Svendsen, Jesper H A1 - Tanaka, Toshihiro A1 - Tanriverdi, Kahraman A1 - Taylor, Kent D A1 - Teder-Laving, Maris A1 - Teumer, Alexander A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Tucker, Nathan R A1 - Tveit, Arnljot A1 - Uitterlinden, André G A1 - van der Harst, Pim A1 - Van Gelder, Isabelle C A1 - Van Wagoner, David R A1 - Verweij, Niek A1 - Vlachopoulou, Efthymia A1 - Völker, Uwe A1 - Wang, Biqi A1 - Weeke, Peter E A1 - Weijs, Bob A1 - Weiss, Raul A1 - Weiss, Stefan A1 - Wells, Quinn S A1 - Wiggins, Kerri L A1 - Wong, Jorge A A1 - Woo, Daniel A1 - Worrall, Bradford B A1 - Yang, Pil-Sung A1 - Yao, Jie A1 - Yoneda, Zachary T A1 - Zeller, Tanja A1 - Zeng, Lingyao A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T AB -

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.

VL - 50 IS - 9 ER - TY - JOUR T1 - Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration. JF - PLoS One Y1 - 2018 A1 - Lorenz, Matthias W A1 - Gao, Lu A1 - Ziegelbauer, Kathrin A1 - Norata, Giuseppe Danilo A1 - Empana, Jean Philippe A1 - Schmidtmann, Irene A1 - Lin, Hung-Ju A1 - McLachlan, Stela A1 - Bokemark, Lena A1 - Ronkainen, Kimmo A1 - Amato, Mauro A1 - Schminke, Ulf A1 - Srinivasan, Sathanur R A1 - Lind, Lars A1 - Okazaki, Shuhei A1 - Stehouwer, Coen D A A1 - Willeit, Peter A1 - Polak, Joseph F A1 - Steinmetz, Helmuth A1 - Sander, Dirk A1 - Poppert, Holger A1 - Desvarieux, Moïse A1 - Ikram, M Arfan A1 - Johnsen, Stein Harald A1 - Staub, Daniel A1 - Sirtori, Cesare R A1 - Iglseder, Bernhard A1 - Beloqui, Oscar A1 - Engström, Gunnar A1 - Friera, Alfonso A1 - Rozza, Francesco A1 - Xie, Wuxiang A1 - Parraga, Grace A1 - Grigore, Liliana A1 - Plichart, Matthieu A1 - Blankenberg, Stefan A1 - Su, Ta-Chen A1 - Schmidt, Caroline A1 - Tuomainen, Tomi-Pekka A1 - Veglia, Fabrizio A1 - Völzke, Henry A1 - Nijpels, Giel A1 - Willeit, Johann A1 - Sacco, Ralph L A1 - Franco, Oscar H A1 - Uthoff, Heiko A1 - Hedblad, Bo A1 - Suarez, Carmen A1 - Izzo, Raffaele A1 - Zhao, Dong A1 - Wannarong, Thapat A1 - Catapano, Alberico A1 - Ducimetiere, Pierre A1 - Espinola-Klein, Christine A1 - Chien, Kuo-Liong A1 - Price, Jackie F A1 - Bergström, Göran A1 - Kauhanen, Jussi A1 - Tremoli, Elena A1 - Dörr, Marcus A1 - Berenson, Gerald A1 - Kitagawa, Kazuo A1 - Dekker, Jacqueline M A1 - Kiechl, Stefan A1 - Sitzer, Matthias A1 - Bickel, Horst A1 - Rundek, Tatjana A1 - Hofman, Albert A1 - Mathiesen, Ellisiv B A1 - Castelnuovo, Samuela A1 - Landecho, Manuel F A1 - Rosvall, Maria A1 - Gabriel, Rafael A1 - de Luca, Nicola A1 - Liu, Jing A1 - Baldassarre, Damiano A1 - Kavousi, Maryam A1 - de Groot, Eric A1 - Bots, Michiel L A1 - Yanez, David N A1 - Thompson, Simon G KW - Aged KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Female KW - Humans KW - Intersectoral Collaboration KW - Male KW - Middle Aged KW - Prognosis KW - Risk Factors AB -

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.

METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C.

CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

VL - 13 IS - 4 ER - TY - JOUR T1 - Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. JF - Nat Genet Y1 - 2018 A1 - Mahajan, Anubha A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Zhao, Wei A1 - Robertson, Neil R A1 - Chu, Audrey Y A1 - Gan, Wei A1 - Kitajima, Hidetoshi A1 - Taliun, Daniel A1 - Rayner, N William A1 - Guo, Xiuqing A1 - Lu, Yingchang A1 - Li, Man A1 - Jensen, Richard A A1 - Hu, Yao A1 - Huo, Shaofeng A1 - Lohman, Kurt K A1 - Zhang, Weihua A1 - Cook, James P A1 - Prins, Bram Peter A1 - Flannick, Jason A1 - Grarup, Niels A1 - Trubetskoy, Vassily Vladimirovich A1 - Kravic, Jasmina A1 - Kim, Young Jin A1 - Rybin, Denis V A1 - Yaghootkar, Hanieh A1 - Müller-Nurasyid, Martina A1 - Meidtner, Karina A1 - Li-Gao, Ruifang A1 - Varga, Tibor V A1 - Marten, Jonathan A1 - Li, Jin A1 - Smith, Albert Vernon A1 - An, Ping A1 - Ligthart, Symen A1 - Gustafsson, Stefan A1 - Malerba, Giovanni A1 - Demirkan, Ayse A1 - Tajes, Juan Fernandez A1 - Steinthorsdottir, Valgerdur A1 - Wuttke, Matthias A1 - Lecoeur, Cécile A1 - Preuss, Michael A1 - Bielak, Lawrence F A1 - Graff, Marielisa A1 - Highland, Heather M A1 - Justice, Anne E A1 - Liu, Dajiang J A1 - Marouli, Eirini A1 - Peloso, Gina Marie A1 - Warren, Helen R A1 - Afaq, Saima A1 - Afzal, Shoaib A1 - Ahlqvist, Emma A1 - Almgren, Peter A1 - Amin, Najaf A1 - Bang, Lia B A1 - Bertoni, Alain G A1 - Bombieri, Cristina A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Burtt, Noel P A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Cho, Yoon Shin A1 - Christensen, Cramer A1 - Eastwood, Sophie V A1 - Eckardt, Kai-Uwe A1 - Fischer, Krista A1 - Gambaro, Giovanni A1 - Giedraitis, Vilmantas A1 - Grove, Megan L A1 - de Haan, Hugoline G A1 - Hackinger, Sophie A1 - Hai, Yang A1 - Han, Sohee A1 - Tybjærg-Hansen, Anne A1 - Hivert, Marie-France A1 - Isomaa, Bo A1 - Jäger, Susanne A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Käräjämäki, AnneMari A1 - Kim, Bong-Jo A1 - Kim, Sung Soo A1 - Koistinen, Heikki A A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Jung-Jin A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Lin, Keng-Hung A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jun A1 - Loh, Marie A1 - Mägi, Reedik A1 - Mamakou, Vasiliki A1 - McKean-Cowdin, Roberta A1 - Nadkarni, Girish A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Ntalla, Ioanna A1 - Peyser, Patricia A A1 - Rathmann, Wolfgang A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Rode, Line A1 - Rolandsson, Olov A1 - Schönherr, Sebastian A1 - Selvin, Elizabeth A1 - Small, Kerrin S A1 - Stančáková, Alena A1 - Surendran, Praveen A1 - Taylor, Kent D A1 - Teslovich, Tanya M A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tin, Adrienne A1 - Tönjes, Anke A1 - Varbo, Anette A1 - Witte, Daniel R A1 - Wood, Andrew R A1 - Yajnik, Pranav A1 - Yao, Jie A1 - Yengo, Loic A1 - Young, Robin A1 - Amouyel, Philippe A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Chowdhury, Rajiv A1 - Collins, Francis S A1 - Dedoussis, George A1 - Dehghan, Abbas A1 - Deloukas, Panos A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Florez, Jose C A1 - Frossard, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Howson, Joanna M M A1 - Ingelsson, Martin A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lindgren, Cecilia M A1 - Männistö, Satu A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Moitry, Marie A1 - Morris, Andrew D A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Orho-Melander, Marju A1 - Owen, Katharine R A1 - Perola, Markus A1 - Peters, Annette A1 - Province, Michael A A1 - Rasheed, Asif A1 - Ridker, Paul M A1 - Rivadineira, Fernando A1 - Rosendaal, Frits R A1 - Rosengren, Anders H A1 - Salomaa, Veikko A1 - Sheu, Wayne H-H A1 - Sladek, Rob A1 - Smith, Blair H A1 - Strauch, Konstantin A1 - Uitterlinden, André G A1 - Varma, Rohit A1 - Willer, Cristen J A1 - Blüher, Matthias A1 - Butterworth, Adam S A1 - Chambers, John Campbell A1 - Chasman, Daniel I A1 - Danesh, John A1 - van Duijn, Cornelia A1 - Dupuis, Josée A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Grallert, Harald A1 - Groop, Leif A1 - Han, Bok-Ghee A1 - Hansen, Torben A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Ingelsson, Erik A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal Singh A1 - Köttgen, Anna A1 - Kuulasmaa, Kari A1 - Laakso, Markku A1 - Lin, Xu A1 - Lind, Lars A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Marchini, Jonathan A1 - Metspalu, Andres A1 - Mook-Kanamori, Dennis A1 - Nordestgaard, Børge G A1 - Palmer, Colin N A A1 - Pankow, James S A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Rauramaa, Rainer A1 - Sattar, Naveed A1 - Schulze, Matthias B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Stumvoll, Michael A1 - Thorsteinsdottir, Unnur A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Zeggini, Eleftheria A1 - Scott, Robert A A1 - Barroso, Inês A1 - Frayling, Timothy M A1 - Goodarzi, Mark O A1 - Meigs, James B A1 - Boehnke, Michael A1 - Saleheen, Danish A1 - Morris, Andrew P A1 - Rotter, Jerome I A1 - McCarthy, Mark I AB -

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

VL - 50 IS - 4 ER - TY - JOUR T1 - Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality. JF - Circulation Y1 - 2019 A1 - Marklund, Matti A1 - Wu, Jason H Y A1 - Imamura, Fumiaki A1 - Del Gobbo, Liana C A1 - Fretts, Amanda A1 - de Goede, Janette A1 - Shi, Peilin A1 - Tintle, Nathan A1 - Wennberg, Maria A1 - Aslibekyan, Stella A1 - Chen, Tzu-An A1 - de Oliveira Otto, Marcia C A1 - Hirakawa, Yoichiro A1 - Eriksen, Helle Højmark A1 - Kröger, Janine A1 - Laguzzi, Federica A1 - Lankinen, Maria A1 - Murphy, Rachel A A1 - Prem, Kiesha A1 - Samieri, Cecilia A1 - Virtanen, Jyrki A1 - Wood, Alexis C A1 - Wong, Kerry A1 - Yang, Wei-Sin A1 - Zhou, Xia A1 - Baylin, Ana A1 - Boer, Jolanda M A A1 - Brouwer, Ingeborg A A1 - Campos, Hannia A1 - Chaves, Paulo H M A1 - Chien, Kuo-Liong A1 - de Faire, Ulf A1 - Djoussé, Luc A1 - Eiriksdottir, Gudny A1 - El-Abbadi, Naglaa A1 - Forouhi, Nita G A1 - Michael Gaziano, J A1 - Geleijnse, Johanna M A1 - Gigante, Bruna A1 - Giles, Graham A1 - Guallar, Eliseo A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Harris, William S A1 - Helmer, Catherine A1 - Hellenius, Mai-Lis A1 - Hodge, Allison A1 - Hu, Frank B A1 - Jacques, Paul F A1 - Jansson, Jan-Håkan A1 - Kalsbeek, Anya A1 - Khaw, Kay-Tee A1 - Koh, Woon-Puay A1 - Laakso, Markku A1 - Leander, Karin A1 - Lin, Hung-Ju A1 - Lind, Lars A1 - Luben, Robert A1 - Luo, Juhua A1 - McKnight, Barbara A1 - Mursu, Jaakko A1 - Ninomiya, Toshiharu A1 - Overvad, Kim A1 - Psaty, Bruce M A1 - Rimm, Eric A1 - Schulze, Matthias B A1 - Siscovick, David A1 - Skjelbo Nielsen, Michael A1 - Smith, Albert V A1 - Steffen, Brian T A1 - Steffen, Lyn A1 - Sun, Qi A1 - Sundström, Johan A1 - Tsai, Michael Y A1 - Tunstall-Pedoe, Hugh A1 - Uusitupa, Matti I J A1 - van Dam, Rob M A1 - Veenstra, Jenna A1 - Monique Verschuren, W M A1 - Wareham, Nick A1 - Willett, Walter A1 - Woodward, Mark A1 - Yuan, Jian-Min A1 - Micha, Renata A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush A1 - Riserus, Ulf AB -

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.

METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).

RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.

CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

VL - 139 IS - 21 ER - TY - JOUR T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals. JF - Nat Genet Y1 - 2019 A1 - Wuttke, Matthias A1 - Li, Yong A1 - Li, Man A1 - Sieber, Karsten B A1 - Feitosa, Mary F A1 - Gorski, Mathias A1 - Tin, Adrienne A1 - Wang, Lihua A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - Kirsten, Holger A1 - Giri, Ayush A1 - Chai, Jin-Fang A1 - Sveinbjornsson, Gardar A1 - Tayo, Bamidele O A1 - Nutile, Teresa A1 - Fuchsberger, Christian A1 - Marten, Jonathan A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - Xu, Yizhe A1 - Horn, Katrin A1 - Noce, Damia A1 - van der Most, Peter J A1 - Sedaghat, Sanaz A1 - Yu, Zhi A1 - Akiyama, Masato A1 - Afaq, Saima A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boissel, Mathilde A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brenner, Hermann A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Butterworth, Adam S A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Canouil, Mickaël A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Chee, Miao-Ling A1 - Chee, Miao-Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cheng, Yurong A1 - Christensen, Kaare A1 - Cifkova, Renata A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Cook, James P A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Sala, Cinzia Felicita A1 - Cusi, Daniele A1 - Danesh, John A1 - Daw, E Warwick A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Degenhardt, Frauke A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Di Angelantonio, Emanuele A1 - Dittrich, Katalin A1 - Divers, Jasmin A1 - Dorajoo, Rajkumar A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Elliott, Paul A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Felix, Janine F A1 - Foo, Valencia Hui Xian A1 - Franco, Oscar H A1 - Franke, Andre A1 - Freedman, Barry I A1 - Freitag-Wolf, Sandra A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Gansevoort, Ron T A1 - Gao, He A1 - Gasparini, Paolo A1 - Gaziano, J Michael A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Giulianini, Franco A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Hellwege, Jacklyn N A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Indridason, Olafur S A1 - Ingelsson, Erik A1 - Ising, Marcus A1 - Jaddoe, Vincent W V A1 - Jakobsdottir, Johanna A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Kerr, Shona M A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - Kuokkanen, Mikko A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Lee, Jeannette Jen-Mai A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lim, Su-Chi A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Jun A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lucae, Susanne A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - Martins, Jade A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mikaelsdottir, Evgenia K A1 - Milaneschi, Yuri A1 - Miliku, Kozeta A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey A1 - O'Donoghue, Michelle L A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Orho-Melander, Marju A1 - Ouwehand, Willem H A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Palsson, Runolfur A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Perola, Markus A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Podgornaia, Anna I A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Pramstaller, Peter P A1 - Preuss, Michael H A1 - Prins, Bram P A1 - Province, Michael A A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rizzi, Federica A1 - Roberts, David J A1 - Robino, Antonietta A1 - Rossing, Peter A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Salvi, Erika A1 - Saum, Kai-Uwe A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Schupf, Nicole A1 - Shaffer, Christian M A1 - Shi, Yuan A1 - Smith, Albert V A1 - Smith, Blair H A1 - Soranzo, Nicole A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Svensson, Per O A1 - Szymczak, Silke A1 - Tai, E-Shyong A1 - Tajuddin, Salman M A1 - Tan, Nicholas Y Q A1 - Taylor, Kent D A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomsen, Hauke A1 - Thorleifsson, Gudmar A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Tzoulaki, Ioanna A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van Dam, Rob M A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Velez Edward, Digna R A1 - Verweij, Niek A1 - Vogelezang, Suzanne A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Waterworth, Dawn M A1 - Bin Wei, Wen A1 - White, Harvey A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Wojczynski, Mary K A1 - Wong, Charlene A1 - Wong, Tien-Yin A1 - Xu, Liang A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Rotter, Jerome I A1 - Bochud, Murielle A1 - Psaty, Bruce M A1 - Vitart, Veronique A1 - Wilson, James G A1 - Dehghan, Abbas A1 - Parsa, Afshin A1 - Chasman, Daniel I A1 - Ho, Kevin A1 - Morris, Andrew P A1 - Devuyst, Olivier A1 - Akilesh, Shreeram A1 - Pendergrass, Sarah A A1 - Sim, Xueling A1 - Böger, Carsten A A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Snieder, Harold A1 - Stefansson, Kari A1 - Hung, Adriana M A1 - Heid, Iris M A1 - Scholz, Markus A1 - Teumer, Alexander A1 - Köttgen, Anna A1 - Pattaro, Cristian KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inheritance Patterns KW - Kidney Function Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Renal Insufficiency, Chronic KW - Uromodulin AB -

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

VL - 51 IS - 6 ER - TY - JOUR T1 - Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation. JF - Circ Genom Precis Med Y1 - 2019 A1 - Dörr, Marcus A1 - Hamburg, Naomi M A1 - Müller, Christian A1 - Smith, Nicholas L A1 - Gustafsson, Stefan A1 - Lehtimäki, Terho A1 - Teumer, Alexander A1 - Zeller, Tanja A1 - Li, Xiaohui A1 - Lind, Lars A1 - Raitakari, Olli T A1 - Völker, Uwe A1 - Blankenberg, Stefan A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Kähönen, Mika A1 - Lemaitre, Rozenn N A1 - Wild, Philipp S A1 - Nauck, Matthias A1 - Völzke, Henry A1 - Münzel, Thomas A1 - Mitchell, Gary F A1 - Psaty, Bruce M A1 - Lindgren, Cecilia M A1 - Larson, Martin G A1 - Felix, Stephan B A1 - Ingelsson, Erik A1 - Lyytikäinen, Leo-Pekka A1 - Herrington, David A1 - Benjamin, Emelia J A1 - Schnabel, Renate B VL - 12 IS - 2 ER - TY - JOUR T1 - Disentangling the genetics of lean mass. JF - Am J Clin Nutr Y1 - 2019 A1 - Karasik, David A1 - Zillikens, M Carola A1 - Hsu, Yi-Hsiang A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Bochud, Murielle A1 - Borecki, Ingrid B A1 - Broer, Linda A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos-Obando, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Chambers, John C A1 - Chen, Zhao A1 - Cho, Nam H A1 - Choi, Hyung Jin A1 - Chou, Wen-Chi A1 - Cummings, Steven R A1 - de Groot, Lisette C P G M A1 - De Jager, Phillip L A1 - Demuth, Ilja A1 - Diatchenko, Luda A1 - Econs, Michael J A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Eriksson, Joel A1 - Eriksson, Johan G A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Gieger, Christian A1 - Grallert, Harald A1 - Gudnason, Vilmundur A1 - Lenore, Launer J A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Homuth, Georg A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Johnson, Toby A1 - Biffar, Reiner A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koller, Daniel L A1 - Kooner, Jaspal S A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kutalik, Zoltán A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lill, Christina A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Livshits, Gregory A1 - Ljunggren, Osten A1 - Loos, Ruth J F A1 - Lorentzon, Mattias A1 - Luan, Jian'an A1 - Luben, Robert N A1 - Malkin, Ida A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Nethander, Maria A1 - Newman, Anne B A1 - O'Connell, Jeffery R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Prince, Richard L A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schipf, Sabine A1 - Shin, Chan Soo A1 - Smith, Albert V A1 - Smith, Shad B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stančáková, Alena A1 - Stefansson, Kari A1 - Steinhagen-Thiessen, Elisabeth A1 - Stolk, Lisette A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - van Schoor, Natasja M A1 - Vandenput, Liesbeth A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - J Wareham, Nicholas A1 - Waterworth, Dawn A1 - Weedon, Michael N A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Yerges-Armstrong, Laura M A1 - Yu, Lei A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Zhou, Yanhua A1 - Nielson, Carrie M A1 - Harris, Tamara B A1 - Demissie, Serkalem A1 - Kiel, Douglas P A1 - Ohlsson, Claes AB -

