%0 Journal Article %J Am J Clin Nutr %D 2013 %T Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. %A Tanaka, Toshiko %A Ngwa, Julius S %A van Rooij, Frank J A %A Zillikens, M Carola %A Wojczynski, Mary K %A Frazier-Wood, Alexis C %A Houston, Denise K %A Kanoni, Stavroula %A Lemaitre, Rozenn N %A Luan, Jian'an %A Mikkilä, Vera %A Renstrom, Frida %A Sonestedt, Emily %A Zhao, Jing Hua %A Chu, Audrey Y %A Qi, Lu %A Chasman, Daniel I %A de Oliveira Otto, Marcia C %A Dhurandhar, Emily J %A Feitosa, Mary F %A Johansson, Ingegerd %A Khaw, Kay-Tee %A Lohman, Kurt K %A Manichaikul, Ani %A McKeown, Nicola M %A Mozaffarian, Dariush %A Singleton, Andrew %A Stirrups, Kathleen %A Viikari, Jorma %A Ye, Zheng %A Bandinelli, Stefania %A Barroso, Inês %A Deloukas, Panos %A Forouhi, Nita G %A Hofman, Albert %A Liu, Yongmei %A Lyytikäinen, Leo-Pekka %A North, Kari E %A Dimitriou, Maria %A Hallmans, Göran %A Kähönen, Mika %A Langenberg, Claudia %A Ordovas, Jose M %A Uitterlinden, André G %A Hu, Frank B %A Kalafati, Ioanna-Panagiota %A Raitakari, Olli %A Franco, Oscar H %A Johnson, Andrew %A Emilsson, Valur %A Schrack, Jennifer A %A Semba, Richard D %A Siscovick, David S %A Arnett, Donna K %A Borecki, Ingrid B %A Franks, Paul W %A Kritchevsky, Stephen B %A Lehtimäki, Terho %A Loos, Ruth J F %A Orho-Melander, Marju %A Rotter, Jerome I %A Wareham, Nicholas J %A Witteman, Jacqueline C M %A Ferrucci, Luigi %A Dedoussis, George %A Cupples, L Adrienne %A Nettleton, Jennifer A %K Alleles %K Atherosclerosis %K Body Mass Index %K Dietary Carbohydrates %K Dietary Fats %K Dietary Proteins %K Energy Intake %K European Continental Ancestry Group %K Fibroblast Growth Factors %K Follow-Up Studies %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Life Style %K Obesity %K Polymorphism, Single Nucleotide %K Prospective Studies %K Quantitative Trait Loci %K Surveys and Questionnaires %X

BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.

OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.

RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).

CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

%B Am J Clin Nutr %V 97 %P 1395-402 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23636237?dopt=Abstract %R 10.3945/ajcn.112.052183 %0 Journal Article %J J Nutr %D 2013 %T 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. %A Hruby, Adela %A Ngwa, Julius S %A Renstrom, Frida %A Wojczynski, Mary K %A Ganna, Andrea %A Hallmans, Göran %A Houston, Denise K %A Jacques, Paul F %A Kanoni, Stavroula %A Lehtimäki, Terho %A Lemaitre, Rozenn N %A Manichaikul, Ani %A North, Kari E %A Ntalla, Ioanna %A Sonestedt, Emily %A Tanaka, Toshiko %A van Rooij, Frank J A %A Bandinelli, Stefania %A Djoussé, Luc %A Grigoriou, Efi %A Johansson, Ingegerd %A Lohman, Kurt K %A Pankow, James S %A Raitakari, Olli T %A Riserus, Ulf %A Yannakoulia, Mary %A Zillikens, M Carola %A Hassanali, Neelam %A Liu, Yongmei %A Mozaffarian, Dariush %A Papoutsakis, Constantina %A Syvänen, Ann-Christine %A Uitterlinden, André G %A Viikari, Jorma %A Groves, Christopher J %A Hofman, Albert %A Lind, Lars %A McCarthy, Mark I %A Mikkilä, Vera %A Mukamal, Kenneth %A Franco, Oscar H %A Borecki, Ingrid B %A Cupples, L Adrienne %A Dedoussis, George V %A Ferrucci, Luigi %A Hu, Frank B %A Ingelsson, Erik %A Kähönen, Mika %A Kao, W H Linda %A Kritchevsky, Stephen B %A Orho-Melander, Marju %A Prokopenko, Inga %A Rotter, Jerome I %A Siscovick, David S %A Witteman, Jacqueline C M %A Franks, Paul W %A Meigs, James B %A McKeown, Nicola M %A Nettleton, Jennifer A %K Blood Glucose %K Female %K Genetic Loci %K Humans %K Insulin %K Magnesium %K Male %K Polymorphism, Single Nucleotide %K Trace Elements %K TRPM Cation Channels %X

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.

%B J Nutr %V 143 %P 345-53 %8 2013 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23343670?dopt=Abstract %R 10.3945/jn.112.172049 %0 Journal Article %J PLoS Genet %D 2013 %T Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. %A O'Seaghdha, Conall M %A Wu, Hongsheng %A Yang, Qiong %A Kapur, Karen %A Guessous, Idris %A Zuber, Annie Mercier %A Köttgen, Anna %A Stoudmann, Candice %A Teumer, Alexander %A Kutalik, Zoltán %A Mangino, Massimo %A Dehghan, Abbas %A Zhang, Weihua %A Eiriksdottir, Gudny %A Li, Guo %A Tanaka, Toshiko %A Portas, Laura %A Lopez, Lorna M %A Hayward, Caroline %A Lohman, Kurt %A Matsuda, Koichi %A Padmanabhan, Sandosh %A Firsov, Dmitri %A Sorice, Rossella %A Ulivi, Sheila %A Brockhaus, A Catharina %A Kleber, Marcus E %A Mahajan, Anubha %A Ernst, Florian D %A Gudnason, Vilmundur %A Launer, Lenore J %A Mace, Aurelien %A Boerwinckle, Eric %A Arking, Dan E %A Tanikawa, Chizu %A Nakamura, Yusuke %A Brown, Morris J %A Gaspoz, Jean-Michel %A Theler, Jean-Marc %A Siscovick, David S %A Psaty, Bruce M %A Bergmann, Sven %A Vollenweider, Peter %A Vitart, Veronique %A Wright, Alan F %A Zemunik, Tatijana %A Boban, Mladen %A Kolcic, Ivana %A Navarro, Pau %A Brown, Edward M %A Estrada, Karol %A Ding, Jingzhong %A Harris, Tamara B %A Bandinelli, Stefania %A Hernandez, Dena %A Singleton, Andrew B %A Girotto, Giorgia %A Ruggiero, Daniela %A d'Adamo, Adamo Pio %A Robino, Antonietta %A Meitinger, Thomas %A Meisinger, Christa %A Davies, Gail %A Starr, John M %A Chambers, John C %A Boehm, Bernhard O %A Winkelmann, Bernhard R %A Huang, Jie %A Murgia, Federico %A Wild, Sarah H %A Campbell, Harry %A Morris, Andrew P %A Franco, Oscar H %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Völker, Uwe %A Hannemann, Anke %A Biffar, Reiner %A Hoffmann, Wolfgang %A Shin, So-Youn %A Lescuyer, Pierre %A Henry, Hughes %A Schurmann, Claudia %A Munroe, Patricia B %A Gasparini, Paolo %A Pirastu, Nicola %A Ciullo, Marina %A Gieger, Christian %A März, Winfried %A Lind, Lars %A Spector, Tim D %A Smith, Albert V %A Rudan, Igor %A Wilson, James F %A Polasek, Ozren %A Deary, Ian J %A Pirastu, Mario %A Ferrucci, Luigi %A Liu, Yongmei %A Kestenbaum, Bryan %A Kooner, Jaspal S %A Witteman, Jacqueline C M %A Nauck, Matthias %A Kao, W H Linda %A Wallaschofski, Henri %A Bonny, Olivier %A Fox, Caroline S %A Bochud, Murielle %K Animals %K Bone and Bones %K Bone Density %K Calcium %K European Continental Ancestry Group %K Gene Expression Regulation %K Genome-Wide Association Study %K Homeostasis %K Humans %K Kidney %K Mice %K Polymorphism, Single Nucleotide %X

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.

%B PLoS Genet %V 9 %P e1003796 %8 2013 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract %R 10.1371/journal.pgen.1003796 %0 Journal Article %J Circulation %D 2013 %T Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. %A Sabater-Lleal, Maria %A Huang, Jie %A Chasman, Daniel %A Naitza, Silvia %A Dehghan, Abbas %A Johnson, Andrew D %A Teumer, Alexander %A Reiner, Alex P %A Folkersen, Lasse %A Basu, Saonli %A Rudnicka, Alicja R %A Trompet, Stella %A Mälarstig, Anders %A Baumert, Jens %A Bis, Joshua C %A Guo, Xiuqing %A Hottenga, Jouke J %A Shin, So-Youn %A Lopez, Lorna M %A Lahti, Jari %A Tanaka, Toshiko %A Yanek, Lisa R %A Oudot-Mellakh, Tiphaine %A Wilson, James F %A Navarro, Pau %A Huffman, Jennifer E %A Zemunik, Tatijana %A Redline, Susan %A Mehra, Reena %A Pulanic, Drazen %A Rudan, Igor %A Wright, Alan F %A Kolcic, Ivana %A Polasek, Ozren %A Wild, Sarah H %A Campbell, Harry %A Curb, J David %A Wallace, Robert %A Liu, Simin %A Eaton, Charles B %A Becker, Diane M %A Becker, Lewis C %A Bandinelli, Stefania %A Räikkönen, Katri %A Widen, Elisabeth %A Palotie, Aarno %A Fornage, Myriam %A Green, David %A Gross, Myron %A Davies, Gail %A Harris, Sarah E %A Liewald, David C %A Starr, John M %A Williams, Frances M K %A Grant, Peter J %A Spector, Timothy D %A Strawbridge, Rona J %A Silveira, Angela %A Sennblad, Bengt %A Rivadeneira, Fernando %A Uitterlinden, André G %A Franco, Oscar H %A Hofman, Albert %A van Dongen, Jenny %A Willemsen, Gonneke %A Boomsma, Dorret I %A Yao, Jie %A Swords Jenny, Nancy %A Haritunians, Talin %A McKnight, Barbara %A Lumley, Thomas %A Taylor, Kent D %A Rotter, Jerome I %A Psaty, Bruce M %A Peters, Annette %A Gieger, Christian %A Illig, Thomas %A Grotevendt, Anne %A Homuth, Georg %A Völzke, Henry %A Kocher, Thomas %A Goel, Anuj %A Franzosi, Maria Grazia %A Seedorf, Udo %A Clarke, Robert %A Steri, Maristella %A Tarasov, Kirill V %A Sanna, Serena %A Schlessinger, David %A Stott, David J %A Sattar, Naveed %A Buckley, Brendan M %A Rumley, Ann %A Lowe, Gordon D %A McArdle, Wendy L %A Chen, Ming-Huei %A Tofler, Geoffrey H %A Song, Jaejoon %A Boerwinkle, Eric %A Folsom, Aaron R %A Rose, Lynda M %A Franco-Cereceda, Anders %A Teichert, Martina %A Ikram, M Arfan %A Mosley, Thomas H %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M %A Sudlow, Cathie L M %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Kooner, Jaspal S %A Danesh, John %A Nelson, Christopher P %A Erdmann, Jeanette %A Reilly, Muredach P %A Kathiresan, Sekar %A Schunkert, Heribert %A Morange, Pierre-Emmanuel %A Ferrucci, Luigi %A Eriksson, Johan G %A Jacobs, David %A Deary, Ian J %A Soranzo, Nicole %A Witteman, Jacqueline C M %A de Geus, Eco J C %A Tracy, Russell P %A Hayward, Caroline %A Koenig, Wolfgang %A Cucca, Francesco %A Jukema, J Wouter %A Eriksson, Per %A Seshadri, Sudha %A Markus, Hugh S %A Watkins, Hugh %A Samani, Nilesh J %A Wallaschofski, Henri %A Smith, Nicholas L %A Tregouet, David %A Ridker, Paul M %A Tang, Weihong %A Strachan, David P %A Hamsten, Anders %A O'Donnell, Christopher J %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Venous Thromboembolism %K Young Adult %X

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

%B Circulation %V 128 %P 1310-24 %8 2013 Sep 17 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.002251 %0 Journal Article %J BMJ %D 2014 %T Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. %A Holmes, Michael V %A Dale, Caroline E %A Zuccolo, Luisa %A Silverwood, Richard J %A Guo, Yiran %A Ye, Zheng %A Prieto-Merino, David %A Dehghan, Abbas %A Trompet, Stella %A Wong, Andrew %A Cavadino, Alana %A Drogan, Dagmar %A Padmanabhan, Sandosh %A Li, Shanshan %A Yesupriya, Ajay %A Leusink, Maarten %A Sundström, Johan %A Hubacek, Jaroslav A %A Pikhart, Hynek %A Swerdlow, Daniel I %A Panayiotou, Andrie G %A Borinskaya, Svetlana A %A Finan, Chris %A Shah, Sonia %A Kuchenbaecker, Karoline B %A Shah, Tina %A Engmann, Jorgen %A Folkersen, Lasse %A Eriksson, Per %A Ricceri, Fulvio %A Melander, Olle %A Sacerdote, Carlotta %A Gamble, Dale M %A Rayaprolu, Sruti %A Ross, Owen A %A McLachlan, Stela %A Vikhireva, Olga %A Sluijs, Ivonne %A Scott, Robert A %A Adamkova, Vera %A Flicker, Leon %A Bockxmeer, Frank M van %A Power, Christine %A Marques-Vidal, Pedro %A Meade, Tom %A Marmot, Michael G %A Ferro, Jose M %A Paulos-Pinheiro, Sofia %A Humphries, Steve E %A Talmud, Philippa J %A Mateo Leach, Irene %A Verweij, Niek %A Linneberg, Allan %A Skaaby, Tea %A Doevendans, Pieter A %A Cramer, Maarten J %A van der Harst, Pim %A Klungel, Olaf H %A Dowling, Nicole F %A Dominiczak, Anna F %A Kumari, Meena %A Nicolaides, Andrew N %A Weikert, Cornelia %A Boeing, Heiner %A Ebrahim, Shah %A Gaunt, Tom R %A Price, Jackie F %A Lannfelt, Lars %A Peasey, Anne %A Kubinova, Ruzena %A Pajak, Andrzej %A Malyutina, Sofia %A Voevoda, Mikhail I %A Tamosiunas, Abdonas %A Maitland-van der Zee, Anke H %A Norman, Paul E %A Hankey, Graeme J %A Bergmann, Manuela M %A Hofman, Albert %A Franco, Oscar H %A Cooper, Jackie %A Palmen, Jutta %A Spiering, Wilko %A de Jong, Pim A %A Kuh, Diana %A Hardy, Rebecca %A Uitterlinden, André G %A Ikram, M Arfan %A Ford, Ian %A Hyppönen, Elina %A Almeida, Osvaldo P %A Wareham, Nicholas J %A Khaw, Kay-Tee %A Hamsten, Anders %A Husemoen, Lise Lotte N %A Tjønneland, Anne %A Tolstrup, Janne S %A Rimm, Eric %A Beulens, Joline W J %A Verschuren, W M Monique %A Onland-Moret, N Charlotte %A Hofker, Marten H %A Wannamethee, S Goya %A Whincup, Peter H %A Morris, Richard %A Vicente, Astrid M %A Watkins, Hugh %A Farrall, Martin %A Jukema, J Wouter %A Meschia, James %A Cupples, L Adrienne %A Sharp, Stephen J %A Fornage, Myriam %A Kooperberg, Charles %A LaCroix, Andrea Z %A Dai, James Y %A Lanktree, Matthew B %A Siscovick, David S %A Jorgenson, Eric %A Spring, Bonnie %A Coresh, Josef %A Li, Yun R %A Buxbaum, Sarah G %A Schreiner, Pamela J %A Ellison, R Curtis %A Tsai, Michael Y %A Patel, Sanjay R %A Redline, Susan %A Johnson, Andrew D %A Hoogeveen, Ron C %A Hakonarson, Hakon %A Rotter, Jerome I %A Boerwinkle, Eric %A de Bakker, Paul I W %A Kivimaki, Mika %A Asselbergs, Folkert W %A Sattar, Naveed %A Lawlor, Debbie A %A Whittaker, John %A Davey Smith, George %A Mukamal, Kenneth %A Psaty, Bruce M %A Wilson, James G %A Lange, Leslie A %A Hamidovic, Ajna %A Hingorani, Aroon D %A Nordestgaard, Børge G %A Bobak, Martin %A Leon, David A %A Langenberg, Claudia %A Palmer, Tom M %A Reiner, Alex P %A Keating, Brendan J %A Dudbridge, Frank %A Casas, Juan P %K Adult %K Aged %K Alcohol Dehydrogenase %K Alcohol Drinking %K Biomarkers %K Coronary Disease %K Female %K Genetic Markers %K Genotype %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Models, Statistical %K Polymorphism, Single Nucleotide %K Stroke %X

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

%B BMJ %V 349 %P g4164 %8 2014 Jul 10 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract %R 10.1136/bmj.g4164 %0 Journal Article %J Am J Hum Genet %D 2014 %T Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. %A Peloso, Gina M %A Auer, Paul L %A Bis, Joshua C %A Voorman, Arend %A Morrison, Alanna C %A Stitziel, Nathan O %A Brody, Jennifer A %A Khetarpal, Sumeet A %A Crosby, Jacy R %A Fornage, Myriam %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Feitosa, Mary F %A Davies, Gail %A Huffman, Jennifer E %A Manichaikul, Ani %A Davis, Brian %A Lohman, Kurt %A Joon, Aron Y %A Smith, Albert V %A Grove, Megan L %A Zanoni, Paolo %A Redon, Valeska %A Demissie, Serkalem %A Lawson, Kim %A Peters, Ulrike %A Carlson, Christopher %A Jackson, Rebecca D %A Ryckman, Kelli K %A Mackey, Rachel H %A Robinson, Jennifer G %A Siscovick, David S %A Schreiner, Pamela J %A Mychaleckyj, Josyf C %A Pankow, James S %A Hofman, Albert %A Uitterlinden, André G %A Harris, Tamara B %A Taylor, Kent D %A Stafford, Jeanette M %A Reynolds, Lindsay M %A Marioni, Riccardo E %A Dehghan, Abbas %A Franco, Oscar H %A Patel, Aniruddh P %A Lu, Yingchang %A Hindy, George %A Gottesman, Omri %A Bottinger, Erwin P %A Melander, Olle %A Orho-Melander, Marju %A Loos, Ruth J F %A Duga, Stefano %A Merlini, Piera Angelica %A Farrall, Martin %A Goel, Anuj %A Asselta, Rosanna %A Girelli, Domenico %A Martinelli, Nicola %A Shah, Svati H %A Kraus, William E %A Li, Mingyao %A Rader, Daniel J %A Reilly, Muredach P %A McPherson, Ruth %A Watkins, Hugh %A Ardissino, Diego %A Zhang, Qunyuan %A Wang, Judy %A Tsai, Michael Y %A Taylor, Herman A %A Correa, Adolfo %A Griswold, Michael E %A Lange, Leslie A %A Starr, John M %A Rudan, Igor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Ordovas, Jose M %A Levy, Daniel %A Chen, Y-D Ida %A Reiner, Alexander P %A Hayward, Caroline %A Polasek, Ozren %A Deary, Ian J %A Borecki, Ingrid B %A Liu, Yongmei %A Gudnason, Vilmundur %A Wilson, James G %A van Duijn, Cornelia M %A Kooperberg, Charles %A Rich, Stephen S %A Psaty, Bruce M %A Rotter, Jerome I %A O'Donnell, Christopher J %A Rice, Kenneth %A Boerwinkle, Eric %A Kathiresan, Sekar %A Cupples, L Adrienne %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Adult %K African Continental Ancestry Group %K Aged %K Alleles %K Animals %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Coronary Disease %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Association Studies %K Genetic Code %K Genetic Variation %K Humans %K Linear Models %K Male %K Mice %K Mice, Inbred C57BL %K Microtubule-Associated Proteins %K Middle Aged %K Phenotype %K Sequence Analysis, DNA %K Subtilisins %K Triglycerides %X

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

%B Am J Hum Genet %V 94 %P 223-32 %8 2014 Feb 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract %R 10.1016/j.ajhg.2014.01.009 %0 Journal Article %J Europace %D 2014 %T B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. %A Sinner, Moritz F %A Stepas, Katherine A %A Moser, Carlee B %A Krijthe, Bouwe P %A Aspelund, Thor %A Sotoodehnia, Nona %A Fontes, João D %A Janssens, A Cecile J W %A Kronmal, Richard A %A Magnani, Jared W %A Witteman, Jacqueline C %A Chamberlain, Alanna M %A Lubitz, Steven A %A Schnabel, Renate B %A Vasan, Ramachandran S %A Wang, Thomas J %A Agarwal, Sunil K %A McManus, David D %A Franco, Oscar H %A Yin, Xiaoyan %A Larson, Martin G %A Burke, Gregory L %A Launer, Lenore J %A Hofman, Albert %A Levy, Daniel %A Gottdiener, John S %A Kääb, Stefan %A Couper, David %A Harris, Tamara B %A Astor, Brad C %A Ballantyne, Christie M %A Hoogeveen, Ron C %A Arai, Andrew E %A Soliman, Elsayed Z %A Ellinor, Patrick T %A Stricker, Bruno H C %A Gudnason, Vilmundur %A Heckbert, Susan R %A Pencina, Michael J %A Benjamin, Emelia J %A Alonso, Alvaro %K Aged %K Atrial Fibrillation %K Biomarkers %K C-Reactive Protein %K Europe %K Female %K Humans %K Incidence %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Predictive Value of Tests %K Risk Assessment %K Risk Factors %K United States %X

AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.

METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.

CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

%B Europace %V 16 %P 1426-33 %8 2014 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25037055?dopt=Abstract %R 10.1093/europace/euu175 %0 Journal Article %J Hypertension %D 2014 %T Common carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration. %A Bots, Michiel L %A Groenewegen, Karlijn A %A Anderson, Todd J %A Britton, Annie R %A Dekker, Jacqueline M %A Engström, Gunnar %A Evans, Greg W %A de Graaf, Jacqueline %A Grobbee, Diederick E %A Hedblad, Bo %A Hofman, Albert %A Holewijn, Suzanne %A Ikeda, Ai %A Kavousi, Maryam %A Kitagawa, Kazuo %A Kitamura, Akihiko %A Ikram, M Arfan %A Lonn, Eva M %A Lorenz, Matthias W %A Mathiesen, Ellisiv B %A Nijpels, Giel %A Okazaki, Shuhei %A O'Leary, Daniel H %A Polak, Joseph F %A Price, Jacqueline F %A Robertson, Christine %A Rembold, Christopher M %A Rosvall, Maria %A Rundek, Tatjana %A Salonen, Jukka T %A Sitzer, Matthias %A Stehouwer, Coen D A %A Franco, Oscar H %A Peters, Sanne A E %A den Ruijter, Hester M %K Adult %K Aged %K Antihypertensive Agents %K Blood Pressure %K Cardiovascular Diseases %K Carotid Artery, Common %K Carotid Intima-Media Thickness %K Cohort Studies %K Female %K Humans %K Hypertension %K Male %K Meta-Analysis as Topic %K Middle Aged %K Risk Assessment %K Risk Factors %X

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

%B Hypertension %V 63 %P 1173-81 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24614213?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.113.02683 %0 Journal Article %J Am J Hum Genet %D 2014 %T Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. %A Ganesh, Santhi K %A Chasman, Daniel I %A Larson, Martin G %A Guo, Xiuqing %A Verwoert, Germain %A Bis, Joshua C %A Gu, Xiangjun %A Smith, Albert V %A Yang, Min-Lee %A Zhang, Yan %A Ehret, Georg %A Rose, Lynda M %A Hwang, Shih-Jen %A Papanicolau, George J %A Sijbrands, Eric J %A Rice, Kenneth %A Eiriksdottir, Gudny %A Pihur, Vasyl %A Ridker, Paul M %A Vasan, Ramachandran S %A Newton-Cheh, Christopher %A Raffel, Leslie J %A Amin, Najaf %A Rotter, Jerome I %A Liu, Kiang %A Launer, Lenore J %A Xu, Ming %A Caulfield, Mark %A Morrison, Alanna C %A Johnson, Andrew D %A Vaidya, Dhananjay %A Dehghan, Abbas %A Li, Guo %A Bouchard, Claude %A Harris, Tamara B %A Zhang, He %A Boerwinkle, Eric %A Siscovick, David S %A Gao, Wei %A Uitterlinden, André G %A Rivadeneira, Fernando %A Hofman, Albert %A Willer, Cristen J %A Franco, Oscar H %A Huo, Yong %A Witteman, Jacqueline C M %A Munroe, Patricia B %A Gudnason, Vilmundur %A Palmas, Walter %A van Duijn, Cornelia %A Fornage, Myriam %A Levy, Daniel %A Psaty, Bruce M %A Chakravarti, Aravinda %K Blood Pressure %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

%B Am J Hum Genet %V 95 %P 49-65 %8 2014 Jul 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24975945?dopt=Abstract %R 10.1016/j.ajhg.2014.06.002 %0 Journal Article %J Hum Mol Genet %D 2014 %T FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals. %A Qi, Qibin %A Kilpeläinen, Tuomas O %A Downer, Mary K %A Tanaka, Toshiko %A Smith, Caren E %A Sluijs, Ivonne %A Sonestedt, Emily %A Chu, Audrey Y %A Renstrom, Frida %A Lin, Xiaochen %A Ängquist, Lars H %A Huang, Jinyan %A Liu, Zhonghua %A Li, Yanping %A Asif Ali, Muhammad %A Xu, Min %A Ahluwalia, Tarunveer Singh %A Boer, Jolanda M A %A Chen, Peng %A Daimon, Makoto %A Eriksson, Johan %A Perola, Markus %A Friedlander, Yechiel %A Gao, Yu-Tang %A Heppe, Denise H M %A Holloway, John W %A Houston, Denise K %A Kanoni, Stavroula %A Kim, Yu-Mi %A Laaksonen, Maarit A %A Jääskeläinen, Tiina %A Lee, Nanette R %A Lehtimäki, Terho %A Lemaitre, Rozenn N %A Lu, Wei %A Luben, Robert N %A Manichaikul, Ani %A Männistö, Satu %A Marques-Vidal, Pedro %A Monda, Keri L %A Ngwa, Julius S %A Perusse, Louis %A van Rooij, Frank J A %A Xiang, Yong-Bing %A Wen, Wanqing %A Wojczynski, Mary K %A Zhu, Jingwen %A Borecki, Ingrid B %A Bouchard, Claude %A Cai, Qiuyin %A Cooper, Cyrus %A Dedoussis, George V %A Deloukas, Panos %A Ferrucci, Luigi %A Forouhi, Nita G %A Hansen, Torben %A Christiansen, Lene %A Hofman, Albert %A Johansson, Ingegerd %A Jørgensen, Torben %A Karasawa, Shigeru %A Khaw, Kay-Tee %A Kim, Mi-Kyung %A Kristiansson, Kati %A Li, Huaixing %A Lin, Xu %A Liu, Yongmei %A Lohman, Kurt K %A Long, Jirong %A Mikkilä, Vera %A Mozaffarian, Dariush %A North, Kari %A Pedersen, Oluf %A Raitakari, Olli %A Rissanen, Harri %A Tuomilehto, Jaakko %A van der Schouw, Yvonne T %A Uitterlinden, André G %A Zillikens, M Carola %A Franco, Oscar H %A Shyong Tai, E %A Ou Shu, Xiao %A Siscovick, David S %A Toft, Ulla %A Verschuren, W M Monique %A Vollenweider, Peter %A Wareham, Nicholas J %A Witteman, Jacqueline C M %A Zheng, Wei %A Ridker, Paul M %A Kang, Jae H %A Liang, Liming %A Jensen, Majken K %A Curhan, Gary C %A Pasquale, Louis R %A Hunter, David J %A Mohlke, Karen L %A Uusitupa, Matti %A Cupples, L Adrienne %A Rankinen, Tuomo %A Orho-Melander, Marju %A Wang, Tao %A Chasman, Daniel I %A Franks, Paul W %A Sørensen, Thorkild I A %A Hu, Frank B %A Loos, Ruth J F %A Nettleton, Jennifer A %A Qi, Lu %K Adult %K African Americans %K Aged %K Alleles %K Asian Continental Ancestry Group %K Body Mass Index %K Dietary Carbohydrates %K Dietary Fats %K Dietary Proteins %K Energy Intake %K European Continental Ancestry Group %K Female %K Gene Frequency %K Humans %K Male %K Middle Aged %K Obesity %K Polymorphism, Single Nucleotide %K Proteins %X

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

%B Hum Mol Genet %V 23 %P 6961-72 %8 2014 Dec 20 %G eng %N 25 %1 http://www.ncbi.nlm.nih.gov/pubmed/25104851?dopt=Abstract %R 10.1093/hmg/ddu411 %0 Journal Article %J Am J Hum Genet %D 2014 %T Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. %A Simino, Jeannette %A Shi, Gang %A Bis, Joshua C %A Chasman, Daniel I %A Ehret, Georg B %A Gu, Xiangjun %A Guo, Xiuqing %A Hwang, Shih-Jen %A Sijbrands, Eric %A Smith, Albert V %A Verwoert, Germaine C %A Bragg-Gresham, Jennifer L %A Cadby, Gemma %A Chen, Peng %A Cheng, Ching-Yu %A Corre, Tanguy %A de Boer, Rudolf A %A Goel, Anuj %A Johnson, Toby %A Khor, Chiea-Chuen %A Lluís-Ganella, Carla %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Sim, Xueling %A Sõber, Siim %A van der Most, Peter J %A Verweij, Niek %A Zhao, Jing Hua %A Amin, Najaf %A Boerwinkle, Eric %A Bouchard, Claude %A Dehghan, Abbas %A Eiriksdottir, Gudny %A Elosua, Roberto %A Franco, Oscar H %A Gieger, Christian %A Harris, Tamara B %A Hercberg, Serge %A Hofman, Albert %A James, Alan L %A Johnson, Andrew D %A Kähönen, Mika %A Khaw, Kay-Tee %A Kutalik, Zoltán %A Larson, Martin G %A Launer, Lenore J %A Li, Guo %A Liu, Jianjun %A Liu, Kiang %A Morrison, Alanna C %A Navis, Gerjan %A Ong, Rick Twee-Hee %A Papanicolau, George J %A Penninx, Brenda W %A Psaty, Bruce M %A Raffel, Leslie J %A Raitakari, Olli T %A Rice, Kenneth %A Rivadeneira, Fernando %A Rose, Lynda M %A Sanna, Serena %A Scott, Robert A %A Siscovick, David S %A Stolk, Ronald P %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Klauw, Melanie M %A Vasan, Ramachandran S %A Vithana, Eranga Nishanthie %A Völker, Uwe %A Völzke, Henry %A Watkins, Hugh %A Young, Terri L %A Aung, Tin %A Bochud, Murielle %A Farrall, Martin %A Hartman, Catharina A %A Laan, Maris %A Lakatta, Edward G %A Lehtimäki, Terho %A Loos, Ruth J F %A Lucas, Gavin %A Meneton, Pierre %A Palmer, Lyle J %A Rettig, Rainer %A Snieder, Harold %A Tai, E Shyong %A Teo, Yik-Ying %A van der Harst, Pim %A Wareham, Nicholas J %A Wijmenga, Cisca %A Wong, Tien Yin %A Fornage, Myriam %A Gudnason, Vilmundur %A Levy, Daniel %A Palmas, Walter %A Ridker, Paul M %A Rotter, Jerome I %A van Duijn, Cornelia M %A Witteman, Jacqueline C M %A Chakravarti, Aravinda %A Rao, Dabeeru C %K Adolescent %K Adult %K Age Factors %K Aged %K Blood Pressure %K Cohort Studies %K Humans %K Middle Aged %K Young Adult %X

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

%B Am J Hum Genet %V 95 %P 24-38 %8 2014 Jul 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24954895?dopt=Abstract %R 10.1016/j.ajhg.2014.05.010 %0 Journal Article %J Nat Genet %D 2014 %T Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. %A Arking, Dan E %A Pulit, Sara L %A Crotti, Lia %A van der Harst, Pim %A Munroe, Patricia B %A Koopmann, Tamara T %A Sotoodehnia, Nona %A Rossin, Elizabeth J %A Morley, Michael %A Wang, Xinchen %A Johnson, Andrew D %A Lundby, Alicia %A Gudbjartsson, Daniel F %A Noseworthy, Peter A %A Eijgelsheim, Mark %A Bradford, Yuki %A Tarasov, Kirill V %A Dörr, Marcus %A Müller-Nurasyid, Martina %A Lahtinen, Annukka M %A Nolte, Ilja M %A Smith, Albert Vernon %A Bis, Joshua C %A Isaacs, Aaron %A Newhouse, Stephen J %A Evans, Daniel S %A Post, Wendy S %A Waggott, Daryl %A Lyytikäinen, Leo-Pekka %A Hicks, Andrew A %A Eisele, Lewin %A Ellinghaus, David %A Hayward, Caroline %A Navarro, Pau %A Ulivi, Sheila %A Tanaka, Toshiko %A Tester, David J %A Chatel, Stéphanie %A Gustafsson, Stefan %A Kumari, Meena %A Morris, Richard W %A Naluai, Åsa T %A Padmanabhan, Sandosh %A Kluttig, Alexander %A Strohmer, Bernhard %A Panayiotou, Andrie G %A Torres, Maria %A Knoflach, Michael %A Hubacek, Jaroslav A %A Slowikowski, Kamil %A Raychaudhuri, Soumya %A Kumar, Runjun D %A Harris, Tamara B %A Launer, Lenore J %A Shuldiner, Alan R %A Alonso, Alvaro %A Bader, Joel S %A Ehret, Georg %A Huang, Hailiang %A Kao, W H Linda %A Strait, James B %A Macfarlane, Peter W %A Brown, Morris %A Caulfield, Mark J %A Samani, Nilesh J %A Kronenberg, Florian %A Willeit, Johann %A Smith, J Gustav %A Greiser, Karin H %A Meyer Zu Schwabedissen, Henriette %A Werdan, Karl %A Carella, Massimo %A Zelante, Leopoldo %A Heckbert, Susan R %A Psaty, Bruce M %A Rotter, Jerome I %A Kolcic, Ivana %A Polasek, Ozren %A Wright, Alan F %A Griffin, Maura %A Daly, Mark J %A Arnar, David O %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Denny, Joshua C %A Roden, Dan M %A Zuvich, Rebecca L %A Emilsson, Valur %A Plump, Andrew S %A Larson, Martin G %A O'Donnell, Christopher J %A Yin, Xiaoyan %A Bobbo, Marco %A D'Adamo, Adamo P %A Iorio, Annamaria %A Sinagra, Gianfranco %A Carracedo, Angel %A Cummings, Steven R %A Nalls, Michael A %A Jula, Antti %A Kontula, Kimmo K %A Marjamaa, Annukka %A Oikarinen, Lasse %A Perola, Markus %A Porthan, Kimmo %A Erbel, Raimund %A Hoffmann, Per %A Jöckel, Karl-Heinz %A Kälsch, Hagen %A Nöthen, Markus M %A den Hoed, Marcel %A Loos, Ruth J F %A Thelle, Dag S %A Gieger, Christian %A Meitinger, Thomas %A Perz, Siegfried %A Peters, Annette %A Prucha, Hanna %A Sinner, Moritz F %A Waldenberger, Melanie %A de Boer, Rudolf A %A Franke, Lude %A van der Vleuten, Pieter A %A Beckmann, Britt Maria %A Martens, Eimo %A Bardai, Abdennasser %A Hofman, Nynke %A Wilde, Arthur A M %A Behr, Elijah R %A Dalageorgou, Chrysoula %A Giudicessi, John R %A Medeiros-Domingo, Argelia %A Barc, Julien %A Kyndt, Florence %A Probst, Vincent %A Ghidoni, Alice %A Insolia, Roberto %A Hamilton, Robert M %A Scherer, Stephen W %A Brandimarto, Jeffrey %A Margulies, Kenneth %A Moravec, Christine E %A del Greco M, Fabiola %A Fuchsberger, Christian %A O'Connell, Jeffrey R %A Lee, Wai K %A Watt, Graham C M %A Campbell, Harry %A Wild, Sarah H %A El Mokhtari, Nour E %A Frey, Norbert %A Asselbergs, Folkert W %A Mateo Leach, Irene %A Navis, Gerjan %A van den Berg, Maarten P %A van Veldhuisen, Dirk J %A Kellis, Manolis %A Krijthe, Bouwe P %A Franco, Oscar H %A Hofman, Albert %A Kors, Jan A %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Kedenko, Lyudmyla %A Lamina, Claudia %A Oostra, Ben A %A Abecasis, Goncalo R %A Lakatta, Edward G %A Mulas, Antonella %A Orrù, Marco %A Schlessinger, David %A Uda, Manuela %A Markus, Marcello R P %A Völker, Uwe %A Snieder, Harold %A Spector, Timothy D %A Arnlöv, Johan %A Lind, Lars %A Sundström, Johan %A Syvänen, Ann-Christine %A Kivimaki, Mika %A Kähönen, Mika %A Mononen, Nina %A Raitakari, Olli T %A Viikari, Jorma S %A Adamkova, Vera %A Kiechl, Stefan %A Brion, Maria %A Nicolaides, Andrew N %A Paulweber, Bernhard %A Haerting, Johannes %A Dominiczak, Anna F %A Nyberg, Fredrik %A Whincup, Peter H %A Hingorani, Aroon D %A Schott, Jean-Jacques %A Bezzina, Connie R %A Ingelsson, Erik %A Ferrucci, Luigi %A Gasparini, Paolo %A Wilson, James F %A Rudan, Igor %A Franke, Andre %A Mühleisen, Thomas W %A Pramstaller, Peter P %A Lehtimäki, Terho J %A Paterson, Andrew D %A Parsa, Afshin %A Liu, Yongmei %A van Duijn, Cornelia M %A Siscovick, David S %A Gudnason, Vilmundur %A Jamshidi, Yalda %A Salomaa, Veikko %A Felix, Stephan B %A Sanna, Serena %A Ritchie, Marylyn D %A Stricker, Bruno H %A Stefansson, Kari %A Boyer, Laurie A %A Cappola, Thomas P %A Olsen, Jesper V %A Lage, Kasper %A Schwartz, Peter J %A Kääb, Stefan %A Chakravarti, Aravinda %A Ackerman, Michael J %A Pfeufer, Arne %A de Bakker, Paul I W %A Newton-Cheh, Christopher %K Adult %K Aged %K Arrhythmias, Cardiac %K Calcium Signaling %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Ventricles %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Myocardium %K Polymorphism, Single Nucleotide %X

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.