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

VL - 109 IS - 2 ER - TY - JOUR T1 - Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. JF - Diabetes Y1 - 2020 A1 - Yaghootkar, Hanieh A1 - Zhang, Yiying A1 - Spracklen, Cassandra N A1 - Karaderi, Tugce A1 - Huang, Lam Opal A1 - Bradfield, Jonathan A1 - Schurmann, Claudia A1 - Fine, Rebecca S A1 - Preuss, Michael H A1 - Kutalik, Zoltán A1 - Wittemans, Laura Bl A1 - Lu, Yingchang A1 - Metz, Sophia A1 - Willems, Sara M A1 - Li-Gao, Ruifang A1 - Grarup, Niels A1 - Wang, Shuai A1 - Molnos, Sophie A1 - Sandoval-Zárate, América A A1 - Nalls, Mike A A1 - Lange, Leslie A A1 - Haesser, Jeffrey A1 - Guo, Xiuqing A1 - Lyytikäinen, Leo-Pekka A1 - Feitosa, Mary F A1 - Sitlani, Colleen M A1 - Venturini, Cristina A1 - Mahajan, Anubha A1 - Kacprowski, Tim A1 - Wang, Carol A A1 - Chasman, Daniel I A1 - Amin, Najaf A1 - Broer, Linda A1 - Robertson, Neil A1 - Young, Kristin L A1 - Allison, Matthew A1 - Auer, Paul L A1 - Blüher, Matthias A1 - Borja, Judith B A1 - Bork-Jensen, Jette A1 - Carrasquilla, Germán D A1 - Christofidou, Paraskevi A1 - Demirkan, Ayse A1 - Doege, Claudia A A1 - Garcia, Melissa E A1 - Graff, Mariaelisa A1 - Guo, Kaiying A1 - Hakonarson, Hakon A1 - Hong, Jaeyoung A1 - Ida Chen, Yii-Der A1 - Jackson, Rebecca A1 - Jakupović, Hermina A1 - Jousilahti, Pekka A1 - Justice, Anne E A1 - Kähönen, Mika A1 - Kizer, Jorge R A1 - Kriebel, Jennifer A1 - LeDuc, Charles A A1 - Li, Jin A1 - Lind, Lars A1 - Luan, Jian'an A1 - Mackey, David A1 - Mangino, Massimo A1 - Männistö, Satu A1 - Martin Carli, Jayne F A1 - Medina-Gómez, Carolina A1 - Mook-Kanamori, Dennis O A1 - Morris, Andrew P A1 - de Mutsert, Renée A1 - Nauck, Matthias A1 - Nedeljkovic, Ivana A1 - Pennell, Craig E A1 - Pradhan, Arund D A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Scott, Robert A A1 - Skaaby, Tea A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Wu, Ying A1 - Yao, Jie A1 - Walker, Mark A1 - North, Kari E A1 - Kovacs, Peter A1 - Ikram, M Arfan A1 - van Duijn, Cornelia M A1 - Ridker, Paul M A1 - Lye, Stephen A1 - Homuth, Georg A1 - Ingelsson, Erik A1 - Spector, Tim D A1 - McKnight, Barbara A1 - Province, Michael A A1 - Lehtimäki, Terho A1 - Adair, Linda S A1 - Rotter, Jerome I A1 - Reiner, Alexander P A1 - Wilson, James G A1 - Harris, Tamara B A1 - Ripatti, Samuli A1 - Grallert, Harald A1 - Meigs, James B A1 - Salomaa, Veikko A1 - Hansen, Torben A1 - Willems van Dijk, Ko A1 - Wareham, Nicholas J A1 - Grant, Struan Fa A1 - Langenberg, Claudia A1 - Frayling, Timothy M A1 - Lindgren, Cecilia M A1 - Mohlke, Karen L A1 - Leibel, Rudolph L A1 - Loos, Ruth Jf A1 - Kilpeläinen, Tuomas O AB -