%B Nat Genet %V 46 %P 826-36 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract %R 10.1038/ng.3014 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2014 %T Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. %A Huang, Jie %A Huffman, Jennifer E %A Yamakuchi, Munekazu %A Yamkauchi, Munekazu %A Trompet, Stella %A Asselbergs, Folkert W %A Sabater-Lleal, Maria %A Trégouët, David-Alexandre %A Chen, Wei-Min %A Smith, Nicholas L %A Kleber, Marcus E %A Shin, So-Youn %A Becker, Diane M %A Tang, Weihong %A Dehghan, Abbas %A Johnson, Andrew D %A Truong, Vinh %A Folkersen, Lasse %A Yang, Qiong %A Oudot-Mellkah, Tiphaine %A Buckley, Brendan M %A Moore, Jason H %A Williams, Frances M K %A Campbell, Harry %A Silbernagel, Günther %A Vitart, Veronique %A Rudan, Igor %A Tofler, Geoffrey H %A Navis, Gerjan J %A DeStefano, Anita %A Wright, Alan F %A Chen, Ming-Huei %A de Craen, Anton J M %A Worrall, Bradford B %A Rudnicka, Alicja R %A Rumley, Ann %A Bookman, Ebony B %A Psaty, Bruce M %A Chen, Fang %A Keene, Keith L %A Franco, Oscar H %A Böhm, Bernhard O %A Uitterlinden, André G %A Carter, Angela M %A Jukema, J Wouter %A Sattar, Naveed %A Bis, Joshua C %A Ikram, Mohammad A %A Sale, Michèle M %A McKnight, Barbara %A Fornage, Myriam %A Ford, Ian %A Taylor, Kent %A Slagboom, P Eline %A McArdle, Wendy L %A Hsu, Fang-Chi %A Franco-Cereceda, Anders %A Goodall, Alison H %A Yanek, Lisa R %A Furie, Karen L %A Cushman, Mary %A Hofman, Albert %A Witteman, Jacqueline C M %A Folsom, Aaron R %A Basu, Saonli %A Matijevic, Nena %A van Gilst, Wiek H %A Wilson, James F %A Westendorp, Rudi G J %A Kathiresan, Sekar %A Reilly, Muredach P %A Tracy, Russell P %A Polasek, Ozren %A Winkelmann, Bernhard R %A Grant, Peter J %A Hillege, Hans L %A Cambien, Francois %A Stott, David J %A Lowe, Gordon D %A Spector, Timothy D %A Meigs, James B %A März, Winfried %A Eriksson, Per %A Becker, Lewis C %A Morange, Pierre-Emmanuel %A Soranzo, Nicole %A Williams, Scott M %A Hayward, Caroline %A van der Harst, Pim %A Hamsten, Anders %A Lowenstein, Charles J %A Strachan, David P %A O'Donnell, Christopher J %K Aged %K Cells, Cultured %K Coronary Artery Disease %K Endothelial Cells %K Europe %K Female %K Gene Expression Regulation %K Gene Silencing %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K R-SNARE Proteins %K Risk Factors %K Stroke %K Syntaxin 1 %K Tissue Plasminogen Activator %K Transfection %K United States %K Up-Regulation %X

OBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

%B Arterioscler Thromb Vasc Biol %V 34 %P 1093-101 %8 2014 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/24578379?dopt=Abstract %R 10.1161/ATVBAHA.113.302088 %0 Journal Article %J PLoS One %D 2014 %T No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. %A Baumert, Jens %A Huang, Jie %A McKnight, Barbara %A Sabater-Lleal, Maria %A Steri, Maristella %A Chu, Audrey Y %A Trompet, Stella %A Lopez, Lorna M %A Fornage, Myriam %A Teumer, Alexander %A Tang, Weihong %A Rudnicka, Alicja R %A Mälarstig, Anders %A Hottenga, Jouke-Jan %A Kavousi, Maryam %A Lahti, Jari %A Tanaka, Toshiko %A Hayward, Caroline %A Huffman, Jennifer E %A Morange, Pierre-Emmanuel %A Rose, Lynda M %A Basu, Saonli %A Rumley, Ann %A Stott, David J %A Buckley, Brendan M %A de Craen, Anton J M %A Sanna, Serena %A Masala, Marco %A Biffar, Reiner %A Homuth, Georg %A Silveira, Angela %A Sennblad, Bengt %A Goel, Anuj %A Watkins, Hugh %A Müller-Nurasyid, Martina %A Rückerl, Regina %A Taylor, Kent %A Chen, Ming-Huei %A de Geus, Eco J C %A Hofman, Albert %A Witteman, Jacqueline C M %A de Maat, Moniek P M %A Palotie, Aarno %A Davies, Gail %A Siscovick, David S %A Kolcic, Ivana %A Wild, Sarah H %A Song, Jaejoon %A McArdle, Wendy L %A Ford, Ian %A Sattar, Naveed %A Schlessinger, David %A Grotevendt, Anne %A Franzosi, Maria Grazia %A Illig, Thomas %A Waldenberger, Melanie %A Lumley, Thomas %A Tofler, Geoffrey H %A Willemsen, Gonneke %A Uitterlinden, André G %A Rivadeneira, Fernando %A Räikkönen, Katri %A Chasman, Daniel I %A Folsom, Aaron R %A Lowe, Gordon D %A Westendorp, Rudi G J %A Slagboom, P Eline %A Cucca, Francesco %A Wallaschofski, Henri %A Strawbridge, Rona J %A Seedorf, Udo %A Koenig, Wolfgang %A Bis, Joshua C %A Mukamal, Kenneth J %A van Dongen, Jenny %A Widen, Elisabeth %A Franco, Oscar H %A Starr, John M %A Liu, Kiang %A Ferrucci, Luigi %A Polasek, Ozren %A Wilson, James F %A Oudot-Mellakh, Tiphaine %A Campbell, Harry %A Navarro, Pau %A Bandinelli, Stefania %A Eriksson, Johan %A Boomsma, Dorret I %A Dehghan, Abbas %A Clarke, Robert %A Hamsten, Anders %A Boerwinkle, Eric %A Jukema, J Wouter %A Naitza, Silvia %A Ridker, Paul M %A Völzke, Henry %A Deary, Ian J %A Reiner, Alexander P %A Trégouët, David-Alexandre %A O'Donnell, Christopher J %A Strachan, David P %A Peters, Annette %A Smith, Nicholas L %K Alcohol Drinking %K Body Mass Index %K Fibrinogen %K Gene-Environment Interaction %K Genomics %K Humans %K Smoking %X

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

%B PLoS One %V 9 %P e111156 %8 2014 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract %R 10.1371/journal.pone.0111156 %0 Journal Article %J J Am Coll Cardiol %D 2014 %T Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. %A Lubitz, Steven A %A Lunetta, Kathryn L %A Lin, Honghuang %A Arking, Dan E %A Trompet, Stella %A Li, Guo %A Krijthe, Bouwe P %A Chasman, Daniel I %A Barnard, John %A Kleber, Marcus E %A Dörr, Marcus %A Ozaki, Kouichi %A Smith, Albert V %A Müller-Nurasyid, Martina %A Walter, Stefan %A Agarwal, Sunil K %A Bis, Joshua C %A Brody, Jennifer A %A Chen, Lin Y %A Everett, Brendan M %A Ford, Ian %A Franco, Oscar H %A Harris, Tamara B %A Hofman, Albert %A Kääb, Stefan %A Mahida, Saagar %A Kathiresan, Sekar %A Kubo, Michiaki %A Launer, Lenore J %A Macfarlane, Peter W %A Magnani, Jared W %A McKnight, Barbara %A McManus, David D %A Peters, Annette %A Psaty, Bruce M %A Rose, Lynda M %A Rotter, Jerome I %A Silbernagel, Guenther %A Smith, Jonathan D %A Sotoodehnia, Nona %A Stott, David J %A Taylor, Kent D %A Tomaschitz, Andreas %A Tsunoda, Tatsuhiko %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Murabito, Joanne M %A Sinner, Moritz F %A Gudnason, Vilmundur %A Felix, Stephan B %A März, Winfried %A Chung, Mina %A Albert, Christine M %A Stricker, Bruno H %A Tanaka, Toshihiro %A Heckbert, Susan R %A Jukema, J Wouter %A Alonso, Alvaro %A Benjamin, Emelia J %A Ellinor, Patrick T %K Adult %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Atrial Fibrillation %K Chromosome Mapping %K Chromosomes, Human, Pair 4 %K Europe %K European Continental Ancestry Group %K Female %K Genetic Markers %K Genetic Predisposition to Disease %K Homeodomain Proteins %K Humans %K Japan %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Transcription Factors %X

OBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

%B J Am Coll Cardiol %V 63 %P 1200-10 %8 2014 Apr 1 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24486271?dopt=Abstract %R 10.1016/j.jacc.2013.12.015 %0 Journal Article %J Nat Commun %D 2014 %T Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. %A Postmus, Iris %A Trompet, Stella %A Deshmukh, Harshal A %A Barnes, Michael R %A Li, Xiaohui %A Warren, Helen R %A Chasman, Daniel I %A Zhou, Kaixin %A Arsenault, Benoit J %A Donnelly, Louise A %A Wiggins, Kerri L %A Avery, Christy L %A Griffin, Paula %A Feng, QiPing %A Taylor, Kent D %A Li, Guo %A Evans, Daniel S %A Smith, Albert V %A de Keyser, Catherine E %A Johnson, Andrew D %A de Craen, Anton J M %A Stott, David J %A Buckley, Brendan M %A Ford, Ian %A Westendorp, Rudi G J %A Slagboom, P Eline %A Sattar, Naveed %A Munroe, Patricia B %A Sever, Peter %A Poulter, Neil %A Stanton, Alice %A Shields, Denis C %A O'Brien, Eoin %A Shaw-Hawkins, Sue %A Chen, Y-D Ida %A Nickerson, Deborah A %A Smith, Joshua D %A Dubé, Marie Pierre %A Boekholdt, S Matthijs %A Hovingh, G Kees %A Kastelein, John J P %A McKeigue, Paul M %A Betteridge, John %A Neil, Andrew %A Durrington, Paul N %A Doney, Alex %A Carr, Fiona %A Morris, Andrew %A McCarthy, Mark I %A Groop, Leif %A Ahlqvist, Emma %A Bis, Joshua C %A Rice, Kenneth %A Smith, Nicholas L %A Lumley, Thomas %A Whitsel, Eric A %A Stürmer, Til %A Boerwinkle, Eric %A Ngwa, Julius S %A O'Donnell, Christopher J %A Vasan, Ramachandran S %A Wei, Wei-Qi %A Wilke, Russell A %A Liu, Ching-Ti %A Sun, Fangui %A Guo, Xiuqing %A Heckbert, Susan R %A Post, Wendy %A Sotoodehnia, Nona %A Arnold, Alice M %A Stafford, Jeanette M %A Ding, Jingzhong %A Herrington, David M %A Kritchevsky, Stephen B %A Eiriksdottir, Gudny %A Launer, Leonore J %A Harris, Tamara B %A Chu, Audrey Y %A Giulianini, Franco %A MacFadyen, Jean G %A Barratt, Bryan J %A Nyberg, Fredrik %A Stricker, Bruno H %A Uitterlinden, André G %A Hofman, Albert %A Rivadeneira, Fernando %A Emilsson, Valur %A Franco, Oscar H %A Ridker, Paul M %A Gudnason, Vilmundur %A Liu, Yongmei %A Denny, Joshua C %A Ballantyne, Christie M %A Rotter, Jerome I %A Adrienne Cupples, L %A Psaty, Bruce M %A Palmer, Colin N A %A Tardif, Jean-Claude %A Colhoun, Helen M %A Hitman, Graham %A Krauss, Ronald M %A Wouter Jukema, J %A Caulfield, Mark J %K Cholesterol, LDL %K Genome-Wide Association Study %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Pharmacogenetics %K Polymorphism, Single Nucleotide %X

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

%B Nat Commun %V 5 %P 5068 %8 2014 Oct 28 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25350695?dopt=Abstract %R 10.1038/ncomms6068 %0 Journal Article %J Hum Mol Genet %D 2014 %T Trans-ethnic meta-analysis of white blood cell phenotypes. %A Keller, Margaux F %A Reiner, Alexander P %A Okada, Yukinori %A van Rooij, Frank J A %A Johnson, Andrew D %A Chen, Ming-Huei %A Smith, Albert V %A Morris, Andrew P %A Tanaka, Toshiko %A Ferrucci, Luigi %A Zonderman, Alan B %A Lettre, Guillaume %A Harris, Tamara %A Garcia, Melissa %A Bandinelli, Stefania %A Qayyum, Rehan %A Yanek, Lisa R %A Becker, Diane M %A Becker, Lewis C %A Kooperberg, Charles %A Keating, Brendan %A Reis, Jared %A Tang, Hua %A Boerwinkle, Eric %A Kamatani, Yoichiro %A Matsuda, Koichi %A Kamatani, Naoyuki %A Nakamura, Yusuke %A Kubo, Michiaki %A Liu, Simin %A Dehghan, Abbas %A Felix, Janine F %A Hofman, Albert %A Uitterlinden, André G %A van Duijn, Cornelia M %A Franco, Oscar H %A Longo, Dan L %A Singleton, Andrew B %A Psaty, Bruce M %A Evans, Michelle K %A Cupples, L Adrienne %A Rotter, Jerome I %A O'Donnell, Christopher J %A Takahashi, Atsushi %A Wilson, James G %A Ganesh, Santhi K %A Nalls, Mike A %K African Americans %K Asian Continental Ancestry Group %K Bayes Theorem %K European Continental Ancestry Group %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Leukocyte Count %K Leukocytes %K Linkage Disequilibrium %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

%B Hum Mol Genet %V 23 %P 6944-60 %8 2014 Dec 20 %G eng %N 25 %1 http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract %R 10.1093/hmg/ddu401 %0 Journal Article %J JAMA %D 2015 %T Association of Cardiometabolic Multimorbidity With Mortality. %A Di Angelantonio, Emanuele %A Kaptoge, Stephen %A Wormser, David %A Willeit, Peter %A Butterworth, Adam S %A Bansal, Narinder %A O'Keeffe, Linda M %A Gao, Pei %A Wood, Angela M %A Burgess, Stephen %A Freitag, Daniel F %A Pennells, Lisa %A Peters, Sanne A %A Hart, Carole L %A Håheim, Lise Lund %A Gillum, Richard F %A Nordestgaard, Børge G %A Psaty, Bruce M %A Yeap, Bu B %A Knuiman, Matthew W %A Nietert, Paul J %A Kauhanen, Jussi %A Salonen, Jukka T %A Kuller, Lewis H %A Simons, Leon A %A van der Schouw, Yvonne T %A Barrett-Connor, Elizabeth %A Selmer, Randi %A Crespo, Carlos J %A Rodriguez, Beatriz %A Verschuren, W M Monique %A Salomaa, Veikko %A Svärdsudd, Kurt %A van der Harst, Pim %A Björkelund, Cecilia %A Wilhelmsen, Lars %A Wallace, Robert B %A Brenner, Hermann %A Amouyel, Philippe %A Barr, Elizabeth L M %A Iso, Hiroyasu %A Onat, Altan %A Trevisan, Maurizio %A D'Agostino, Ralph B %A Cooper, Cyrus %A Kavousi, Maryam %A Welin, Lennart %A Roussel, Ronan %A Hu, Frank B %A Sato, Shinichi %A Davidson, Karina W %A Howard, Barbara V %A Leening, Maarten J G %A Leening, Maarten %A Rosengren, Annika %A Dörr, Marcus %A Deeg, Dorly J H %A Kiechl, Stefan %A Stehouwer, Coen D A %A Nissinen, Aulikki %A Giampaoli, Simona %A Donfrancesco, Chiara %A Kromhout, Daan %A Price, Jackie F %A Peters, Annette %A Meade, Tom W %A Casiglia, Edoardo %A Lawlor, Debbie A %A Gallacher, John %A Nagel, Dorothea %A Franco, Oscar H %A Assmann, Gerd %A Dagenais, Gilles R %A Jukema, J Wouter %A Sundström, Johan %A Woodward, Mark %A Brunner, Eric J %A Khaw, Kay-Tee %A Wareham, Nicholas J %A Whitsel, Eric A %A Njølstad, Inger %A Hedblad, Bo %A Wassertheil-Smoller, Sylvia %A Engström, Gunnar %A Rosamond, Wayne D %A Selvin, Elizabeth %A Sattar, Naveed %A Thompson, Simon G %A Danesh, John %K Adult %K Aged %K Comorbidity %K Diabetes Mellitus %K Female %K Humans %K Life Expectancy %K Male %K Middle Aged %K Mortality %K Myocardial Infarction %K Risk Factors %K Stroke %X

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing.

OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.

DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.

EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).

MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy.

RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.

CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

%B JAMA %V 314 %P 52-60 %8 2015 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26151266?dopt=Abstract %R 10.1001/jama.2015.7008 %0 Journal Article %J Circ Cardiovasc Genet %D 2015 %T Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease. %A Yu, Bing %A Li, Alexander H %A Muzny, Donna %A Veeraraghavan, Narayanan %A de Vries, Paul S %A Bis, Joshua C %A Musani, Solomon K %A Alexander, Danny %A Morrison, Alanna C %A Franco, Oscar H %A Uitterlinden, Andre %A Hofman, Albert %A Dehghan, Abbas %A Wilson, James G %A Psaty, Bruce M %A Gibbs, Richard %A Wei, Peng %A Boerwinkle, Eric %K Adult %K African Americans %K Alleles %K Coronary Disease %K European Continental Ancestry Group %K Female %K Histidine %K Histidine Ammonia-Lyase %K Humans %K Male %K Mutation %X

BACKGROUND: Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.

METHODS AND RESULTS: By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2×10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2×10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9×10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.

CONCLUSIONS: Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.

%B Circ Cardiovasc Genet %V 8 %P 351-5 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25575548?dopt=Abstract %R 10.1161/CIRCGENETICS.114.000697 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians. %A Fretts, Amanda M %A Follis, Jack L %A Nettleton, Jennifer A %A Lemaitre, Rozenn N %A Ngwa, Julius S %A Wojczynski, Mary K %A Kalafati, Ioanna Panagiota %A Varga, Tibor V %A Frazier-Wood, Alexis C %A Houston, Denise K %A Lahti, Jari %A Ericson, Ulrika %A van den Hooven, Edith H %A Mikkilä, Vera %A Kiefte-de Jong, Jessica C %A Mozaffarian, Dariush %A Rice, Kenneth %A Renstrom, Frida %A North, Kari E %A McKeown, Nicola M %A Feitosa, Mary F %A Kanoni, Stavroula %A Smith, Caren E %A Garcia, Melissa E %A Tiainen, Anna-Maija %A Sonestedt, Emily %A Manichaikul, Ani %A van Rooij, Frank J A %A Dimitriou, Maria %A Raitakari, Olli %A Pankow, James S %A Djoussé, Luc %A Province, Michael A %A Hu, Frank B %A Lai, Chao-Qiang %A Keller, Margaux F %A Perälä, Mia-Maria %A Rotter, Jerome I %A Hofman, Albert %A Graff, Misa %A Kähönen, Mika %A Mukamal, Kenneth %A Johansson, Ingegerd %A Ordovas, Jose M %A Liu, Yongmei %A Männistö, Satu %A Uitterlinden, André G %A Deloukas, Panos %A Seppälä, Ilkka %A Psaty, Bruce M %A Cupples, L Adrienne %A Borecki, Ingrid B %A Franks, Paul W %A Arnett, Donna K %A Nalls, Mike A %A Eriksson, Johan G %A Orho-Melander, Marju %A Franco, Oscar H %A Lehtimäki, Terho %A Dedoussis, George V %A Meigs, James B %A Siscovick, David S %K Blood Glucose %K Cohort Studies %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hyperglycemia %K Hyperinsulinism %K Insulin %K Insulin Resistance %K Insulin-Secreting Cells %K Meat %K Meat Products %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.

RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.

CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

%B Am J Clin Nutr %V 102 %P 1266-78 %8 2015 Nov %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26354543?dopt=Abstract %R 10.3945/ajcn.114.101238 %0 Journal Article %J PLoS One %D 2015 %T Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. %A Bis, Joshua C %A Sitlani, Colleen %A Irvin, Ryan %A Avery, Christy L %A Smith, Albert Vernon %A Sun, Fangui %A Evans, Daniel S %A Musani, Solomon K %A Li, Xiaohui %A Trompet, Stella %A Krijthe, Bouwe P %A Harris, Tamara B %A Quibrera, P Miguel %A Brody, Jennifer A %A Demissie, Serkalem %A Davis, Barry R %A Wiggins, Kerri L %A Tranah, Gregory J %A Lange, Leslie A %A Sotoodehnia, Nona %A Stott, David J %A Franco, Oscar H %A Launer, Lenore J %A Stürmer, Til %A Taylor, Kent D %A Cupples, L Adrienne %A Eckfeldt, John H %A Smith, Nicholas L %A Liu, Yongmei %A Wilson, James G %A Heckbert, Susan R %A Buckley, Brendan M %A Ikram, M Arfan %A Boerwinkle, Eric %A Chen, Yii-Der Ida %A de Craen, Anton J M %A Uitterlinden, André G %A Rotter, Jerome I %A Ford, Ian %A Hofman, Albert %A Sattar, Naveed %A Slagboom, P Eline %A Westendorp, Rudi G J %A Gudnason, Vilmundur %A Vasan, Ramachandran S %A Lumley, Thomas %A Cummings, Steven R %A Taylor, Herman A %A Post, Wendy %A Jukema, J Wouter %A Stricker, Bruno H %A Whitsel, Eric A %A Psaty, Bruce M %A Arnett, Donna %K African Americans %K Aged %K Antihypertensive Agents %K Cardiovascular Diseases %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Treatment Outcome %X

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

%B PLoS One %V 10 %P e0140496 %8 2015 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract %R 10.1371/journal.pone.0140496 %0 Journal Article %J Hum Mol Genet %D 2015 %T Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. %A Nettleton, Jennifer A %A Follis, Jack L %A Ngwa, Julius S %A Smith, Caren E %A Ahmad, Shafqat %A Tanaka, Toshiko %A Wojczynski, Mary K %A Voortman, Trudy %A Lemaitre, Rozenn N %A Kristiansson, Kati %A Nuotio, Marja-Liisa %A Houston, Denise K %A Perälä, Mia-Maria %A Qi, Qibin %A Sonestedt, Emily %A Manichaikul, Ani %A Kanoni, Stavroula %A Ganna, Andrea %A Mikkilä, Vera %A North, Kari E %A Siscovick, David S %A Harald, Kennet %A McKeown, Nicola M %A Johansson, Ingegerd %A Rissanen, Harri %A Liu, Yongmei %A Lahti, Jari %A Hu, Frank B %A Bandinelli, Stefania %A Rukh, Gull %A Rich, Stephen %A Booij, Lisanne %A Dmitriou, Maria %A Ax, Erika %A Raitakari, Olli %A Mukamal, Kenneth %A Männistö, Satu %A Hallmans, Göran %A Jula, Antti %A Ericson, Ulrika %A Jacobs, David R %A van Rooij, Frank J A %A Deloukas, Panos %A Sjogren, Per %A Kähönen, Mika %A Djoussé, Luc %A Perola, Markus %A Barroso, Inês %A Hofman, Albert %A Stirrups, Kathleen %A Viikari, Jorma %A Uitterlinden, André G %A Kalafati, Ioanna P %A Franco, Oscar H %A Mozaffarian, Dariush %A Salomaa, Veikko %A Borecki, Ingrid B %A Knekt, Paul %A Kritchevsky, Stephen B %A Eriksson, Johan G %A Dedoussis, George V %A Qi, Lu %A Ferrucci, Luigi %A Orho-Melander, Marju %A Zillikens, M Carola %A Ingelsson, Erik %A Lehtimäki, Terho %A Renstrom, Frida %A Cupples, L Adrienne %A Loos, Ruth J F %A Franks, Paul W %K Adult %K Body Mass Index %K Case-Control Studies %K Diet, Western %K Epistasis, Genetic %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Obesity %K Polymorphism, Single Nucleotide %X

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

%B Hum Mol Genet %V 24 %P 4728-38 %8 2015 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/25994509?dopt=Abstract %R 10.1093/hmg/ddv186 %0 Journal Article %J Nat Commun %D 2015 %T Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels. %A van Leeuwen, Elisabeth M %A Karssen, Lennart C %A Deelen, Joris %A Isaacs, Aaron %A Medina-Gómez, Carolina %A Mbarek, Hamdi %A Kanterakis, Alexandros %A Trompet, Stella %A Postmus, Iris %A Verweij, Niek %A van Enckevort, David J %A Huffman, Jennifer E %A White, Charles C %A Feitosa, Mary F %A Bartz, Traci M %A Manichaikul, Ani %A Joshi, Peter K %A Peloso, Gina M %A Deelen, Patrick %A van Dijk, Freerk %A Willemsen, Gonneke %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda W J H %A Francioli, Laurent C %A Menelaou, Androniki %A Pulit, Sara L %A Rivadeneira, Fernando %A Hofman, Albert %A Oostra, Ben A %A Franco, Oscar H %A Mateo Leach, Irene %A Beekman, Marian %A de Craen, Anton J M %A Uh, Hae-Won %A Trochet, Holly %A Hocking, Lynne J %A Porteous, David J %A Sattar, Naveed %A Packard, Chris J %A Buckley, Brendan M %A Brody, Jennifer A %A Bis, Joshua C %A Rotter, Jerome I %A Mychaleckyj, Josyf C %A Campbell, Harry %A Duan, Qing %A Lange, Leslie A %A Wilson, James F %A Hayward, Caroline %A Polasek, Ozren %A Vitart, Veronique %A Rudan, Igor %A Wright, Alan F %A Rich, Stephen S %A Psaty, Bruce M %A Borecki, Ingrid B %A Kearney, Patricia M %A Stott, David J %A Adrienne Cupples, L %A Jukema, J Wouter %A van der Harst, Pim %A Sijbrands, Eric J %A Hottenga, Jouke-Jan %A Uitterlinden, André G %A Swertz, Morris A %A van Ommen, Gert-Jan B %A de Bakker, Paul I W %A Eline Slagboom, P %A Boomsma, Dorret I %A Wijmenga, Cisca %A van Duijn, Cornelia M %K ATP-Binding Cassette Transporters %K Cholesterol %K Gene Frequency %K Genetic Association Studies %K Humans %K Mutation, Missense %K Netherlands %X

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

%B Nat Commun %V 6 %P 6065 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25751400?dopt=Abstract %R 10.1038/ncomms7065 %0 Journal Article %J Nat Commun %D 2015 %T Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. %A Wessel, Jennifer %A Chu, Audrey Y %A Willems, Sara M %A Wang, Shuai %A Yaghootkar, Hanieh %A Brody, Jennifer A %A Dauriz, Marco %A Hivert, Marie-France %A Raghavan, Sridharan %A Lipovich, Leonard %A Hidalgo, Bertha %A Fox, Keolu %A Huffman, Jennifer E %A An, Ping %A Lu, Yingchang %A Rasmussen-Torvik, Laura J %A Grarup, Niels %A Ehm, Margaret G %A Li, Li %A Baldridge, Abigail S %A Stančáková, Alena %A Abrol, Ravinder %A Besse, Céline %A Boland, Anne %A Bork-Jensen, Jette %A Fornage, Myriam %A Freitag, Daniel F %A Garcia, Melissa E %A Guo, Xiuqing %A Hara, Kazuo %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Lange, Leslie A %A Layton, Jill C %A Li, Man %A Hua Zhao, Jing %A Meidtner, Karina %A Morrison, Alanna C %A Nalls, Mike A %A Peters, Marjolein J %A Sabater-Lleal, Maria %A Schurmann, Claudia %A Silveira, Angela %A Smith, Albert V %A Southam, Lorraine %A Stoiber, Marcus H %A Strawbridge, Rona J %A Taylor, Kent D %A Varga, Tibor V %A Allin, Kristine H %A Amin, Najaf %A Aponte, Jennifer L %A Aung, Tin %A Barbieri, Caterina %A Bihlmeyer, Nathan A %A Boehnke, Michael %A Bombieri, Cristina %A Bowden, Donald W %A Burns, Sean M %A Chen, Yuning %A Chen, Yii-DerI %A Cheng, Ching-Yu %A Correa, Adolfo %A Czajkowski, Jacek %A Dehghan, Abbas %A Ehret, Georg B %A Eiriksdottir, Gudny %A Escher, Stefan A %A Farmaki, Aliki-Eleni %A Frånberg, Mattias %A Gambaro, Giovanni %A Giulianini, Franco %A Goddard, William A %A Goel, Anuj %A Gottesman, Omri %A Grove, Megan L %A Gustafsson, Stefan %A Hai, Yang %A Hallmans, Göran %A Heo, Jiyoung %A Hoffmann, Per %A Ikram, Mohammad K %A Jensen, Richard A %A Jørgensen, Marit E %A Jørgensen, Torben %A Karaleftheri, Maria %A Khor, Chiea C %A Kirkpatrick, Andrea %A Kraja, Aldi T %A Kuusisto, Johanna %A Lange, Ethan M %A Lee, I T %A Lee, Wen-Jane %A Leong, Aaron %A Liao, Jiemin %A Liu, Chunyu %A Liu, Yongmei %A Lindgren, Cecilia M %A Linneberg, Allan %A Malerba, Giovanni %A Mamakou, Vasiliki %A Marouli, Eirini %A Maruthur, Nisa M %A Matchan, Angela %A McKean-Cowdin, Roberta %A McLeod, Olga %A Metcalf, Ginger A %A Mohlke, Karen L %A Muzny, Donna M %A Ntalla, Ioanna %A Palmer, Nicholette D %A Pasko, Dorota %A Peter, Andreas %A Rayner, Nigel W %A Renstrom, Frida %A Rice, Ken %A Sala, Cinzia F %A Sennblad, Bengt %A Serafetinidis, Ioannis %A Smith, Jennifer A %A Soranzo, Nicole %A Speliotes, Elizabeth K %A Stahl, Eli A %A Stirrups, Kathleen %A Tentolouris, Nikos %A Thanopoulou, Anastasia %A Torres, Mina %A Traglia, Michela %A Tsafantakis, Emmanouil %A Javad, Sundas %A Yanek, Lisa R %A Zengini, Eleni %A Becker, Diane M %A Bis, Joshua C %A Brown, James B %A Cupples, L Adrienne %A Hansen, Torben %A Ingelsson, Erik %A Karter, Andrew J %A Lorenzo, Carlos %A Mathias, Rasika A %A Norris, Jill M %A Peloso, Gina M %A Sheu, Wayne H-H %A Toniolo, Daniela %A Vaidya, Dhananjay %A Varma, Rohit %A Wagenknecht, Lynne E %A Boeing, Heiner %A Bottinger, Erwin P %A Dedoussis, George %A Deloukas, Panos %A Ferrannini, Ele %A Franco, Oscar H %A Franks, Paul W %A Gibbs, Richard A %A Gudnason, Vilmundur %A Hamsten, Anders %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A Hofman, Albert %A Jansson, Jan-Håkan %A Langenberg, Claudia %A Launer, Lenore J %A Levy, Daniel %A Oostra, Ben A %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Padmanabhan, Sandosh %A Pankow, James S %A Polasek, Ozren %A Province, Michael A %A Rich, Stephen S %A Ridker, Paul M %A Rudan, Igor %A Schulze, Matthias B %A Smith, Blair H %A Uitterlinden, André G %A Walker, Mark %A Watkins, Hugh %A Wong, Tien Y %A Zeggini, Eleftheria %A Laakso, Markku %A Borecki, Ingrid B %A Chasman, Daniel I %A Pedersen, Oluf %A Psaty, Bruce M %A Tai, E Shyong %A van Duijn, Cornelia M %A Wareham, Nicholas J %A Waterworth, Dawn M %A Boerwinkle, Eric %A Kao, W H Linda %A Florez, Jose C %A Loos, Ruth J F %A Wilson, James G %A Frayling, Timothy M %A Siscovick, David S %A Dupuis, Josée %A Rotter, Jerome I %A Meigs, James B %A Scott, Robert A %A Goodarzi, Mark O %K African Continental Ancestry Group %K Blood Glucose %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Exome %K Fasting %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Glucagon-Like Peptide-1 Receptor %K Glucose-6-Phosphatase %K Humans %K Insulin %K Mutation Rate %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %X

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

%B Nat Commun %V 6 %P 5897 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract %R 10.1038/ncomms6897 %0 Journal Article %J Blood %D 2015 %T Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. %A Huffman, Jennifer E %A de Vries, Paul S %A Morrison, Alanna C %A Sabater-Lleal, Maria %A Kacprowski, Tim %A Auer, Paul L %A Brody, Jennifer A %A Chasman, Daniel I %A Chen, Ming-Huei %A Guo, Xiuqing %A Lin, Li-An %A Marioni, Riccardo E %A Müller-Nurasyid, Martina %A Yanek, Lisa R %A Pankratz, Nathan %A Grove, Megan L %A de Maat, Moniek P M %A Cushman, Mary %A Wiggins, Kerri L %A Qi, Lihong %A Sennblad, Bengt %A Harris, Sarah E %A Polasek, Ozren %A Riess, Helene %A Rivadeneira, Fernando %A Rose, Lynda M %A Goel, Anuj %A Taylor, Kent D %A Teumer, Alexander %A Uitterlinden, André G %A Vaidya, Dhananjay %A Yao, Jie %A Tang, Weihong %A Levy, Daniel %A Waldenberger, Melanie %A Becker, Diane M %A Folsom, Aaron R %A Giulianini, Franco %A Greinacher, Andreas %A Hofman, Albert %A Huang, Chiang-Ching %A Kooperberg, Charles %A Silveira, Angela %A Starr, John M %A Strauch, Konstantin %A Strawbridge, Rona J %A Wright, Alan F %A McKnight, Barbara %A Franco, Oscar H %A Zakai, Neil %A Mathias, Rasika A %A Psaty, Bruce M %A Ridker, Paul M %A Tofler, Geoffrey H %A Völker, Uwe %A Watkins, Hugh %A Fornage, Myriam %A Hamsten, Anders %A Deary, Ian J %A Boerwinkle, Eric %A Koenig, Wolfgang %A Rotter, Jerome I %A Hayward, Caroline %A Dehghan, Abbas %A Reiner, Alex P %A O'Donnell, Christopher J %A Smith, Nicholas L %K Cohort Studies %K Factor VII %K Factor VIII %K Fibrinogen %K Gene Frequency %K Genetic Association Studies %K Genetic Variation %K Humans %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels %K von Willebrand Factor %X

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

%B Blood %V 126 %P e19-29 %8 2015 Sep 10 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract %R 10.1182/blood-2015-02-624551 %0 Journal Article %J J Clin Endocrinol Metab %D 2015 %T Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis. %A Chaker, Layal %A Baumgartner, Christine %A den Elzen, Wendy P J %A Ikram, M Arfan %A Blum, Manuel R %A Collet, Tinh-Hai %A Bakker, Stephan J L %A Dehghan, Abbas %A Drechsler, Christiane %A Luben, Robert N %A Hofman, Albert %A Portegies, Marileen L P %A Medici, Marco %A Iervasi, Giorgio %A Stott, David J %A Ford, Ian %A Bremner, Alexandra %A Wanner, Christoph %A Ferrucci, Luigi %A Newman, Anne B %A Dullaart, Robin P %A Sgarbi, José A %A Ceresini, Graziano %A Maciel, Rui M B %A Westendorp, Rudi G %A Jukema, J Wouter %A Imaizumi, Misa %A Franklyn, Jayne A %A Bauer, Douglas C %A Walsh, John P %A Razvi, Salman %A Khaw, Kay-Tee %A Cappola, Anne R %A Völzke, Henry %A Franco, Oscar H %A Gussekloo, Jacobijn %A Rodondi, Nicolas %A Peeters, Robin P %K Adult %K Asymptomatic Diseases %K Female %K Humans %K Hypothyroidism %K Incidence %K Male %K Risk Factors %K Stroke %K Thyrotropin %X

OBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism.

DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels.

DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations.

CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

%B J Clin Endocrinol Metab %V 100 %P 2181-91 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25856213?dopt=Abstract %R 10.1210/jc.2015-1438 %0 Journal Article %J JAMA Intern Med %D 2015 %T Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts. %A Asvold, Bjørn O %A Vatten, Lars J %A Bjøro, Trine %A Bauer, Douglas C %A Bremner, Alexandra %A Cappola, Anne R %A Ceresini, Graziano %A den Elzen, Wendy P J %A Ferrucci, Luigi %A Franco, Oscar H %A Franklyn, Jayne A %A Gussekloo, Jacobijn %A Iervasi, Giorgio %A Imaizumi, Misa %A Kearney, Patricia M %A Khaw, Kay-Tee %A Maciel, Rui M B %A Newman, Anne B %A Peeters, Robin P %A Psaty, Bruce M %A Razvi, Salman %A Sgarbi, José A %A Stott, David J %A Trompet, Stella %A Vanderpump, Mark P J %A Völzke, Henry %A Walsh, John P %A Westendorp, Rudi G J %A Rodondi, Nicolas %K Cohort Studies %K Coronary Disease %K Humans %K Hypothyroidism %K Thyrotropin %X

IMPORTANCE: Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD).

OBJECTIVE: To assess the association between differences in thyroid function within the reference range and CHD risk.

DESIGN, SETTING, AND PARTICIPANTS: Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline.

EXPOSURES: Thyroid function as expressed by serum thyrotropin levels at baseline.

MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status.

RESULTS: Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results.

CONCLUSIONS AND RELEVANCE: Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

%B JAMA Intern Med %V 175 %P 1037-47 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25893284?dopt=Abstract %R 10.1001/jamainternmed.2015.0930 %0 Journal Article %J PLoS Genet %D 2016 %T Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. %A Smith, J Gustav %A Felix, Janine F %A Morrison, Alanna C %A Kalogeropoulos, Andreas %A Trompet, Stella %A Wilk, Jemma B %A Gidlöf, Olof %A Wang, Xinchen %A Morley, Michael %A Mendelson, Michael %A Joehanes, Roby %A Ligthart, Symen %A Shan, Xiaoyin %A Bis, Joshua C %A Wang, Ying A %A Sjögren, Marketa %A Ngwa, Julius %A Brandimarto, Jeffrey %A Stott, David J %A Aguilar, David %A Rice, Kenneth M %A Sesso, Howard D %A Demissie, Serkalem %A Buckley, Brendan M %A Taylor, Kent D %A Ford, Ian %A Yao, Chen %A Liu, Chunyu %A Sotoodehnia, Nona %A van der Harst, Pim %A Stricker, Bruno H Ch %A Kritchevsky, Stephen B %A Liu, Yongmei %A Gaziano, J Michael %A Hofman, Albert %A Moravec, Christine S %A Uitterlinden, André G %A Kellis, Manolis %A van Meurs, Joyce B %A Margulies, Kenneth B %A Dehghan, Abbas %A Levy, Daniel %A Olde, Björn %A Psaty, Bruce M %A Cupples, L Adrienne %A Jukema, J Wouter %A Djoussé, Luc %A Franco, Oscar H %A Boerwinkle, Eric %A Boyer, Laurie A %A Newton-Cheh, Christopher %A Butler, Javed %A Vasan, Ramachandran S %A Cappola, Thomas P %A Smith, Nicholas L %X

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

%B PLoS Genet %V 12 %P e1006034 %8 2016 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27149122?dopt=Abstract %R 10.1371/journal.pgen.1006034 %0 Journal Article %J Genome Biol %D 2016 %T DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. %A Ligthart, Symen %A Marzi, Carola %A Aslibekyan, Stella %A Mendelson, Michael M %A Conneely, Karen N %A Tanaka, Toshiko %A Colicino, Elena %A Waite, Lindsay L %A Joehanes, Roby %A Guan, Weihua %A Brody, Jennifer A %A Elks, Cathy %A Marioni, Riccardo %A Jhun, Min A %A Agha, Golareh %A Bressler, Jan %A Ward-Caviness, Cavin K %A Chen, Brian H %A Huan, Tianxiao %A Bakulski, Kelly %A Salfati, Elias L %A Fiorito, Giovanni %A Wahl, Simone %A Schramm, Katharina %A Sha, Jin %A Hernandez, Dena G %A Just, Allan C %A Smith, Jennifer A %A Sotoodehnia, Nona %A Pilling, Luke C %A Pankow, James S %A Tsao, Phil S %A Liu, Chunyu %A Zhao, Wei %A Guarrera, Simonetta %A Michopoulos, Vasiliki J %A Smith, Alicia K %A Peters, Marjolein J %A Melzer, David %A Vokonas, Pantel %A Fornage, Myriam %A Prokisch, Holger %A Bis, Joshua C %A Chu, Audrey Y %A Herder, Christian %A Grallert, Harald %A Yao, Chen %A Shah, Sonia %A McRae, Allan F %A Lin, Honghuang %A Horvath, Steve %A Fallin, Daniele %A Hofman, Albert %A Wareham, Nicholas J %A Wiggins, Kerri L %A Feinberg, Andrew P %A Starr, John M %A Visscher, Peter M %A Murabito, Joanne M %A Kardia, Sharon L R %A Absher, Devin M %A Binder, Elisabeth B %A Singleton, Andrew B %A Bandinelli, Stefania %A Peters, Annette %A Waldenberger, Melanie %A Matullo, Giuseppe %A Schwartz, Joel D %A Demerath, Ellen W %A Uitterlinden, André G %A van Meurs, Joyce B J %A Franco, Oscar H %A Chen, Yii-Der Ida %A Levy, Daniel %A Turner, Stephen T %A Deary, Ian J %A Ressler, Kerry J %A Dupuis, Josée %A Ferrucci, Luigi %A Ong, Ken K %A Assimes, Themistocles L %A Boerwinkle, Eric %A Koenig, Wolfgang %A Arnett, Donna K %A Baccarelli, Andrea A %A Benjamin, Emelia J %A Dehghan, Abbas %X

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

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

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

%B Genome Biol %V 17 %P 255 %8 2016 Dec 12 %G eng %N 1 %R 10.1186/s13059-016-1119-5 %0 Journal Article %J Genet Epidemiol %D 2016 %T An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group. %A Sung, Yun Ju %A Winkler, Thomas W %A Manning, Alisa K %A Aschard, Hugues %A Gudnason, Vilmundur %A Harris, Tamara B %A Smith, Albert V %A Boerwinkle, Eric %A Brown, Michael R %A Morrison, Alanna C %A Fornage, Myriam %A Lin, Li-An %A Richard, Melissa %A Bartz, Traci M %A Psaty, Bruce M %A Hayward, Caroline %A Polasek, Ozren %A Marten, Jonathan %A Rudan, Igor %A Feitosa, Mary F %A Kraja, Aldi T %A Province, Michael A %A Deng, Xuan %A Fisher, Virginia A %A Zhou, Yanhua %A Bielak, Lawrence F %A Smith, Jennifer %A Huffman, Jennifer E %A Padmanabhan, Sandosh %A Smith, Blair H %A Ding, Jingzhong %A Liu, Yongmei %A Lohman, Kurt %A Bouchard, Claude %A Rankinen, Tuomo %A Rice, Treva K %A Arnett, Donna %A Schwander, Karen %A Guo, Xiuqing %A Palmas, Walter %A Rotter, Jerome I %A Alfred, Tamuno %A Bottinger, Erwin P %A Loos, Ruth J F %A Amin, Najaf %A Franco, Oscar H %A van Duijn, Cornelia M %A Vojinovic, Dina %A Chasman, Daniel I %A Ridker, Paul M %A Rose, Lynda M %A Kardia, Sharon %A Zhu, Xiaofeng %A Rice, Kenneth %A Borecki, Ingrid B %A Rao, Dabeeru C %A Gauderman, W James %A Cupples, L Adrienne %X

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

%B Genet Epidemiol %V 40 %P 404-15 %8 2016 Jul %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27230302?dopt=Abstract %R 10.1002/gepi.21978 %0 Journal Article %J PLoS One %D 2016 %T Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. %A Dehghan, Abbas %A Bis, Joshua C %A White, Charles C %A Smith, Albert Vernon %A Morrison, Alanna C %A Cupples, L Adrienne %A Trompet, Stella %A Chasman, Daniel I %A Lumley, Thomas %A Völker, Uwe %A Buckley, Brendan M %A Ding, Jingzhong %A Jensen, Majken K %A Folsom, Aaron R %A Kritchevsky, Stephen B %A Girman, Cynthia J %A Ford, Ian %A Dörr, Marcus %A Salomaa, Veikko %A Uitterlinden, André G %A Eiriksdottir, Gudny %A Vasan, Ramachandran S %A Franceschini, Nora %A Carty, Cara L %A Virtamo, Jarmo %A Demissie, Serkalem %A Amouyel, Philippe %A Arveiler, Dominique %A Heckbert, Susan R %A Ferrieres, Jean %A Ducimetiere, Pierre %A Smith, Nicholas L %A Wang, Ying A %A Siscovick, David S %A Rice, Kenneth M %A Wiklund, Per-Gunnar %A Taylor, Kent D %A Evans, Alun %A Kee, Frank %A Rotter, Jerome I %A Karvanen, Juha %A Kuulasmaa, Kari %A Heiss, Gerardo %A Kraft, Peter %A Launer, Lenore J %A Hofman, Albert %A Markus, Marcello R P %A Rose, Lynda M %A Silander, Kaisa %A Wagner, Peter %A Benjamin, Emelia J %A Lohman, Kurt %A Stott, David J %A Rivadeneira, Fernando %A Harris, Tamara B %A Levy, Daniel %A Liu, Yongmei %A Rimm, Eric B %A Jukema, J Wouter %A Völzke, Henry %A Ridker, Paul M %A Blankenberg, Stefan %A Franco, Oscar H %A Gudnason, Vilmundur %A Psaty, Bruce M %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Aged %K Cohort Studies %K Cooperative Behavior %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

%B PLoS One %V 11 %P e0144997 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract %R 10.1371/journal.pone.0144997 %0 Journal Article %J Eur J Prev Cardiol %D 2016 %T Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration. %A Willeit, Peter %A Thompson, Simon G %A Agewall, Stefan %A Bergström, Göran %A Bickel, Horst %A Catapano, Alberico L %A Chien, Kuo-Liong %A de Groot, Eric %A Empana, Jean-Philippe %A Etgen, Thorleif %A Franco, Oscar H %A Iglseder, Bernhard %A Johnsen, Stein H %A Kavousi, Maryam %A Lind, Lars %A Liu, Jing %A Mathiesen, Ellisiv B %A Norata, Giuseppe D %A Olsen, Michael H %A Papagianni, Aikaterini %A Poppert, Holger %A Price, Jackie F %A Sacco, Ralph L %A Yanez, David N %A Zhao, Dong %A Schminke, Ulf %A Bülbül, Alpaslan %A Polak, Joseph F %A Sitzer, Matthias %A Hofman, Albert %A Grigore, Liliana %A Dörr, Marcus %A Su, Ta-Chen %A Ducimetiere, Pierre %A Xie, Wuxiang %A Ronkainen, Kimmo %A Kiechl, Stefan %A Rundek, Tatjana %A Robertson, Christine %A Fagerberg, Björn %A Bokemark, Lena %A Steinmetz, Helmuth %A Ikram, M Arfan %A Völzke, Henry %A Lin, Hung-Ju %A Plichart, Matthieu %A Tuomainen, Tomi-Pekka %A Desvarieux, Moïse %A McLachlan, Stela %A Schmidt, Caroline %A Kauhanen, Jussi %A Willeit, Johann %A Lorenz, Matthias W %A Sander, Dirk %X

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.

%B Eur J Prev Cardiol %V 23 %P 194-205 %8 2016 Jan %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25416041?dopt=Abstract %R 10.1177/2047487314560664 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2016 %T KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. %A Schumann, Gunter %A Liu, Chunyu %A O'Reilly, Paul %A Gao, He %A Song, Parkyong %A Xu, Bing %A Ruggeri, Barbara %A Amin, Najaf %A Jia, Tianye %A Preis, Sarah %A Segura Lepe, Marcelo %A Akira, Shizuo %A Barbieri, Caterina %A Baumeister, Sebastian %A Cauchi, Stephane %A Clarke, Toni-Kim %A Enroth, Stefan %A Fischer, Krista %A Hällfors, Jenni %A Harris, Sarah E %A Hieber, Saskia %A Hofer, Edith %A Hottenga, Jouke-Jan %A Johansson, Asa %A Joshi, Peter K %A Kaartinen, Niina %A Laitinen, Jaana %A Lemaitre, Rozenn %A Loukola, Anu %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Mangino, Massimo %A Manichaikul, Ani %A Mbarek, Hamdi %A Milaneschi, Yuri %A Moayyeri, Alireza %A Mukamal, Kenneth %A Nelson, Christopher %A Nettleton, Jennifer %A Partinen, Eemil %A Rawal, Rajesh %A Robino, Antonietta %A Rose, Lynda %A Sala, Cinzia %A Satoh, Takashi %A Schmidt, Reinhold %A Schraut, Katharina %A Scott, Robert %A Smith, Albert Vernon %A Starr, John M %A Teumer, Alexander %A Trompet, Stella %A Uitterlinden, André G %A Venturini, Cristina %A Vergnaud, Anne-Claire %A Verweij, Niek %A Vitart, Veronique %A Vuckovic, Dragana %A Wedenoja, Juho %A Yengo, Loic %A Yu, Bing %A Zhang, Weihua %A Zhao, Jing Hua %A Boomsma, Dorret I %A Chambers, John %A Chasman, Daniel I %A Daniela, Toniolo %A de Geus, Eco %A Deary, Ian %A Eriksson, Johan G %A Esko, Tõnu %A Eulenburg, Volker %A Franco, Oscar H %A Froguel, Philippe %A Gieger, Christian %A Grabe, Hans J %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Heath, Andrew C %A Hocking, Lynne %A Hofman, Albert %A Huth, Cornelia %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kaprio, Jaakko %A Kooner, Jaspal S %A Kutalik, Zoltán %A Lahti, Jari %A Langenberg, Claudia %A Lehtimäki, Terho %A Liu, Yongmei %A Madden, Pamela A F %A Martin, Nicholas %A Morrison, Alanna %A Penninx, Brenda %A Pirastu, Nicola %A Psaty, Bruce %A Raitakari, Olli %A Ridker, Paul %A Rose, Richard %A Rotter, Jerome I %A Samani, Nilesh J %A Schmidt, Helena %A Spector, Tim D %A Stott, David %A Strachan, David %A Tzoulaki, Ioanna %A van der Harst, Pim %A van Duijn, Cornelia M %A Marques-Vidal, Pedro %A Vollenweider, Peter %A Wareham, Nicholas J %A Whitfield, John B %A Wilson, James %A Wolffenbuttel, Bruce %A Bakalkin, Georgy %A Evangelou, Evangelos %A Liu, Yun %A Rice, Kenneth M %A Desrivières, Sylvane %A Kliewer, Steven A %A Mangelsdorf, David J %A Müller, Christian P %A Levy, Daniel %A Elliott, Paul %X

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

%B Proc Natl Acad Sci U S A %V 113 %P 14372-14377 %8 2016 Dec 13 %G eng %N 50 %R 10.1073/pnas.1611243113 %0 Journal Article %J Nat Genet %D 2016 %T Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. %A Liu, Chunyu %A Kraja, Aldi T %A Smith, Jennifer A %A Brody, Jennifer A %A Franceschini, Nora %A Bis, Joshua C %A Rice, Kenneth %A Morrison, Alanna C %A Lu, Yingchang %A Weiss, Stefan %A Guo, Xiuqing %A Palmas, Walter %A Martin, Lisa W %A Chen, Yii-Der Ida %A Surendran, Praveen %A Drenos, Fotios %A Cook, James P %A Auer, Paul L %A Chu, Audrey Y %A Giri, Ayush %A Zhao, Wei %A Jakobsdottir, Johanna %A Lin, Li-An %A Stafford, Jeanette M %A Amin, Najaf %A Mei, Hao %A Yao, Jie %A Voorman, Arend %A Larson, Martin G %A Grove, Megan L %A Smith, Albert V %A Hwang, Shih-Jen %A Chen, Han %A Huan, Tianxiao %A Kosova, Gulum %A Stitziel, Nathan O %A Kathiresan, Sekar %A Samani, Nilesh %A Schunkert, Heribert %A Deloukas, Panos %A Li, Man %A Fuchsberger, Christian %A Pattaro, Cristian %A Gorski, Mathias %A Kooperberg, Charles %A Papanicolaou, George J %A Rossouw, Jacques E %A Faul, Jessica D %A Kardia, Sharon L R %A Bouchard, Claude %A Raffel, Leslie J %A Uitterlinden, André G %A Franco, Oscar H %A Vasan, Ramachandran S %A O'Donnell, Christopher J %A Taylor, Kent D %A Liu, Kiang %A Bottinger, Erwin P %A Gottesman, Omri %A Daw, E Warwick %A Giulianini, Franco %A Ganesh, Santhi %A Salfati, Elias %A Harris, Tamara B %A Launer, Lenore J %A Dörr, Marcus %A Felix, Stephan B %A Rettig, Rainer %A Völzke, Henry %A Kim, Eric %A Lee, Wen-Jane %A Lee, I-Te %A Sheu, Wayne H-H %A Tsosie, Krystal S %A Edwards, Digna R Velez %A Liu, Yongmei %A Correa, Adolfo %A Weir, David R %A Völker, Uwe %A Ridker, Paul M %A Boerwinkle, Eric %A Gudnason, Vilmundur %A Reiner, Alexander P %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Edwards, Todd L %A Chakravarti, Aravinda %A Rotter, Jerome I %A Psaty, Bruce M %A Loos, Ruth J F %A Fornage, Myriam %A Ehret, Georg B %A Newton-Cheh, Christopher %A Levy, Daniel %A Chasman, Daniel I %X

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

%B Nat Genet %V 48 %P 1162-70 %8 2016 Oct %G eng %N 10 %R 10.1038/ng.3660 %0 Journal Article %J Hum Mol Genet %D 2016 %T A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. %A de Vries, Paul S %A Chasman, Daniel I %A Sabater-Lleal, Maria %A Chen, Ming-Huei %A Huffman, Jennifer E %A Steri, Maristella %A Tang, Weihong %A Teumer, Alexander %A Marioni, Riccardo E %A Grossmann, Vera %A Hottenga, Jouke J %A Trompet, Stella %A Müller-Nurasyid, Martina %A Zhao, Jing Hua %A Brody, Jennifer A %A Kleber, Marcus E %A Guo, Xiuqing %A Wang, Jie Jin %A Auer, Paul L %A Attia, John R %A Yanek, Lisa R %A Ahluwalia, Tarunveer S %A Lahti, Jari %A Venturini, Cristina %A Tanaka, Toshiko %A Bielak, Lawrence F %A Joshi, Peter K %A Rocanin-Arjo, Ares %A Kolcic, Ivana %A Navarro, Pau %A Rose, Lynda M %A Oldmeadow, Christopher %A Riess, Helene %A Mazur, Johanna %A Basu, Saonli %A Goel, Anuj %A Yang, Qiong %A Ghanbari, Mohsen %A Willemsen, Gonneke %A Rumley, Ann %A Fiorillo, Edoardo %A de Craen, Anton J M %A Grotevendt, Anne %A Scott, Robert %A Taylor, Kent D %A Delgado, Graciela E %A Yao, Jie %A Kifley, Annette %A Kooperberg, Charles %A Qayyum, Rehan %A Lopez, Lorna M %A Berentzen, Tina L %A Räikkönen, Katri %A Mangino, Massimo %A Bandinelli, Stefania %A Peyser, Patricia A %A Wild, Sarah %A Trégouët, David-Alexandre %A Wright, Alan F %A Marten, Jonathan %A Zemunik, Tatijana %A Morrison, Alanna C %A Sennblad, Bengt %A Tofler, Geoffrey %A de Maat, Moniek P M %A de Geus, Eco J C %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Binder, Harald %A Völker, Uwe %A Waldenberger, Melanie %A Khaw, Kay-Tee %A McKnight, Barbara %A Huang, Jie %A Jenny, Nancy S %A Holliday, Elizabeth G %A Qi, Lihong %A Mcevoy, Mark G %A Becker, Diane M %A Starr, John M %A Sarin, Antti-Pekka %A Hysi, Pirro G %A Hernandez, Dena G %A Jhun, Min A %A Campbell, Harry %A Hamsten, Anders %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Koenig, Wolfgang %A Psaty, Bruce M %A Haritunians, Talin %A Liu, Jingmin %A Palotie, Aarno %A Uitterlinden, André G %A Stott, David J %A Hofman, Albert %A Franco, Oscar H %A Polasek, Ozren %A Rudan, Igor %A Morange, Pierre-Emmanuel %A Wilson, James F %A Kardia, Sharon L R %A Ferrucci, Luigi %A Spector, Tim D %A Eriksson, Johan G %A Hansen, Torben %A Deary, Ian J %A Becker, Lewis C %A Scott, Rodney J %A Mitchell, Paul %A März, Winfried %A Wareham, Nick J %A Peters, Annette %A Greinacher, Andreas %A Wild, Philipp S %A Jukema, J Wouter %A Boomsma, Dorret I %A Hayward, Caroline %A Cucca, Francesco %A Tracy, Russell %A Watkins, Hugh %A Reiner, Alex P %A Folsom, Aaron R %A Ridker, Paul M %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

%B Hum Mol Genet %V 25 %P 358-70 %8 2016 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract %R 10.1093/hmg/ddv454 %0 Journal Article %J J Med Genet %D 2016 %T Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. %A van Leeuwen, Elisabeth M %A Sabo, Aniko %A Bis, Joshua C %A Huffman, Jennifer E %A Manichaikul, Ani %A Smith, Albert V %A Feitosa, Mary F %A Demissie, Serkalem %A Joshi, Peter K %A Duan, Qing %A Marten, Jonathan %A van Klinken, Jan B %A Surakka, Ida %A Nolte, Ilja M %A Zhang, Weihua %A Mbarek, Hamdi %A Li-Gao, Ruifang %A Trompet, Stella %A Verweij, Niek %A Evangelou, Evangelos %A Lyytikäinen, Leo-Pekka %A Tayo, Bamidele O %A Deelen, Joris %A van der Most, Peter J %A van der Laan, Sander W %A Arking, Dan E %A Morrison, Alanna %A Dehghan, Abbas %A Franco, Oscar H %A Hofman, Albert %A Rivadeneira, Fernando %A Sijbrands, Eric J %A Uitterlinden, André G %A Mychaleckyj, Josyf C %A Campbell, Archie %A Hocking, Lynne J %A Padmanabhan, Sandosh %A Brody, Jennifer A %A Rice, Kenneth M %A White, Charles C %A Harris, Tamara %A Isaacs, Aaron %A Campbell, Harry %A Lange, Leslie A %A Rudan, Igor %A Kolcic, Ivana %A Navarro, Pau %A Zemunik, Tatijana %A Salomaa, Veikko %A Kooner, Angad S %A Kooner, Jaspal S %A Lehne, Benjamin %A Scott, William R %A Tan, Sian-Tsung %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda W J H %A Willemsen, Gonneke %A de Mutsert, Renée %A Ford, Ian %A Gansevoort, Ron T %A Segura-Lepe, Marcelo P %A Raitakari, Olli T %A Viikari, Jorma S %A Nikus, Kjell %A Forrester, Terrence %A McKenzie, Colin A %A de Craen, Anton J M %A de Ruijter, Hester M %A Pasterkamp, Gerard %A Snieder, Harold %A Oldehinkel, Albertine J %A Slagboom, P Eline %A Cooper, Richard S %A Kähönen, Mika %A Lehtimäki, Terho %A Elliott, Paul %A van der Harst, Pim %A Jukema, J Wouter %A Mook-Kanamori, Dennis O %A Boomsma, Dorret I %A Chambers, John C %A Swertz, Morris %A Ripatti, Samuli %A Willems van Dijk, Ko %A Vitart, Veronique %A Polasek, Ozren %A Hayward, Caroline %A Wilson, James G %A Wilson, James F %A Gudnason, Vilmundur %A Rich, Stephen S %A Psaty, Bruce M %A Borecki, Ingrid B %A Boerwinkle, Eric %A Rotter, Jerome I %A Cupples, L Adrienne %A van Duijn, Cornelia M %X