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

ER - TY - JOUR T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. JF - Nat Commun Y1 - 2020 A1 - Ntalla, Ioanna A1 - Weng, Lu-Chen A1 - Cartwright, James H A1 - Hall, Amelia Weber A1 - Sveinbjornsson, Gardar A1 - Tucker, Nathan R A1 - Choi, Seung Hoan A1 - Chaffin, Mark D A1 - Roselli, Carolina A1 - Barnes, Michael R A1 - Mifsud, Borbala A1 - Warren, Helen R A1 - Hayward, Caroline A1 - Marten, Jonathan A1 - Cranley, James J A1 - Concas, Maria Pina A1 - Gasparini, Paolo A1 - Boutin, Thibaud A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Araujo, Nathalia M A1 - Lima-Costa, Maria Fernanda A1 - Ribeiro, Antonio Luiz P A1 - Souza, Renan P A1 - Tarazona-Santos, Eduardo A1 - Giedraitis, Vilmantas A1 - Ingelsson, Erik A1 - Mahajan, Anubha A1 - Morris, Andrew P A1 - del Greco M, Fabiola A1 - Foco, Luisa A1 - Gögele, Martin A1 - Hicks, Andrew A A1 - Cook, James P A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Sundström, Johan A1 - Nelson, Christopher P A1 - Riaz, Muhammad B A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Ulivi, Sheila A1 - Kähönen, Mika A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Nikus, Kjell A1 - Caulfield, Mark J A1 - Dominiczak, Anna A1 - Padmanabhan, Sandosh A1 - Montasser, May E A1 - O'Connell, Jeff R A1 - Ryan, Kathleen A1 - Shuldiner, Alan R A1 - Aeschbacher, Stefanie A1 - Conen, David A1 - Risch, Lorenz A1 - Thériault, Sébastien A1 - Hutri-Kähönen, Nina A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Raitakari, Olli T A1 - Barnes, Catriona L K A1 - Campbell, Harry A1 - Joshi, Peter K A1 - Wilson, James F A1 - Isaacs, Aaron A1 - Kors, Jan A A1 - van Duijn, Cornelia M A1 - Huang, Paul L A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Nadkarni, Girish N A1 - Preuss, Michael H A1 - Correa, Adolfo A1 - Mei, Hao A1 - Wilson, James A1 - Meitinger, Thomas A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Rienstra, Michiel A1 - van de Vegte, Yordi J A1 - van der Harst, Pim A1 - Verweij, Niek A1 - Kääb, Stefan A1 - Schramm, Katharina A1 - Sinner, Moritz F A1 - Strauch, Konstantin A1 - Cutler, Michael J A1 - Fatkin, Diane A1 - London, Barry A1 - Olesen, Morten A1 - Roden, Dan M A1 - Benjamin Shoemaker, M A1 - Gustav Smith, J A1 - Biggs, Mary L A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Sotoodehnia, Nona A1 - De Grandi, Alessandro A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Ford, Ian A1 - Wouter Jukema, J A1 - Macfarlane, Peter W A1 - Trompet, Stella A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Völker, Uwe A1 - Weiss, Stefan A1 - Havulinna, Aki S A1 - Jula, Antti A1 - Sääksjärvi, Katri A1 - Salomaa, Veikko A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Lin, Henry J A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Yao, Jie A1 - de Mutsert, Renée A1 - Maan, Arie C A1 - Mook-Kanamori, Dennis O A1 - Noordam, Raymond A1 - Cucca, Francesco A1 - Ding, Jun A1 - Lakatta, Edward G A1 - Qian, Yong A1 - Tarasov, Kirill V A1 - Levy, Daniel A1 - Lin, Honghuang A1 - Newton-Cheh, Christopher H A1 - Lunetta, Kathryn L A1 - Murray, Alison D A1 - Porteous, David J A1 - Smith, Blair H A1 - Stricker, Bruno H A1 - Uitterlinden, Andre A1 - van den Berg, Marten E A1 - Haessler, Jeffrey A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Peters, Ulrike A1 - Reiner, Alexander P A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Gogarten, Stephanie M A1 - Kerr, Kathleen F A1 - Laurie, Cathy C A1 - Seyerle, Amanda A A1 - Stilp, Adrienne A1 - Assa, Solmaz A1 - Abdullah Said, M A1 - Yldau van der Ende, M A1 - Lambiase, Pier D A1 - Orini, Michele A1 - Ramirez, Julia A1 - Van Duijvenboden, Stefan A1 - Arnar, David O A1 - Gudbjartsson, Daniel F A1 - Holm, Hilma A1 - Sulem, Patrick A1 - Thorleifsson, Gudmar A1 - Thorolfsdottir, Rosa B A1 - Thorsteinsdottir, Unnur A1 - Benjamin, Emelia J A1 - Tinker, Andrew A1 - Stefansson, Kari A1 - Ellinor, Patrick T A1 - Jamshidi, Yalda A1 - Lubitz, Steven A A1 - Munroe, Patricia B AB -

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

VL - 11 IS - 1 ER - TY - JOUR T1 - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. JF - Nat Commun Y1 - 2021 A1 - Tin, Adrienne A1 - Schlosser, Pascal A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Yu, Zhi A1 - Weihs, Antoine A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Kuhns, Victoria L Halperin A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Bressler, Jan A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - Delgado, Graciela E A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Floyd, James S A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Gelber, Allan C A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Ladd-Acosta, Christine A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Lloyd-Jones, Donald M A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Völker, Uwe A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Waldenberger, Melanie A1 - Levy, Daniel A1 - Akilesh, Shreeram A1 - Woodward, Owen M A1 - Susztak, Katalin A1 - Teumer, Alexander A1 - Köttgen, Anna KW - Amino Acid Transport System y+ KW - Cohort Studies KW - CpG Islands KW - DNA Methylation KW - Epigenome KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Transport Proteins, Facilitative KW - Gout KW - Humans KW - Male KW - Uric Acid AB -

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

VL - 12 IS - 1 ER - TY - JOUR T1 - Meta-analyses identify DNA methylation associated with kidney function and damage. JF - Nat Commun Y1 - 2021 A1 - Schlosser, Pascal A1 - Tin, Adrienne A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Weihs, Antoine A1 - Yu, Zhi A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Chambers, John C A1 - Cole, Shelley A A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - de Klein, Niek A1 - Delgado, Graciela E A1 - Domingo-Relloso, Arce A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Evans, Kathryn L A1 - Floyd, James S A1 - Fornage, Myriam A1 - Franke, Lude A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kramer, Holly A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Liu, Yongmei A1 - Lloyd-Jones, Donald M A1 - Lohman, Kurt A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Navas-Acien, Ana A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Rosas, Sylvia E A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - Tellez-Plaza, Maria A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Verweij, Niek A1 - Walker, Rosie M A1 - Wielscher, Matthias A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Susztak, Katalin A1 - Köttgen, Anna A1 - Teumer, Alexander KW - Adult KW - Aged KW - CpG Islands KW - DNA Methylation KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Interferon Regulatory Factors KW - Kidney KW - Kidney Function Tests KW - LIM Domain Proteins KW - Male KW - Membrane Proteins KW - Middle Aged KW - Renal Insufficiency, Chronic KW - Transcription Factors AB -