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

%B J Med Genet %V 53 %P 441-9 %8 2016 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/27036123?dopt=Abstract %R 10.1136/jmedgenet-2015-103439 %0 Journal Article %J J Med Genet %D 2016 %T Meta-analysis of genome-wide association studies of HDL cholesterol response to statins. %A Postmus, Iris %A Warren, Helen R %A Trompet, Stella %A Arsenault, Benoit J %A Avery, Christy L %A Bis, Joshua C %A Chasman, Daniel I %A de Keyser, Catherine E %A Deshmukh, Harshal A %A Evans, Daniel S %A Feng, QiPing %A Li, Xiaohui %A Smit, Roelof A J %A Smith, Albert V %A Sun, Fangui %A Taylor, Kent D %A Arnold, Alice M %A Barnes, Michael R %A Barratt, Bryan J %A Betteridge, John %A Boekholdt, S Matthijs %A Boerwinkle, Eric %A Buckley, Brendan M %A Chen, Y-D Ida %A de Craen, Anton J M %A Cummings, Steven R %A Denny, Joshua C %A Dubé, Marie Pierre %A Durrington, Paul N %A Eiriksdottir, Gudny %A Ford, Ian %A Guo, Xiuqing %A Harris, Tamara B %A Heckbert, Susan R %A Hofman, Albert %A Hovingh, G Kees %A Kastelein, John J P %A Launer, Leonore J %A Liu, Ching-Ti %A Liu, Yongmei %A Lumley, Thomas %A McKeigue, Paul M %A Munroe, Patricia B %A Neil, Andrew %A Nickerson, Deborah A %A Nyberg, Fredrik %A O'Brien, Eoin %A O'Donnell, Christopher J %A Post, Wendy %A Poulter, Neil %A Vasan, Ramachandran S %A Rice, Kenneth %A Rich, Stephen S %A Rivadeneira, Fernando %A Sattar, Naveed %A Sever, Peter %A Shaw-Hawkins, Sue %A Shields, Denis C %A Slagboom, P Eline %A Smith, Nicholas L %A Smith, Joshua D %A Sotoodehnia, Nona %A Stanton, Alice %A Stott, David J %A Stricker, Bruno H %A Stürmer, Til %A Uitterlinden, André G %A Wei, Wei-Qi %A Westendorp, Rudi G J %A Whitsel, Eric A %A Wiggins, Kerri L %A Wilke, Russell A %A Ballantyne, Christie M %A Colhoun, Helen M %A Cupples, L Adrienne %A Franco, Oscar H %A Gudnason, Vilmundur %A Hitman, Graham %A Palmer, Colin N A %A Psaty, Bruce M %A Ridker, Paul M %A Stafford, Jeanette M %A Stein, Charles M %A Tardif, Jean-Claude %A Caulfield, Mark J %A Jukema, J Wouter %A Rotter, Jerome I %A Krauss, Ronald M %X

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

%B J Med Genet %V 53 %P 835-845 %8 2016 Dec %G eng %N 12 %R 10.1136/jmedgenet-2016-103966 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. %A Natarajan, Pradeep %A Bis, Joshua C %A Bielak, Lawrence F %A Cox, Amanda J %A Dörr, Marcus %A Feitosa, Mary F %A Franceschini, Nora %A Guo, Xiuqing %A Hwang, Shih-Jen %A Isaacs, Aaron %A Jhun, Min A %A Kavousi, Maryam %A Li-Gao, Ruifang %A Lyytikäinen, Leo-Pekka %A Marioni, Riccardo E %A Schminke, Ulf %A Stitziel, Nathan O %A Tada, Hayato %A van Setten, Jessica %A Smith, Albert V %A Vojinovic, Dina %A Yanek, Lisa R %A Yao, Jie %A Yerges-Armstrong, Laura M %A Amin, Najaf %A Baber, Usman %A Borecki, Ingrid B %A Carr, J Jeffrey %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A de Jong, Pim A %A de Koning, Harry %A de Vos, Bob D %A Demirkan, Ayse %A Fuster, Valentin %A Franco, Oscar H %A Goodarzi, Mark O %A Harris, Tamara B %A Heckbert, Susan R %A Heiss, Gerardo %A Hoffmann, Udo %A Hofman, Albert %A Išgum, Ivana %A Jukema, J Wouter %A Kähönen, Mika %A Kardia, Sharon L R %A Kral, Brian G %A Launer, Lenore J %A Massaro, Joseph %A Mehran, Roxana %A Mitchell, Braxton D %A Mosley, Thomas H %A de Mutsert, Renée %A Newman, Anne B %A Nguyen, Khanh-Dung %A North, Kari E %A O'Connell, Jeffrey R %A Oudkerk, Matthijs %A Pankow, James S %A Peloso, Gina M %A Post, Wendy %A Province, Michael A %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rivadeneira, Fernando %A Rosendaal, Frits %A Sartori, Samantha %A Taylor, Kent D %A Teumer, Alexander %A Trompet, Stella %A Turner, Stephen T %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Lugt, Aad %A Völker, Uwe %A Wardlaw, Joanna M %A Wassel, Christina L %A Weiss, Stefan %A Wojczynski, Mary K %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Bowden, Donald W %A Deary, Ian J %A Dehghan, Abbas %A Felix, Stephan B %A Gudnason, Vilmundur %A Lehtimäki, Terho %A Mathias, Rasika %A Mook-Kanamori, Dennis O %A Psaty, Bruce M %A Rader, Daniel J %A Rotter, Jerome I %A Wilson, James G %A van Duijn, Cornelia M %A Völzke, Henry %A Kathiresan, Sekar %A Peyser, Patricia A %A O'Donnell, Christopher J %X

BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.

METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).

CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

%B Circ Cardiovasc Genet %8 2016 Nov 21 %G eng %R 10.1161/CIRCGENETICS.116.001572 %0 Journal Article %J Am J Hum Genet %D 2016 %T Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. %A Eicher, John D %A Chami, Nathalie %A Kacprowski, Tim %A Nomura, Akihiro %A Chen, Ming-Huei %A Yanek, Lisa R %A Tajuddin, Salman M %A Schick, Ursula M %A Slater, Andrew J %A Pankratz, Nathan %A Polfus, Linda %A Schurmann, Claudia %A Giri, Ayush %A Brody, Jennifer A %A Lange, Leslie A %A Manichaikul, Ani %A Hill, W David %A Pazoki, Raha %A Elliot, Paul %A Evangelou, Evangelos %A Tzoulaki, Ioanna %A Gao, He %A Vergnaud, Anne-Claire %A Mathias, Rasika A %A Becker, Diane M %A Becker, Lewis C %A Burt, Amber %A Crosslin, David R %A Lyytikäinen, Leo-Pekka %A Nikus, Kjell %A Hernesniemi, Jussi %A Kähönen, Mika %A Raitoharju, Emma %A Mononen, Nina %A Raitakari, Olli T %A Lehtimäki, Terho %A Cushman, Mary %A Zakai, Neil A %A Nickerson, Deborah A %A Raffield, Laura M %A Quarells, Rakale %A Willer, Cristen J %A Peloso, Gina M %A Abecasis, Goncalo R %A Liu, Dajiang J %A Deloukas, Panos %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Fornage, Myriam %A Richard, Melissa %A Tardif, Jean-Claude %A Rioux, John D %A Dubé, Marie-Pierre %A de Denus, Simon %A Lu, Yingchang %A Bottinger, Erwin P %A Loos, Ruth J F %A Smith, Albert Vernon %A Harris, Tamara B %A Launer, Lenore J %A Gudnason, Vilmundur %A Velez Edwards, Digna R %A Torstenson, Eric S %A Liu, Yongmei %A Tracy, Russell P %A Rotter, Jerome I %A Rich, Stephen S %A Highland, Heather M %A Boerwinkle, Eric %A Li, Jin %A Lange, Ethan %A Wilson, James G %A Mihailov, Evelin %A Mägi, Reedik %A Hirschhorn, Joel %A Metspalu, Andres %A Esko, Tõnu %A Vacchi-Suzzi, Caterina %A Nalls, Mike A %A Zonderman, Alan B %A Evans, Michele K %A Engström, Gunnar %A Orho-Melander, Marju %A Melander, Olle %A O'Donoghue, Michelle L %A Waterworth, Dawn M %A Wallentin, Lars %A White, Harvey D %A Floyd, James S %A Bartz, Traci M %A Rice, Kenneth M %A Psaty, Bruce M %A Starr, J M %A Liewald, David C M %A Hayward, Caroline %A Deary, Ian J %A Greinacher, Andreas %A Völker, Uwe %A Thiele, Thomas %A Völzke, Henry %A van Rooij, Frank J A %A Uitterlinden, André G %A Franco, Oscar H %A Dehghan, Abbas %A Edwards, Todd L %A Ganesh, Santhi K %A Kathiresan, Sekar %A Faraday, Nauder %A Auer, Paul L %A Reiner, Alex P %A Lettre, Guillaume %A Johnson, Andrew D %X

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

%B Am J Hum Genet %V 99 %P 40-55 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346686?dopt=Abstract %R 10.1016/j.ajhg.2016.05.005 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. %A Yu, Bing %A Pulit, Sara L %A Hwang, Shih-Jen %A Brody, Jennifer A %A Amin, Najaf %A Auer, Paul L %A Bis, Joshua C %A Boerwinkle, Eric %A Burke, Gregory L %A Chakravarti, Aravinda %A Correa, Adolfo %A Dreisbach, Albert W %A Franco, Oscar H %A Ehret, Georg B %A Franceschini, Nora %A Hofman, Albert %A Lin, Dan-Yu %A Metcalf, Ginger A %A Musani, Solomon K %A Muzny, Donna %A Palmas, Walter %A Raffel, Leslie %A Reiner, Alex %A Rice, Ken %A Rotter, Jerome I %A Veeraraghavan, Narayanan %A Fox, Ervin %A Guo, Xiuqing %A North, Kari E %A Gibbs, Richard A %A van Duijn, Cornelia M %A Psaty, Bruce M %A Levy, Daniel %A Newton-Cheh, Christopher %A Morrison, Alanna C %X

BACKGROUND: Rare genetic variants influence blood pressure (BP).

METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).

CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

%B Circ Cardiovasc Genet %V 9 %P 64-70 %8 2016 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26658788?dopt=Abstract %R 10.1161/CIRCGENETICS.115.001215 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. %A Li, Man %A Li, Yong %A Weeks, Olivia %A Mijatovic, Vladan %A Teumer, Alexander %A Huffman, Jennifer E %A Tromp, Gerard %A Fuchsberger, Christian %A Gorski, Mathias %A Lyytikäinen, Leo-Pekka %A Nutile, Teresa %A Sedaghat, Sanaz %A Sorice, Rossella %A Tin, Adrienne %A Yang, Qiong %A Ahluwalia, Tarunveer S %A Arking, Dan E %A Bihlmeyer, Nathan A %A Böger, Carsten A %A Carroll, Robert J %A Chasman, Daniel I %A Cornelis, Marilyn C %A Dehghan, Abbas %A Faul, Jessica D %A Feitosa, Mary F %A Gambaro, Giovanni %A Gasparini, Paolo %A Giulianini, Franco %A Heid, Iris %A Huang, Jinyan %A Imboden, Medea %A Jackson, Anne U %A Jeff, Janina %A Jhun, Min A %A Katz, Ronit %A Kifley, Annette %A Kilpeläinen, Tuomas O %A Kumar, Ashish %A Laakso, Markku %A Li-Gao, Ruifang %A Lohman, Kurt %A Lu, Yingchang %A Mägi, Reedik %A Malerba, Giovanni %A Mihailov, Evelin %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Robino, Antonietta %A Ruderfer, Douglas %A Salvi, Erika %A Schick, Ursula M %A Schulz, Christina-Alexandra %A Smith, Albert V %A Smith, Jennifer A %A Traglia, Michela %A Yerges-Armstrong, Laura M %A Zhao, Wei %A Goodarzi, Mark O %A Kraja, Aldi T %A Liu, Chunyu %A Wessel, Jennifer %A Boerwinkle, Eric %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Braga, Daniele %A Brandslund, Ivan %A Brody, Jennifer A %A Campbell, Archie %A Carey, David J %A Christensen, Cramer %A Coresh, Josef %A Crook, Errol %A Curhan, Gary C %A Cusi, Daniele %A de Boer, Ian H %A de Vries, Aiko P J %A Denny, Joshua C %A Devuyst, Olivier %A Dreisbach, Albert W %A Endlich, Karlhans %A Esko, Tõnu %A Franco, Oscar H %A Fulop, Tibor %A Gerhard, Glenn S %A Glümer, Charlotte %A Gottesman, Omri %A Grarup, Niels %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hocking, Lynne %A Hofman, Albert %A Hu, Frank B %A Husemoen, Lise Lotte N %A Jackson, Rebecca D %A Jørgensen, Torben %A Jørgensen, Marit E %A Kähönen, Mika %A Kardia, Sharon L R %A König, Wolfgang %A Kooperberg, Charles %A Kriebel, Jennifer %A Launer, Lenore J %A Lauritzen, Torsten %A Lehtimäki, Terho %A Levy, Daniel %A Linksted, Pamela %A Linneberg, Allan %A Liu, Yongmei %A Loos, Ruth J F %A Lupo, Antonio %A Meisinger, Christine %A Melander, Olle %A Metspalu, Andres %A Mitchell, Paul %A Nauck, Matthias %A Nürnberg, Peter %A Orho-Melander, Marju %A Parsa, Afshin %A Pedersen, Oluf %A Peters, Annette %A Peters, Ulrike %A Polasek, Ozren %A Porteous, David %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Qi, Lu %A Raitakari, Olli T %A Reiner, Alex P %A Rettig, Rainer %A Ridker, Paul M %A Rivadeneira, Fernando %A Rossouw, Jacques E %A Schmidt, Frank %A Siscovick, David %A Soranzo, Nicole %A Strauch, Konstantin %A Toniolo, Daniela %A Turner, Stephen T %A Uitterlinden, André G %A Ulivi, Sheila %A Velayutham, Dinesh %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wang, Jie Jin %A Weir, David R %A Witte, Daniel %A Kuivaniemi, Helena %A Fox, Caroline S %A Franceschini, Nora %A Goessling, Wolfram %A Köttgen, Anna %A Chu, Audrey Y %X

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

%B J Am Soc Nephrol %8 2016 Dec 05 %G eng %R 10.1681/ASN.2016020131 %0 Journal Article %J J Clin Endocrinol Metab %D 2016 %T Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis. %A Chaker, Layal %A Baumgartner, Christine %A den Elzen, Wendy P J %A Collet, Tinh-Hai %A Ikram, M Arfan %A Blum, Manuel R %A Dehghan, Abbas %A Drechsler, Christiane %A Luben, Robert N %A Portegies, Marileen L P %A Iervasi, Giorgio %A Medici, Marco %A Stott, David J %A Dullaart, Robin P %A Ford, Ian %A Bremner, Alexandra %A Newman, Anne B %A Wanner, Christoph %A Sgarbi, José A %A Dörr, Marcus %A Longstreth, W T %A Psaty, Bruce M %A Ferrucci, Luigi %A Maciel, Rui M B %A Westendorp, Rudi G %A Jukema, J Wouter %A Ceresini, Graziano %A Imaizumi, Misa %A Hofman, Albert %A Bakker, Stephan J L %A Franklyn, Jayne A %A Khaw, Kay-Tee %A Bauer, Douglas C %A Walsh, John P %A Razvi, Salman %A Gussekloo, Jacobijn %A Völzke, Henry %A Franco, Oscar H %A Cappola, Anne R %A Rodondi, Nicolas %A Peeters, Robin P %X

CONTEXT: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.

DESIGN AND SETTING: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L.

RESULTS: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes.

CONCLUSION: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.

%B J Clin Endocrinol Metab %V 101 %P 4270-4282 %8 2016 Nov %G eng %N 11 %R 10.1210/jc.2016-2255 %0 Journal Article %J Am J Hum Genet %D 2016 %T Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis. %A Polfus, Linda M %A Khajuria, Rajiv K %A Schick, Ursula M %A Pankratz, Nathan %A Pazoki, Raha %A Brody, Jennifer A %A Chen, Ming-Huei %A Auer, Paul L %A Floyd, James S %A Huang, Jie %A Lange, Leslie %A van Rooij, Frank J A %A Gibbs, Richard A %A Metcalf, Ginger %A Muzny, Donna %A Veeraraghavan, Narayanan %A Walter, Klaudia %A Chen, Lu %A Yanek, Lisa %A Becker, Lewis C %A Peloso, Gina M %A Wakabayashi, Aoi %A Kals, Mart %A Metspalu, Andres %A Esko, Tõnu %A Fox, Keolu %A Wallace, Robert %A Franceschini, Nora %A Matijevic, Nena %A Rice, Kenneth M %A Bartz, Traci M %A Lyytikäinen, Leo-Pekka %A Kähönen, Mika %A Lehtimäki, Terho %A Raitakari, Olli T %A Li-Gao, Ruifang %A Mook-Kanamori, Dennis O %A Lettre, Guillaume %A van Duijn, Cornelia M %A Franco, Oscar H %A Rich, Stephen S %A Rivadeneira, Fernando %A Hofman, Albert %A Uitterlinden, André G %A Wilson, James G %A Psaty, Bruce M %A Soranzo, Nicole %A Dehghan, Abbas %A Boerwinkle, Eric %A Zhang, Xiaoling %A Johnson, Andrew D %A O'Donnell, Christopher J %A Johnsen, Jill M %A Reiner, Alexander P %A Ganesh, Santhi K %A Sankaran, Vijay G %B Am J Hum Genet %V 99 %P 785 %8 2016 Sep 01 %G eng %N 3 %R 10.1016/j.ajhg.2016.08.002 %0 Journal Article %J JAMA Cardiol %D 2017 %T Association of Coronary Artery Calcium Score vs Age With Cardiovascular Risk in Older Adults: An Analysis of Pooled Population-Based Studies. %A Yano, Yuichiro %A O'Donnell, Christopher J %A Kuller, Lewis %A Kavousi, Maryam %A Erbel, Raimund %A Ning, Hongyan %A D'Agostino, Ralph %A Newman, Anne B %A Nasir, Khurram %A Hofman, Albert %A Lehmann, Nils %A Dhana, Klodian %A Blankstein, Ron %A Hoffmann, Udo %A Möhlenkamp, Stefan %A Massaro, Joseph M %A Mahabadi, Amir-Abbas %A Lima, João A C %A Ikram, M Arfan %A Jöckel, Karl-Heinz %A Franco, Oscar H %A Liu, Kiang %A Lloyd-Jones, Donald %A Greenland, Philip %X

Importance: Besides age, other discriminators of atherosclerotic cardiovascular disease (ASCVD) risk are needed in older adults.

Objectives: To examine the predictive ability of coronary artery calcium (CAC) score vs age for incident ASCVD and how risk prediction changes by adding CAC score and removing only age from prediction models.

Design, Setting, and Participants: We conducted an analysis of pooled US population-based studies, including the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Results were compared with 2 European cohorts, the Rotterdam Study and the Heinz Nixdorf Recall Study. Participants underwent CAC scoring between 1998 and 2006 using cardiac computed tomography. The participants included adults older than 60 years without known ASCVD at baseline.

Exposures: Coronary artery calcium scores.

Main Outcomes and Measures: Incident ASCVD events including coronary heart disease (CHD) and stroke.

Results: The study included 4778 participants from 3 US cohorts, with a mean age of 70.1 years; 2582 (54.0%) were women, and 2431 (50.9%) were nonwhite. Over 11 years of follow-up (44 152 person-years), 405 CHD and 228 stroke events occurred. Coronary artery calcium score (vs age) had a greater association with incident CHD (C statistic, 0.733 vs 0.690; C statistics difference, 0.043; 95% CI of difference, 0.009-0.075) and modestly improved prediction of incident stroke (C statistic, 0.695 vs 0.670; C statistics difference, 0.025; 95% CI of difference, -0.015 to 0.064). Adding CAC score to models including traditional cardiovascular risk factors, with only age being removed, provided improved discrimination for incident CHD (C statistic, 0.735 vs 0.703; C statistics difference, 0.032; 95% CI of difference, 0.002-0.062) but not for stroke. Coronary artery calcium score was more likely than age to provide higher category-free net reclassification improvement among participants who experienced an ASCVD event (0.390; 95% CI, 0.312-0.467 vs 0.08; 95% CI -0.001 to 0.181) and to result in more accurate reclassification of risk for ASCVD events among these individuals. The findings were similar in the 2 European cohorts (n = 4990).

Conclusions and Relevance: Coronary artery calcium may be an alternative marker besides age to better discriminate between lower and higher CHD risk in older adults. Whether CAC score can assist in guiding the decision to initiate statin treatment for primary prevention in older adults requires further investigation.

%B JAMA Cardiol %8 2017 Jul 26 %G eng %R 10.1001/jamacardio.2017.2498 %0 Journal Article %J PLoS One %D 2017 %T Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. %A de Vries, Paul S %A Sabater-Lleal, Maria %A Chasman, Daniel I %A Trompet, Stella %A Ahluwalia, Tarunveer S %A Teumer, Alexander %A Kleber, Marcus E %A Chen, Ming-Huei %A Wang, Jie Jin %A Attia, John R %A Marioni, Riccardo E %A Steri, Maristella %A Weng, Lu-Chen %A Pool, Rene %A Grossmann, Vera %A Brody, Jennifer A %A Venturini, Cristina %A Tanaka, Toshiko %A Rose, Lynda M %A Oldmeadow, Christopher %A Mazur, Johanna %A Basu, Saonli %A Frånberg, Mattias %A Yang, Qiong %A Ligthart, Symen %A Hottenga, Jouke J %A Rumley, Ann %A Mulas, Antonella %A de Craen, Anton J M %A Grotevendt, Anne %A Taylor, Kent D %A Delgado, Graciela E %A Kifley, Annette %A Lopez, Lorna M %A Berentzen, Tina L %A Mangino, Massimo %A Bandinelli, Stefania %A Morrison, Alanna C %A Hamsten, Anders %A Tofler, Geoffrey %A de Maat, Moniek P M %A Draisma, Harmen H M %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Lackner, Karl J %A Völker, Uwe %A McKnight, Barbara %A Huang, Jie %A Holliday, Elizabeth G %A McEvoy, Mark A %A Starr, John M %A Hysi, Pirro G %A Hernandez, Dena G %A Guan, Weihua %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Psaty, Bruce M %A Uitterlinden, André G %A de Geus, Eco J C %A Stott, David J %A Binder, Harald %A Hofman, Albert %A Franco, Oscar H %A Rotter, Jerome I %A Ferrucci, Luigi %A Spector, Tim D %A Deary, Ian J %A März, Winfried %A Greinacher, Andreas %A Wild, Philipp S %A Cucca, Francesco %A Boomsma, Dorret I %A Watkins, Hugh %A Tang, Weihong %A Ridker, Paul M %A Jukema, Jan W %A Scott, Rodney J %A Mitchell, Paul %A Hansen, Torben %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

%B PLoS One %V 12 %P e0167742 %8 2017 %G eng %N 1 %R 10.1371/journal.pone.0167742 %0 Journal Article %J Am J Hum Genet %D 2017 %T DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. %A Richard, Melissa A %A Huan, Tianxiao %A Ligthart, Symen %A Gondalia, Rahul %A Jhun, Min A %A Brody, Jennifer A %A Irvin, Marguerite R %A Marioni, Riccardo %A Shen, Jincheng %A Tsai, Pei-Chien %A Montasser, May E %A Jia, Yucheng %A Syme, Catriona %A Salfati, Elias L %A Boerwinkle, Eric %A Guan, Weihua %A Mosley, Thomas H %A Bressler, Jan %A Morrison, Alanna C %A Liu, Chunyu %A Mendelson, Michael M %A Uitterlinden, André G %A van Meurs, Joyce B %A Franco, Oscar H %A Zhang, Guosheng %A Li, Yun %A Stewart, James D %A Bis, Joshua C %A Psaty, Bruce M %A Chen, Yii-Der Ida %A Kardia, Sharon L R %A Zhao, Wei %A Turner, Stephen T %A Absher, Devin %A Aslibekyan, Stella %A Starr, John M %A McRae, Allan F %A Hou, Lifang %A Just, Allan C %A Schwartz, Joel D %A Vokonas, Pantel S %A Menni, Cristina %A Spector, Tim D %A Shuldiner, Alan %A Damcott, Coleen M %A Rotter, Jerome I %A Palmas, Walter %A Liu, Yongmei %A Paus, Tomáš %A Horvath, Steve %A O'Connell, Jeffrey R %A Guo, Xiuqing %A Pausova, Zdenka %A Assimes, Themistocles L %A Sotoodehnia, Nona %A Smith, Jennifer A %A Arnett, Donna K %A Deary, Ian J %A Baccarelli, Andrea A %A Bell, Jordana T %A Whitsel, Eric %A Dehghan, Abbas %A Levy, Daniel %A Fornage, Myriam %K Aged %K Blood Pressure %K CpG Islands %K Cross-Sectional Studies %K DNA Methylation %K Epigenesis, Genetic %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Middle Aged %K Nerve Tissue Proteins %K Quantitative Trait Loci %K Tetraspanins %X

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

%B Am J Hum Genet %V 101 %P 888-902 %8 2017 Dec 07 %G eng %N 6 %R 10.1016/j.ajhg.2017.09.028 %0 Journal Article %J Sci Rep %D 2017 %T Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. %A Weng, Lu-Chen %A Lunetta, Kathryn L %A Müller-Nurasyid, Martina %A Smith, Albert Vernon %A Thériault, Sébastien %A Weeke, Peter E %A Barnard, John %A Bis, Joshua C %A Lyytikäinen, Leo-Pekka %A Kleber, Marcus E %A Martinsson, Andreas %A Lin, Henry J %A Rienstra, Michiel %A Trompet, Stella %A Krijthe, Bouwe P %A Dörr, Marcus %A Klarin, Derek %A Chasman, Daniel I %A Sinner, Moritz F %A Waldenberger, Melanie %A Launer, Lenore J %A Harris, Tamara B %A Soliman, Elsayed Z %A Alonso, Alvaro %A Paré, Guillaume %A Teixeira, Pedro L %A Denny, Joshua C %A Shoemaker, M Benjamin %A Van Wagoner, David R %A Smith, Jonathan D %A Psaty, Bruce M %A Sotoodehnia, Nona %A Taylor, Kent D %A Kähönen, Mika %A Nikus, Kjell %A Delgado, Graciela E %A Melander, Olle %A Engström, Gunnar %A Yao, Jie %A Guo, Xiuqing %A Christophersen, Ingrid E %A Ellinor, Patrick T %A Geelhoed, Bastiaan %A Verweij, Niek %A Macfarlane, Peter %A Ford, Ian %A Heeringa, Jan %A Franco, Oscar H %A Uitterlinden, André G %A Völker, Uwe %A Teumer, Alexander %A Rose, Lynda M %A Kääb, Stefan %A Gudnason, Vilmundur %A Arking, Dan E %A Conen, David %A Roden, Dan M %A Chung, Mina K %A Heckbert, Susan R %A Benjamin, Emelia J %A Lehtimäki, Terho %A März, Winfried %A Smith, J Gustav %A Rotter, Jerome I %A van der Harst, Pim %A Jukema, J Wouter %A Stricker, Bruno H %A Felix, Stephan B %A Albert, Christine M %A Lubitz, Steven A %X

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

%B Sci Rep %V 7 %P 11303 %8 2017 Sep 12 %G eng %N 1 %R 10.1038/s41598-017-09396-7 %0 Journal Article %J Nat Commun %D 2017 %T Genetic loci associated with heart rate variability and their effects on cardiac disease risk. %A Nolte, Ilja M %A Munoz, M Loretto %A Tragante, Vinicius %A Amare, Azmeraw T %A Jansen, Rick %A Vaez, Ahmad %A von der Heyde, Benedikt %A Avery, Christy L %A Bis, Joshua C %A Dierckx, Bram %A van Dongen, Jenny %A Gogarten, Stephanie M %A Goyette, Philippe %A Hernesniemi, Jussi %A Huikari, Ville %A Hwang, Shih-Jen %A Jaju, Deepali %A Kerr, Kathleen F %A Kluttig, Alexander %A Krijthe, Bouwe P %A Kumar, Jitender %A van der Laan, Sander W %A Lyytikäinen, Leo-Pekka %A Maihofer, Adam X %A Minassian, Arpi %A van der Most, Peter J %A Müller-Nurasyid, Martina %A Nivard, Michel %A Salvi, Erika %A Stewart, James D %A Thayer, Julian F %A Verweij, Niek %A Wong, Andrew %A Zabaneh, Delilah %A Zafarmand, Mohammad H %A Abdellaoui, Abdel %A Albarwani, Sulayma %A Albert, Christine %A Alonso, Alvaro %A Ashar, Foram %A Auvinen, Juha %A Axelsson, Tomas %A Baker, Dewleen G %A de Bakker, Paul I W %A Barcella, Matteo %A Bayoumi, Riad %A Bieringa, Rob J %A Boomsma, Dorret %A Boucher, Gabrielle %A Britton, Annie R %A Christophersen, Ingrid %A Dietrich, Andrea %A Ehret, George B %A Ellinor, Patrick T %A Eskola, Markku %A Felix, Janine F %A Floras, John S %A Franco, Oscar H %A Friberg, Peter %A Gademan, Maaike G J %A Geyer, Mark A %A Giedraitis, Vilmantas %A Hartman, Catharina A %A Hemerich, Daiane %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huikuri, Heikki %A Hutri-Kähönen, Nina %A Jouven, Xavier %A Junttila, Juhani %A Juonala, Markus %A Kiviniemi, Antti M %A Kors, Jan A %A Kumari, Meena %A Kuznetsova, Tatiana %A Laurie, Cathy C %A Lefrandt, Joop D %A Li, Yong %A Li, Yun %A Liao, Duanping %A Limacher, Marian C %A Lin, Henry J %A Lindgren, Cecilia M %A Lubitz, Steven A %A Mahajan, Anubha %A McKnight, Barbara %A Zu Schwabedissen, Henriette Meyer %A Milaneschi, Yuri %A Mononen, Nina %A Morris, Andrew P %A Nalls, Mike A %A Navis, Gerjan %A Neijts, Melanie %A Nikus, Kjell %A North, Kari E %A O'Connor, Daniel T %A Ormel, Johan %A Perz, Siegfried %A Peters, Annette %A Psaty, Bruce M %A Raitakari, Olli T %A Risbrough, Victoria B %A Sinner, Moritz F %A Siscovick, David %A Smit, Johannes H %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Staessen, Jan A %A Stein, Phyllis K %A Stilp, Adrienne M %A Stolarz-Skrzypek, Katarzyna %A Strauch, Konstantin %A Sundström, Johan %A Swenne, Cees A %A Syvänen, Ann-Christine %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thornton, Timothy A %A Tinker, Lesley E %A Uitterlinden, André G %A van Setten, Jessica %A Voss, Andreas %A Waldenberger, Melanie %A Wilhelmsen, Kirk C %A Willemsen, Gonneke %A Wong, Quenna %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Cusi, Daniele %A Evans, Michele K %A Greiser, Halina K %A van der Harst, Pim %A Hassan, Mohammad %A Ingelsson, Erik %A Jarvelin, Marjo-Riitta %A Kääb, Stefan %A Kähönen, Mika %A Kivimaki, Mika %A Kooperberg, Charles %A Kuh, Diana %A Lehtimäki, Terho %A Lind, Lars %A Nievergelt, Caroline M %A O'Donnell, Chris J %A Oldehinkel, Albertine J %A Penninx, Brenda %A Reiner, Alexander P %A Riese, Harriëtte %A van Roon, Arie M %A Rioux, John D %A Rotter, Jerome I %A Sofer, Tamar %A Stricker, Bruno H %A Tiemeier, Henning %A Vrijkotte, Tanja G M %A Asselbergs, Folkert W %A Brundel, Bianca J J M %A Heckbert, Susan R %A Whitsel, Eric A %A den Hoed, Marcel %A Snieder, Harold %A de Geus, Eco J C %X

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 %B Nat Commun %V 8 %P 15805 %8 2017 Jun 14 %G eng %R 10.1038/ncomms15805 %0 Journal Article %J PLoS One %D 2017 %T Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. %A Mozaffarian, Dariush %A Dashti, Hassan S %A Wojczynski, Mary K %A Chu, Audrey Y %A Nettleton, Jennifer A %A Männistö, Satu %A Kristiansson, Kati %A Reedik, Mägi %A Lahti, Jari %A Houston, Denise K %A Cornelis, Marilyn C %A van Rooij, Frank J A %A Dimitriou, Maria %A Kanoni, Stavroula %A Mikkilä, Vera %A Steffen, Lyn M %A de Oliveira Otto, Marcia C %A Qi, Lu %A Psaty, Bruce %A Djoussé, Luc %A Rotter, Jerome I %A Harald, Kennet %A Perola, Markus %A Rissanen, Harri %A Jula, Antti %A Krista, Fischer %A Mihailov, Evelin %A Feitosa, Mary F %A Ngwa, Julius S %A Xue, Luting %A Jacques, Paul F %A Perälä, Mia-Maria %A Palotie, Aarno %A Liu, Yongmei %A Nalls, Nike A %A Ferrucci, Luigi %A Hernandez, Dena %A Manichaikul, Ani %A Tsai, Michael Y %A Kiefte-de Jong, Jessica C %A Hofman, Albert %A Uitterlinden, André G %A Rallidis, Loukianos %A Ridker, Paul M %A Rose, Lynda M %A Buring, Julie E %A Lehtimäki, Terho %A Kähönen, Mika %A Viikari, Jorma %A Lemaitre, Rozenn %A Salomaa, Veikko %A Knekt, Paul %A Metspalu, Andres %A Borecki, Ingrid B %A Cupples, L Adrienne %A Eriksson, Johan G %A Kritchevsky, Stephen B %A Bandinelli, Stefania %A Siscovick, David %A Franco, Oscar H %A Deloukas, Panos %A Dedoussis, George %A Chasman, Daniel I %A Raitakari, Olli %A Tanaka, Toshiko %K Adult %K Aged %K Cohort Studies %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Europe %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Seafood %K United States %X

BACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.

OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.

DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.

RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.

CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

%B PLoS One %V 12 %P e0186456 %8 2017 %G eng %N 12 %R 10.1371/journal.pone.0186456 %0 Journal Article %J J Med Genet %D 2017 %T A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. %A Noordam, Raymond %A Sitlani, Colleen M %A Avery, Christy L %A Stewart, James D %A Gogarten, Stephanie M %A Wiggins, Kerri L %A Trompet, Stella %A Warren, Helen R %A Sun, Fangui %A Evans, Daniel S %A Li, Xiaohui %A Li, Jin %A Smith, Albert V %A Bis, Joshua C %A Brody, Jennifer A %A Busch, Evan L %A Caulfield, Mark J %A Chen, Yii-der I %A Cummings, Steven R %A Cupples, L Adrienne %A Duan, Qing %A Franco, Oscar H %A Méndez-Giráldez, Rául %A Harris, Tamara B %A Heckbert, Susan R %A van Heemst, Diana %A Hofman, Albert %A Floyd, James S %A Kors, Jan A %A Launer, Lenore J %A Li, Yun %A Li-Gao, Ruifang %A Lange, Leslie A %A Lin, Henry J %A de Mutsert, Renée %A Napier, Melanie D %A Newton-Cheh, Christopher %A Poulter, Neil %A Reiner, Alexander P %A Rice, Kenneth M %A Roach, Jeffrey %A Rodriguez, Carlos J %A Rosendaal, Frits R %A Sattar, Naveed %A Sever, Peter %A Seyerle, Amanda A %A Slagboom, P Eline %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stott, David J %A Stürmer, Til %A Taylor, Kent D %A Thornton, Timothy A %A Uitterlinden, André G %A Wilhelmsen, Kirk C %A Wilson, James G %A Gudnason, Vilmundur %A Jukema, J Wouter %A Laurie, Cathy C %A Liu, Yongmei %A Mook-Kanamori, Dennis O %A Munroe, Patricia B %A Rotter, Jerome I %A Vasan, Ramachandran S %A Psaty, Bruce M %A Stricker, Bruno H %A Whitsel, Eric A %X

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

%B J Med Genet %V 54 %P 313-323 %8 2017 May %G eng %N 5 %R 10.1136/jmedgenet-2016-104112 %0 Journal Article %J Mol Nutr Food Res %D 2017 %T Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent. %A Smith, Caren E %A Follis, Jack L %A Dashti, Hassan S %A Tanaka, Toshiko %A Graff, Mariaelisa %A Fretts, Amanda M %A Kilpeläinen, Tuomas O %A Wojczynski, Mary K %A Richardson, Kris %A Nalls, Mike A %A Schulz, Christina-Alexandra %A Liu, Yongmei %A Frazier-Wood, Alexis C %A van Eekelen, Esther %A Wang, Carol %A de Vries, Paul S %A Mikkilä, Vera %A Rohde, Rebecca %A Psaty, Bruce M %A Hansen, Torben %A Feitosa, Mary F %A Lai, Chao-Qiang %A Houston, Denise K %A Ferruci, Luigi %A Ericson, Ulrika %A Wang, Zhe %A de Mutsert, Renée %A Oddy, Wendy H %A de Jonge, Ester A L %A Seppälä, Ilkka %A Justice, Anne E %A Lemaitre, Rozenn N %A Sørensen, Thorkild I A %A Province, Michael A %A Parnell, Laurence D %A Garcia, Melissa E %A Bandinelli, Stefania %A Orho-Melander, Marju %A Rich, Stephen S %A Rosendaal, Frits R %A Pennell, Craig E %A Kiefte-de Jong, Jessica C %A Kähönen, Mika %A Young, Kristin L %A Pedersen, Oluf %A Aslibekyan, Stella %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Zillikens, M Carola %A Raitakari, Olli T %A North, Kari E %A Overvad, Kim %A Arnett, Donna K %A Hofman, Albert %A Lehtimäki, Terho %A Tjønneland, Anne %A Uitterlinden, André G %A Rivadeneira, Fernando %A Franco, Oscar H %A German, J Bruce %A Siscovick, David S %A Cupples, L Adrienne %A Ordovas, Jose M %X

SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.

METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.

CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.