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

VL - 12 IS - 1 ER - TY - JOUR T1 - Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. JF - Commun Biol Y1 - 2022 A1 - Winkler, Thomas W A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Rowan, Bryce X A1 - Stanzick, Kira J A1 - Thomas, Laurent F A1 - Tin, Adrienne A1 - Hoppmann, Anselm A1 - Chu, Audrey Y A1 - Tayo, Bamidele A1 - Thio, Chris H L A1 - Cusi, Daniele A1 - Chai, Jin-Fang A1 - Sieber, Karsten B A1 - Horn, Katrin A1 - Li, Man A1 - Scholz, Markus A1 - Cocca, Massimiliano A1 - Wuttke, Matthias A1 - van der Most, Peter J A1 - Yang, Qiong A1 - Ghasemi, Sahar A1 - Nutile, Teresa A1 - Li, Yong A1 - Pontali, Giulia A1 - Günther, Felix A1 - Dehghan, Abbas A1 - Correa, Adolfo A1 - Parsa, Afshin A1 - Feresin, Agnese A1 - de Vries, Aiko P J A1 - Zonderman, Alan B A1 - Smith, Albert V A1 - Oldehinkel, Albertine J A1 - De Grandi, Alessandro A1 - Rosenkranz, Alexander R A1 - Franke, Andre A1 - Teren, Andrej A1 - Metspalu, Andres A1 - Hicks, Andrew A A1 - Morris, Andrew P A1 - Tönjes, Anke A1 - Morgan, Anna A1 - Podgornaia, Anna I A1 - Peters, Annette A1 - Körner, Antje A1 - Mahajan, Anubha A1 - Campbell, Archie A1 - Freedman, Barry I A1 - Spedicati, Beatrice A1 - Ponte, Belen A1 - Schöttker, Ben A1 - Brumpton, Ben A1 - Banas, Bernhard A1 - Krämer, Bernhard K A1 - Jung, Bettina A1 - Åsvold, Bjørn Olav A1 - Smith, Blair H A1 - Ning, Boting A1 - Penninx, Brenda W J H A1 - Vanderwerff, Brett R A1 - Psaty, Bruce M A1 - Kammerer, Candace M A1 - Langefeld, Carl D A1 - Hayward, Caroline A1 - Spracklen, Cassandra N A1 - Robinson-Cohen, Cassianne A1 - Hartman, Catharina A A1 - Lindgren, Cecilia M A1 - Wang, Chaolong A1 - Sabanayagam, Charumathi A1 - Heng, Chew-Kiat A1 - Lanzani, Chiara A1 - Khor, Chiea-Chuen A1 - Cheng, Ching-Yu A1 - Fuchsberger, Christian A1 - Gieger, Christian A1 - Shaffer, Christian M A1 - Schulz, Christina-Alexandra A1 - Willer, Cristen J A1 - Chasman, Daniel I A1 - Gudbjartsson, Daniel F A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Czamara, Darina A1 - Porteous, David J A1 - Waterworth, Dawn M A1 - Mascalzoni, Deborah A1 - Mook-Kanamori, Dennis O A1 - Reilly, Dermot F A1 - Daw, E Warwick A1 - Hofer, Edith A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Tai, E-Shyong A1 - Catamo, Eulalia A1 - Rizzi, Federica A1 - Guo, Feng A1 - Rivadeneira, Fernando A1 - Guilianini, Franco A1 - Sveinbjornsson, Gardar A1 - Ehret, Georg A1 - Waeber, Gérard A1 - Biino, Ginevra A1 - Girotto, Giorgia A1 - Pistis, Giorgio A1 - Nadkarni, Girish N A1 - Delgado, Graciela E A1 - Montgomery, Grant W A1 - Snieder, Harold A1 - Campbell, Harry A1 - White, Harvey D A1 - Gao, He A1 - Stringham, Heather M A1 - Schmidt, Helena A1 - Li, Hengtong A1 - Brenner, Hermann A1 - Holm, Hilma A1 - Kirsten, Holgen A1 - Kramer, Holly A1 - Rudan, Igor A1 - Nolte, Ilja M A1 - Tzoulaki, Ioanna A1 - Olafsson, Isleifur A1 - Martins, Jade A1 - Cook, James P A1 - Wilson, James F A1 - Halbritter, Jan A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Kooner, Jaspal S A1 - Lee, Jeannette Jen-Mai A1 - O'Connell, Jeffrey A1 - Rotter, Jerome I A1 - Liu, Jianjun A1 - Xu, Jie A1 - Thiery, Joachim A1 - Arnlöv, Johan A1 - Kuusisto, Johanna A1 - Jakobsdottir, Johanna A1 - Tremblay, Johanne A1 - Chambers, John C A1 - Whitfield, John B A1 - Gaziano, John M A1 - Marten, Jonathan A1 - Coresh, Josef A1 - Jonas, Jost B A1 - Mychaleckyj, Josyf C A1 - Christensen, Kaare A1 - Eckardt, Kai-Uwe A1 - Mohlke, Karen L A1 - Endlich, Karlhans A1 - Dittrich, Katalin A1 - Ryan, Kathleen A A1 - Rice, Kenneth M A1 - Taylor, Kent D A1 - Ho, Kevin A1 - Nikus, Kjell A1 - Matsuda, Koichi A1 - Strauch, Konstantin A1 - Miliku, Kozeta A1 - Hveem, Kristian A1 - Lind, Lars A1 - Wallentin, Lars A1 - Yerges-Armstrong, Laura M A1 - Raffield, Laura M A1 - Phillips, Lawrence S A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Lange, Leslie A A1 - Citterio, Lorena A1 - Klaric, Lucija A1 - Ikram, M Arfan A1 - Ising, Marcus A1 - Kleber, Marcus E A1 - Francescatto, Margherita A1 - Concas, Maria Pina A1 - Ciullo, Marina A1 - Piratsu, Mario A1 - Orho-Melander, Marju A1 - Laakso, Markku A1 - Loeffler, Markus A1 - Perola, Markus A1 - de Borst, Martin H A1 - Gögele, Martin A1 - Bianca, Martina La A1 - Lukas, Mary Ann A1 - Feitosa, Mary F A1 - Biggs, Mary L A1 - Wojczynski, Mary K A1 - Kavousi, Maryam A1 - Kanai, Masahiro A1 - Akiyama, Masato A1 - Yasuda, Masayuki A1 - Nauck, Matthias A1 - Waldenberger, Melanie A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Boehnke, Michael A1 - Preuss, Michael H A1 - Stumvoll, Michael A1 - Province, Michael A A1 - Evans, Michele K A1 - O'Donoghue, Michelle L A1 - Kubo, Michiaki A1 - Kähönen, Mika A1 - Kastarinen, Mika A1 - Nalls, Mike A A1 - Kuokkanen, Mikko A1 - Ghanbari, Mohsen A1 - Bochud, Murielle A1 - Josyula, Navya Shilpa A1 - Martin, Nicholas G A1 - Tan, Nicholas Y Q A1 - Palmer, Nicholette D A1 - Pirastu, Nicola A1 - Schupf, Nicole A1 - Verweij, Niek A1 - Hutri-Kähönen, Nina A1 - Mononen, Nina A1 - Bansal, Nisha A1 - Devuyst, Olivier A1 - Melander, Olle A1 - Raitakari, Olli T A1 - Polasek, Ozren A1 - Manunta, Paolo A1 - Gasparini, Paolo A1 - Mishra, Pashupati P A1 - Sulem, Patrick A1 - Magnusson, Patrik K E A1 - Elliott, Paul A1 - Ridker, Paul M A1 - Hamet, Pavel A1 - Svensson, Per O A1 - Joshi, Peter K A1 - Kovacs, Peter A1 - Pramstaller, Peter P A1 - Rossing, Peter A1 - Vollenweider, Peter A1 - van der Harst, Pim A1 - Dorajoo, Rajkumar A1 - Sim, Ralene Z H A1 - Burkhardt, Ralph A1 - Tao, Ran A1 - Noordam, Raymond A1 - Mägi, Reedik A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Rueedi, Rico A1 - van Dam, Rob M A1 - Carroll, Robert J A1 - Gansevoort, Ron T A1 - Loos, Ruth J F A1 - Felicita, Sala Cinzia A1 - Sedaghat, Sanaz A1 - Padmanabhan, Sandosh A1 - Freitag-Wolf, Sandra A1 - Pendergrass, Sarah A A1 - Graham, Sarah E A1 - Gordon, Scott D A1 - Hwang, Shih-Jen A1 - Kerr, Shona M A1 - Vaccargiu, Simona A1 - Patil, Snehal B A1 - Hallan, Stein A1 - Bakker, Stephan J L A1 - Lim, Su-Chi A1 - Lucae, Susanne A1 - Vogelezang, Suzanne A1 - Bergmann, Sven A1 - Corre, Tanguy A1 - Ahluwalia, Tarunveer S A1 - Lehtimäki, Terho A1 - Boutin, Thibaud S A1 - Meitinger, Thomas A1 - Wong, Tien-Yin A1 - Bergler, Tobias A1 - Rabelink, Ton J A1 - Esko, Tõnu A1 - Haller, Toomas A1 - Thorsteinsdottir, Unnur A1 - Völker, Uwe A1 - Foo, Valencia Hui Xian A1 - Salomaa, Veikko A1 - Vitart, Veronique A1 - Giedraitis, Vilmantas A1 - Gudnason, Vilmundur A1 - Jaddoe, Vincent W V A1 - Huang, Wei A1 - Zhang, Weihua A1 - Wei, Wen Bin A1 - Kiess, Wieland A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Gào, Xīn A1 - Sim, Xueling A1 - Wang, Ya Xing A1 - Friedlander, Yechiel A1 - Tham, Yih-Chung A1 - Kamatani, Yoichiro A1 - Okada, Yukinori A1 - Milaneschi, Yuri A1 - Yu, Zhi A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Hung, Adriana M A1 - Kronenberg, Florian A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Heid, Iris M KW - Creatinine KW - Diabetes Mellitus KW - Diabetic Nephropathies KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney AB -

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

VL - 5 IS - 1 ER - TY - JOUR T1 - Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. JF - Kidney Int Y1 - 2022 A1 - Gorski, Mathias A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Thomas, Laurent F A1 - Graham, Sarah E A1 - Sveinbjornsson, Gardar A1 - Winkler, Thomas W A1 - Günther, Felix A1 - Stark, Klaus J A1 - Chai, Jin-Fang A1 - Tayo, Bamidele O A1 - Wuttke, Matthias A1 - Li, Yong A1 - Tin, Adrienne A1 - Ahluwalia, Tarunveer S A1 - Arnlöv, Johan A1 - Åsvold, Bjørn Olav A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Böhnke, Michael A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Brumpton, Ben A1 - Carroll, Robert J A1 - Chaker, Layal A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Chu, Audrey Y A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Cook, James P A1 - Coresh, Josef A1 - Cusi, Daniele A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Feitosa, Mary F A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Fuchsberger, Christian A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Gudbjartsson, Daniel F A1 - Hallan, Stein A1 - Hamet, Pavel A1 - Hishida, Asahi A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Holm, Hilma A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Hutri-Kähönen, Nina A1 - Hveem, Kristian A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Karabegović, Irma A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Li, Man A1 - Lieb, Wolfgang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Matias-Garcia, Pamela R A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Naito, Mariko A1 - Nakatochi, Masahiro A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - O'Donoghue, Michelle L A1 - O'Connell, Jeffrey A1 - Olafsson, Isleifur A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Pirastu, Mario A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Sabanayagam, Charumathi A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Scholz, Markus A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Sieber, Karsten B A1 - Sim, Xueling A1 - Sims, Mario A1 - Snieder, Harold A1 - Stanzick, Kira J A1 - Thorsteinsdottir, Unnur A1 - Stocker, Hannah A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Sulem, Patrick A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Thio, Chris H L A1 - Tremblay, Johanne A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Wakai, Kenji A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wallner, Stefan A1 - Wang, Judy A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Willer, Cristen J A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yerges-Armstrong, Laura M A1 - Zimmermann, Martina A1 - Zonderman, Alan B A1 - Bergler, Tobias A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Heid, Iris M AB -

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

ER - TY - JOUR T1 - Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. JF - Nat Genet Y1 - 2022 A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Zhang, Weihua A1 - Ng, Maggie C Y A1 - Petty, Lauren E A1 - Kitajima, Hidetoshi A1 - Yu, Grace Z A1 - Rüeger, Sina A1 - Speidel, Leo A1 - Kim, Young Jin A1 - Horikoshi, Momoko A1 - Mercader, Josep M A1 - Taliun, Daniel A1 - Moon, Sanghoon A1 - Kwak, Soo-Heon A1 - Robertson, Neil R A1 - Rayner, Nigel W A1 - Loh, Marie A1 - Kim, Bong-Jo A1 - Chiou, Joshua A1 - Miguel-Escalada, Irene A1 - Della Briotta Parolo, Pietro A1 - Lin, Kuang A1 - Bragg, Fiona A1 - Preuss, Michael H A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Guo, Xiuqing A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Scott, Robert A A1 - Lee, Jung-Jin A1 - Huerta-Chagoya, Alicia A1 - Graff, Mariaelisa A1 - Chai, Jin-Fang A1 - Parra, Esteban J A1 - Yao, Jie A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Steinthorsdottir, Valgerdur A1 - Cook, James P A1 - Kals, Mart A1 - Grarup, Niels A1 - Schmidt, Ellen M A1 - Pan, Ian A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Ahmad, Meraj A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Lecoeur, Cécile A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Jensen, Richard A A1 - Tajuddin, Salman A1 - Kabagambe, Edmond K A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Flanagan, Jack A1 - Abaitua, Fernando A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Akiyama, Masato A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bian, Zheng A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Brummett, Chad M A1 - Buchanan, Thomas A A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Fuchsberger, Christian A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Goodarzi, Mark O A1 - Gordon-Larsen, Penny A1 - Gorkin, David A1 - Gross, Myron A1 - Guo, Yu A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Kamatani, Yoichiro A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kohara, Katsuhiko A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lyssenko, Valeriya A1 - Mamakou, Vasiliki A1 - Mani, K Radha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nadkarni, Girish N A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Nongmaithem, Suraj S A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Preissl, Sebastian A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Kathryn A1 - Sabanayagam, Charumathi A1 - Sander, Maike A1 - Sandow, Kevin A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Schurmann, Claudia A1 - Shahriar, Mohammad A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shriner, Daniel A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Suzuki, Ken A1 - Takahashi, Atsushi A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Torres, Jason M A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Vujkovic, Marijana A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Whitsel, Eric A A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamauchi, Toshimasa A1 - Yengo, Loic A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Hanis, Craig L A1 - Peyser, Patricia A A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Zeggini, Eleftheria A1 - Yokota, Mitsuhiro A1 - Rich, Stephen S A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Engert, James C A1 - Chen, Yii-Der Ida A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Kardia, Sharon L R A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Groop, Leif A1 - Mook-Kanamori, Dennis O A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Bottinger, Erwin P A1 - Dehghan, Abbas A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Palmer, Colin N A A1 - Liu, Simin A1 - Abecasis, Goncalo A1 - Kooner, Jaspal S A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A A1 - Florez, Jose C A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Mägi, Reedik A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Maeda, Shiro A1 - Kadowaki, Takashi A1 - Lee, Juyoung A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Myers, Simon R A1 - Ferrer, Jorge A1 - Gaulton, Kyle J A1 - Meigs, James B A1 - Mohlke, Karen L A1 - Gloyn, Anna L A1 - Bowden, Donald W A1 - Below, Jennifer E A1 - Chambers, John C A1 - Sim, Xueling A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - McCarthy, Mark I A1 - Morris, Andrew P KW - Diabetes Mellitus, Type 2 KW - Ethnicity KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

VL - 54 IS - 5 ER - TY - JOUR T1 - PUFA ω-3 and ω-6 biomarkers and sleep: a pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE). JF - Am J Clin Nutr Y1 - 2022 A1 - Murphy, Rachel A A1 - Tintle, Nathan A1 - Harris, William S A1 - Darvishian, Maryam A1 - Marklund, Matti A1 - Virtanen, Jyrki K A1 - Hantunen, Sari A1 - de Mello, Vanessa D A1 - Tuomilehto, Jaakko A1 - Lindström, Jaana A1 - Bolt, Matthew A A1 - Brouwer, Ingeborg A A1 - Wood, Alexis C A1 - Senn, Mackenzie A1 - Redline, Susan A1 - Tsai, Michael Y A1 - Gudnason, Vilmundur A1 - Eiriksdottir, Gudny A1 - Lindberg, Eva A1 - Shadyab, Aladdin H A1 - Liu, Buyun A1 - Carnethon, Mercedes A1 - Uusitupa, Matti A1 - Djoussé, Luc A1 - Riserus, Ulf A1 - Lind, Lars A1 - van Dam, Rob M A1 - Koh, Woon-Puay A1 - Shi, Peilin A1 - Siscovick, David A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Biomarkers KW - Cohort Studies KW - Cross-Sectional Studies KW - Fatty Acids KW - Fatty Acids, Omega-3 KW - Humans KW - Outcome Assessment, Health Care KW - Sleep AB -

BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.

OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.

METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.

RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified.

CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

VL - 115 IS - 3 ER - TY - JOUR T1 - Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. JF - BMJ Y1 - 2023 A1 - Ong, Kwok Leung A1 - Marklund, Matti A1 - Huang, Liping A1 - Rye, Kerry-Anne A1 - Hui, Nicholas A1 - Pan, Xiong-Fei A1 - Rebholz, Casey M A1 - Kim, Hyunju A1 - Steffen, Lyn M A1 - van Westing, Anniek C A1 - Geleijnse, Johanna M A1 - Hoogeveen, Ellen K A1 - Chen, Yun-Yu A1 - Chien, Kuo-Liong A1 - Fretts, Amanda M A1 - Lemaitre, Rozenn N A1 - Imamura, Fumiaki A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Birukov, Anna A1 - Jäger, Susanne A1 - Kuxhaus, Olga A1 - Schulze, Matthias B A1 - de Mello, Vanessa Derenji A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - Lindström, Jaana A1 - Tintle, Nathan A1 - Harris, William S A1 - Yamasaki, Keisuke A1 - Hirakawa, Yoichiro A1 - Ninomiya, Toshiharu A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Virtanen, Jyrki K A1 - Voutilainen, Ari A1 - Jayasena, Tharusha A1 - Thalamuthu, Anbupalam A1 - Poljak, Anne A1 - Bustamante, Sonia A1 - Sachdev, Perminder S A1 - Senn, Mackenzie K A1 - Rich, Stephen S A1 - Tsai, Michael Y A1 - Wood, Alexis C A1 - Laakso, Markku A1 - Lankinen, Maria A1 - Yang, Xiaowei A1 - Sun, Liang A1 - Li, Huaixing A1 - Lin, Xu A1 - Nowak, Christoph A1 - Arnlöv, Johan A1 - Riserus, Ulf A1 - Lind, Lars A1 - Le Goff, Mélanie A1 - Samieri, Cecilia A1 - Helmer, Catherine A1 - Qian, Frank A1 - Micha, Renata A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Mozaffarian, Dariush A1 - Wu, Jason HY KW - alpha-Linolenic Acid KW - Fatty Acids, Omega-3 KW - Fatty Acids, Unsaturated KW - Humans KW - Middle Aged KW - Prospective Studies KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.

MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate.

RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.

CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

VL - 380 ER - TY - JOUR T1 - Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. 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Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Alaine Broadaway, K A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - 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Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Torben A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Kyung Min A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Lithgart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lynch, Julie A A1 - Lyssenko, Valeriya A1 - Maeda, Shiro A1 - Mamakou, Vasiliki A1 - Mansuri, Sohail Rafik A1 - Matsuda, Koichi A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Project, Biobank Japan A1 - BioBank, Penn Medicine A1 - Center, Regeneron Genetics A1 - Consortium, eMERGE A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Geoffrey Hayes, M A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

ER - TY - JOUR T1 - Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. JF - Nature Y1 - 2024 A1 - Suzuki, Ken A1 - Hatzikotoulas, Konstantinos A1 - Southam, Lorraine A1 - Taylor, Henry J A1 - Yin, Xianyong A1 - Lorenz, Kim M A1 - Mandla, Ravi A1 - Huerta-Chagoya, Alicia A1 - Melloni, Giorgio E M A1 - Kanoni, Stavroula A1 - Rayner, Nigel W A1 - Bocher, Ozvan A1 - Arruda, Ana Luiza A1 - Sonehara, Kyuto A1 - Namba, Shinichi A1 - Lee, Simon S K A1 - Preuss, Michael H A1 - Petty, Lauren E A1 - Schroeder, Philip A1 - Vanderwerff, Brett A1 - Kals, Mart A1 - Bragg, Fiona A1 - Lin, Kuang A1 - Guo, Xiuqing A1 - Zhang, Weihua A1 - Yao, Jie A1 - Kim, Young Jin A1 - Graff, Mariaelisa A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Moon, Sanghoon A1 - Scott, Robert A A1 - Cook, James P A1 - Lee, Jung-Jin A1 - Pan, Ian A1 - Taliun, Daniel A1 - Parra, Esteban J A1 - Chai, Jin-Fang A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Thorleifsson, Gudmar A1 - Grarup, Niels A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Broadaway, K Alaine A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Thangam, Manonanthini A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - 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Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Torben A1 - Kamanu, Frederick K A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Kyung Min A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lynch, Julie A A1 - Lyssenko, Valeriya A1 - Maeda, Shiro A1 - Mamakou, Vasiliki A1 - Mansuri, Sohail Rafik A1 - Matsuda, Koichi A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D A1 - Moura, Filipe A A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Ahlqvist, Emma A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Marston, Nicholas A A1 - Ruff, Christian T A1 - van Heel, David A A1 - Finer, Sarah A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

ER -