%B Mol Nutr Food Res %8 2017 Sep 21 %G eng %R 10.1002/mnfr.201700347 %0 Journal Article %J Am J Hum Genet %D 2017 %T Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. %A van Rooij, Frank J A %A Qayyum, Rehan %A Smith, Albert V %A Zhou, Yi %A Trompet, Stella %A Tanaka, Toshiko %A Keller, Margaux F %A Chang, Li-Ching %A Schmidt, Helena %A Yang, Min-Lee %A Chen, Ming-Huei %A Hayes, James %A Johnson, Andrew D %A Yanek, Lisa R %A Mueller, Christian %A Lange, Leslie %A Floyd, James S %A Ghanbari, Mohsen %A Zonderman, Alan B %A Jukema, J Wouter %A Hofman, Albert %A van Duijn, Cornelia M %A Desch, Karl C %A Saba, Yasaman %A Ozel, Ayse B %A Snively, Beverly M %A Wu, Jer-Yuarn %A Schmidt, Reinhold %A Fornage, Myriam %A Klein, Robert J %A Fox, Caroline S %A Matsuda, Koichi %A Kamatani, Naoyuki %A Wild, Philipp S %A Stott, David J %A Ford, Ian %A Slagboom, P Eline %A Yang, Jaden %A Chu, Audrey Y %A Lambert, Amy J %A Uitterlinden, André G %A Franco, Oscar H %A Hofer, Edith %A Ginsburg, David %A Hu, Bella %A Keating, Brendan %A Schick, Ursula M %A Brody, Jennifer A %A Li, Jun Z %A Chen, Zhao %A Zeller, Tanja %A Guralnik, Jack M %A Chasman, Daniel I %A Peters, Luanne L %A Kubo, Michiaki %A Becker, Diane M %A Li, Jin %A Eiriksdottir, Gudny %A Rotter, Jerome I %A Levy, Daniel %A Grossmann, Vera %A Patel, Kushang V %A Chen, Chien-Hsiun %A Ridker, Paul M %A Tang, Hua %A Launer, Lenore J %A Rice, Kenneth M %A Li-Gao, Ruifang %A Ferrucci, Luigi %A Evans, Michelle K %A Choudhuri, Avik %A Trompouki, Eirini %A Abraham, Brian J %A Yang, Song %A Takahashi, Atsushi %A Kamatani, Yoichiro %A Kooperberg, Charles %A Harris, Tamara B %A Jee, Sun Ha %A Coresh, Josef %A Tsai, Fuu-Jen %A Longo, Dan L %A Chen, Yuan-Tsong %A Felix, Janine F %A Yang, Qiong %A Psaty, Bruce M %A Boerwinkle, Eric %A Becker, Lewis C %A Mook-Kanamori, Dennis O %A Wilson, James G %A Gudnason, Vilmundur %A O'Donnell, Christopher J %A Dehghan, Abbas %A Cupples, L Adrienne %A Nalls, Michael A %A Morris, Andrew P %A Okada, Yukinori %A Reiner, Alexander P %A Zon, Leonard I %A Ganesh, Santhi K %X

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

%B Am J Hum Genet %V 100 %P 51-63 %8 2017 Jan 05 %G eng %N 1 %R 10.1016/j.ajhg.2016.11.016 %0 Journal Article %J Nat Genet %D 2017 %T Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. %A Christophersen, Ingrid E %A Rienstra, Michiel %A Roselli, Carolina %A Yin, Xiaoyan %A Geelhoed, Bastiaan %A Barnard, John %A Lin, Honghuang %A Arking, Dan E %A Smith, Albert V %A Albert, Christine M %A Chaffin, Mark %A Tucker, Nathan R %A Li, Molong %A Klarin, Derek %A Bihlmeyer, Nathan A %A Low, Siew-Kee %A Weeke, Peter E %A Müller-Nurasyid, Martina %A Smith, J Gustav %A Brody, Jennifer A %A Niemeijer, Maartje N %A Dörr, Marcus %A Trompet, Stella %A Huffman, Jennifer %A Gustafsson, Stefan %A Schurmann, Claudia %A Kleber, Marcus E %A Lyytikäinen, Leo-Pekka %A Seppälä, Ilkka %A Malik, Rainer %A Horimoto, Andrea R V R %A Perez, Marco %A Sinisalo, Juha %A Aeschbacher, Stefanie %A Thériault, Sébastien %A Yao, Jie %A Radmanesh, Farid %A Weiss, Stefan %A Teumer, Alexander %A Choi, Seung Hoan %A Weng, Lu-Chen %A Clauss, Sebastian %A Deo, Rajat %A Rader, Daniel J %A Shah, Svati H %A Sun, Albert %A Hopewell, Jemma C %A Debette, Stephanie %A Chauhan, Ganesh %A Yang, Qiong %A Worrall, Bradford B %A Paré, Guillaume %A Kamatani, Yoichiro %A Hagemeijer, Yanick P %A Verweij, Niek %A Siland, Joylene E %A Kubo, Michiaki %A Smith, Jonathan D %A Van Wagoner, David R %A Bis, Joshua C %A Perz, Siegfried %A Psaty, Bruce M %A Ridker, Paul M %A Magnani, Jared W %A Harris, Tamara B %A Launer, Lenore J %A Shoemaker, M Benjamin %A Padmanabhan, Sandosh %A Haessler, Jeffrey %A Bartz, Traci M %A Waldenberger, Melanie %A Lichtner, Peter %A Arendt, Marina %A Krieger, Jose E %A Kähönen, Mika %A Risch, Lorenz %A Mansur, Alfredo J %A Peters, Annette %A Smith, Blair H %A Lind, Lars %A Scott, Stuart A %A Lu, Yingchang %A Bottinger, Erwin B %A Hernesniemi, Jussi %A Lindgren, Cecilia M %A Wong, Jorge A %A Huang, Jie %A Eskola, Markku %A Morris, Andrew P %A Ford, Ian %A Reiner, Alex P %A Delgado, Graciela %A Chen, Lin Y %A Chen, Yii-Der Ida %A Sandhu, Roopinder K %A Li, Man %A Boerwinkle, Eric %A Eisele, Lewin %A Lannfelt, Lars %A Rost, Natalia %A Anderson, Christopher D %A Taylor, Kent D %A Campbell, Archie %A Magnusson, Patrik K %A Porteous, David %A Hocking, Lynne J %A Vlachopoulou, Efthymia %A Pedersen, Nancy L %A Nikus, Kjell %A Orho-Melander, Marju %A Hamsten, Anders %A Heeringa, Jan %A Denny, Joshua C %A Kriebel, Jennifer %A Darbar, Dawood %A Newton-Cheh, Christopher %A Shaffer, Christian %A Macfarlane, Peter W %A Heilmann-Heimbach, Stefanie %A Almgren, Peter %A Huang, Paul L %A Sotoodehnia, Nona %A Soliman, Elsayed Z %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Völker, Uwe %A Jöckel, Karl-Heinz %A Sinner, Moritz F %A Lin, Henry J %A Guo, Xiuqing %A Dichgans, Martin %A Ingelsson, Erik %A Kooperberg, Charles %A Melander, Olle %A Loos, Ruth J F %A Laurikka, Jari %A Conen, David %A Rosand, Jonathan %A van der Harst, Pim %A Lokki, Marja-Liisa %A Kathiresan, Sekar %A Pereira, Alexandre %A Jukema, J Wouter %A Hayward, Caroline %A Rotter, Jerome I %A März, Winfried %A Lehtimäki, Terho %A Stricker, Bruno H %A Chung, Mina K %A Felix, Stephan B %A Gudnason, Vilmundur %A Alonso, Alvaro %A Roden, Dan M %A Kääb, Stefan %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Tanaka, Toshihiro %A Lunetta, Kathryn L %A Lubitz, Steven A %A Ellinor, Patrick T %X

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.

%B Nat Genet %V 49 %P 946-952 %8 2017 Jun %G eng %N 6 %R 10.1038/ng.3843 %0 Journal Article %J J Clin Invest %D 2017 %T Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. %A Wild, Philipp S %A Felix, Janine F %A Schillert, Arne %A Teumer, Alexander %A Chen, Ming-Huei %A Leening, Maarten J G %A Völker, Uwe %A Großmann, Vera %A Brody, Jennifer A %A Irvin, Marguerite R %A Shah, Sanjiv J %A Pramana, Setia %A Lieb, Wolfgang %A Schmidt, Reinhold %A Stanton, Alice V %A Malzahn, Dörthe %A Smith, Albert Vernon %A Sundström, Johan %A Minelli, Cosetta %A Ruggiero, Daniela %A Lyytikäinen, Leo-Pekka %A Tiller, Daniel %A Smith, J Gustav %A Monnereau, Claire %A Di Tullio, Marco R %A Musani, Solomon K %A Morrison, Alanna C %A Pers, Tune H %A Morley, Michael %A Kleber, Marcus E %A Aragam, Jayashri %A Benjamin, Emelia J %A Bis, Joshua C %A Bisping, Egbert %A Broeckel, Ulrich %A Cheng, Susan %A Deckers, Jaap W %A del Greco M, Fabiola %A Edelmann, Frank %A Fornage, Myriam %A Franke, Lude %A Friedrich, Nele %A Harris, Tamara B %A Hofer, Edith %A Hofman, Albert %A Huang, Jie %A Hughes, Alun D %A Kähönen, Mika %A Investigators, Knhi %A Kruppa, Jochen %A Lackner, Karl J %A Lannfelt, Lars %A Laskowski, Rafael %A Launer, Lenore J %A Leosdottir, Margrét %A Lin, Honghuang %A Lindgren, Cecilia M %A Loley, Christina %A MacRae, Calum A %A Mascalzoni, Deborah %A Mayet, Jamil %A Medenwald, Daniel %A Morris, Andrew P %A Müller, Christian %A Müller-Nurasyid, Martina %A Nappo, Stefania %A Nilsson, Peter M %A Nuding, Sebastian %A Nutile, Teresa %A Peters, Annette %A Pfeufer, Arne %A Pietzner, Diana %A Pramstaller, Peter P %A Raitakari, Olli T %A Rice, Kenneth M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Ruohonen, Saku T %A Sacco, Ralph L %A Samdarshi, Tandaw E %A Schmidt, Helena %A Sharp, Andrew S P %A Shields, Denis C %A Sorice, Rossella %A Sotoodehnia, Nona %A Stricker, Bruno H %A Surendran, Praveen %A Thom, Simon %A Töglhofer, Anna M %A Uitterlinden, André G %A Wachter, Rolf %A Völzke, Henry %A Ziegler, Andreas %A Münzel, Thomas %A März, Winfried %A Cappola, Thomas P %A Hirschhorn, Joel N %A Mitchell, Gary F %A Smith, Nicholas L %A Fox, Ervin R %A Dueker, Nicole D %A Jaddoe, Vincent W V %A Melander, Olle %A Russ, Martin %A Lehtimäki, Terho %A Ciullo, Marina %A Hicks, Andrew A %A Lind, Lars %A Gudnason, Vilmundur %A Pieske, Burkert %A Barron, Anthony J %A Zweiker, Robert %A Schunkert, Heribert %A Ingelsson, Erik %A Liu, Kiang %A Arnett, Donna K %A Psaty, Bruce M %A Blankenberg, Stefan %A Larson, Martin G %A Felix, Stephan B %A Franco, Oscar H %A Zeller, Tanja %A Vasan, Ramachandran S %A Dörr, Marcus %X

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.

%B J Clin Invest %V 127 %P 1798-1812 %8 2017 May 01 %G eng %N 5 %R 10.1172/JCI84840 %0 Journal Article %J Am J Hum Genet %D 2017 %T Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. %A Manousaki, Despoina %A Dudding, Tom %A Haworth, Simon %A Hsu, Yi-Hsiang %A Liu, Ching-Ti %A Medina-Gómez, Carolina %A Voortman, Trudy %A van der Velde, Nathalie %A Melhus, Håkan %A Robinson-Cohen, Cassianne %A Cousminer, Diana L %A Nethander, Maria %A Vandenput, Liesbeth %A Noordam, Raymond %A Forgetta, Vincenzo %A Greenwood, Celia M T %A Biggs, Mary L %A Psaty, Bruce M %A Rotter, Jerome I %A Zemel, Babette S %A Mitchell, Jonathan A %A Taylor, Bruce %A Lorentzon, Mattias %A Karlsson, Magnus %A Jaddoe, Vincent V W %A Tiemeier, Henning %A Campos-Obando, Natalia %A Franco, Oscar H %A Utterlinden, Andre G %A Broer, Linda %A van Schoor, Natasja M %A Ham, Annelies C %A Ikram, M Arfan %A Karasik, David %A de Mutsert, Renée %A Rosendaal, Frits R %A den Heijer, Martin %A Wang, Thomas J %A Lind, Lars %A Orwoll, Eric S %A Mook-Kanamori, Dennis O %A Michaëlsson, Karl %A Kestenbaum, Bryan %A Ohlsson, Claes %A Mellström, Dan %A de Groot, Lisette C P G M %A Grant, Struan F A %A Kiel, Douglas P %A Zillikens, M Carola %A Rivadeneira, Fernando %A Sawcer, Stephen %A Timpson, Nicholas J %A Richards, J Brent %K Cholestanetriol 26-Monooxygenase %K Cytochrome P450 Family 2 %K Gene Frequency %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Multiple Sclerosis %K Polymorphism, Single Nucleotide %K Risk Factors %K Vitamin D %K Vitamin D Deficiency %X

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.

%B Am J Hum Genet %V 101 %P 227-238 %8 2017 Aug 03 %G eng %N 2 %R 10.1016/j.ajhg.2017.06.014 %0 Journal Article %J Hypertension %D 2017 %T Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. %A Wain, Louise V %A Vaez, Ahmad %A Jansen, Rick %A Joehanes, Roby %A van der Most, Peter J %A Erzurumluoglu, A Mesut %A O'Reilly, Paul F %A Cabrera, Claudia P %A Warren, Helen R %A Rose, Lynda M %A Verwoert, Germaine C %A Hottenga, Jouke-Jan %A Strawbridge, Rona J %A Esko, Tõnu %A Arking, Dan E %A Hwang, Shih-Jen %A Guo, Xiuqing %A Kutalik, Zoltán %A Trompet, Stella %A Shrine, Nick %A Teumer, Alexander %A Ried, Janina S %A Bis, Joshua C %A Smith, Albert V %A Amin, Najaf %A Nolte, Ilja M %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Wareham, Nicholas J %A Hofer, Edith %A Joshi, Peter K %A Kristiansson, Kati %A Traglia, Michela %A Havulinna, Aki S %A Goel, Anuj %A Nalls, Mike A %A Sõber, Siim %A Vuckovic, Dragana %A Luan, Jian'an %A del Greco M, Fabiola %A Ayers, Kristin L %A Marrugat, Jaume %A Ruggiero, Daniela %A Lopez, Lorna M %A Niiranen, Teemu %A Enroth, Stefan %A Jackson, Anne U %A Nelson, Christopher P %A Huffman, Jennifer E %A Zhang, Weihua %A Marten, Jonathan %A Gandin, Ilaria %A Harris, Sarah E %A Zemunik, Tatijana %A Lu, Yingchang %A Evangelou, Evangelos %A Shah, Nabi %A de Borst, Martin H %A Mangino, Massimo %A Prins, Bram P %A Campbell, Archie %A Li-Gao, Ruifang %A Chauhan, Ganesh %A Oldmeadow, Christopher %A Abecasis, Goncalo %A Abedi, Maryam %A Barbieri, Caterina M %A Barnes, Michael R %A Batini, Chiara %A Beilby, John %A Blake, Tineka %A Boehnke, Michael %A Bottinger, Erwin P %A Braund, Peter S %A Brown, Morris %A Brumat, Marco %A Campbell, Harry %A Chambers, John C %A Cocca, Massimiliano %A Collins, Francis %A Connell, John %A Cordell, Heather J %A Damman, Jeffrey J %A Davies, Gail %A de Geus, Eco J %A de Mutsert, Renée %A Deelen, Joris %A Demirkale, Yusuf %A Doney, Alex S F %A Dörr, Marcus %A Farrall, Martin %A Ferreira, Teresa %A Frånberg, Mattias %A Gao, He %A Giedraitis, Vilmantas %A Gieger, Christian %A Giulianini, Franco %A Gow, Alan J %A Hamsten, Anders %A Harris, Tamara B %A Hofman, Albert %A Holliday, Elizabeth G %A Hui, Jennie %A Jarvelin, Marjo-Riitta %A Johansson, Asa %A Johnson, Andrew D %A Jousilahti, Pekka %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Khaw, Kay-Tee %A Kolcic, Ivana %A Koskinen, Seppo %A Langenberg, Claudia %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Mach, François %A Mamasoula, Chrysovalanto %A Menni, Cristina %A Mifsud, Borbala %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew D %A Morrison, Alanna C %A Munson, Peter J %A Nandakumar, Priyanka %A Nguyen, Quang Tri %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A Org, Elin %A Padmanabhan, Sandosh %A Palotie, Aarno %A Paré, Guillaume %A Pattie, Alison %A Penninx, Brenda W J H %A Poulter, Neil %A Pramstaller, Peter P %A Raitakari, Olli T %A Ren, Meixia %A Rice, Kenneth %A Ridker, Paul M %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rotter, Jerome I %A Rudan, Igor %A Saba, Yasaman %A Saint Pierre, Aude %A Sala, Cinzia F %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Scott, Rodney %A Seelen, Marc A %A Shields, Denis C %A Siscovick, David %A Sorice, Rossella %A Stanton, Alice %A Stott, David J %A Sundström, Johan %A Swertz, Morris %A Taylor, Kent D %A Thom, Simon %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, André G %A Völker, Uwe %A Vollenweider, Peter %A Wild, Sarah %A Willemsen, Gonneke %A Wright, Alan F %A Yao, Jie %A Thériault, Sébastien %A Conen, David %A Attia, John %A Sever, Peter %A Debette, Stephanie %A Mook-Kanamori, Dennis O %A Zeggini, Eleftheria %A Spector, Tim D %A van der Harst, Pim %A Palmer, Colin N A %A Vergnaud, Anne-Claire %A Loos, Ruth J F %A Polasek, Ozren %A Starr, John M %A Girotto, Giorgia %A Hayward, Caroline %A Kooner, Jaspal S %A Lindgren, Cecila M %A Vitart, Veronique %A Samani, Nilesh J %A Tuomilehto, Jaakko %A Gyllensten, Ulf %A Knekt, Paul %A Deary, Ian J %A Ciullo, Marina %A Elosua, Roberto %A Keavney, Bernard D %A Hicks, Andrew A %A Scott, Robert A %A Gasparini, Paolo %A Laan, Maris %A Liu, Yongmei %A Watkins, Hugh %A Hartman, Catharina A %A Salomaa, Veikko %A Toniolo, Daniela %A Perola, Markus %A Wilson, James F %A Schmidt, Helena %A Zhao, Jing Hua %A Lehtimäki, Terho %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Peters, Annette %A Rettig, Rainer %A James, Alan %A Jukema, J Wouter %A Strachan, David P %A Palmas, Walter %A Metspalu, Andres %A Ingelsson, Erik %A Boomsma, Dorret I %A Franco, Oscar H %A Bochud, Murielle %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Elliott, Paul %A Chasman, Daniel I %A Chakravarti, Aravinda %A Knight, Joanne %A Morris, Andrew P %A Levy, Daniel %A Tobin, Martin D %A Snieder, Harold %A Caulfield, Mark J %A Ehret, Georg B %X

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.

%B Hypertension %8 2017 Jul 24 %G eng %R 10.1161/HYPERTENSIONAHA.117.09438 %0 Journal Article %J Eur Heart J %D 2018 %T A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. %A Ashar, Foram N %A Mitchell, Rebecca N %A Albert, Christine M %A Newton-Cheh, Christopher %A Brody, Jennifer A %A Müller-Nurasyid, Martina %A Moes, Anna %A Meitinger, Thomas %A Mak, Angel %A Huikuri, Heikki %A Junttila, M Juhani %A Goyette, Philippe %A Pulit, Sara L %A Pazoki, Raha %A Tanck, Michael W %A Blom, Marieke T %A Zhao, XiaoQing %A Havulinna, Aki S %A Jabbari, Reza %A Glinge, Charlotte %A Tragante, Vinicius %A Escher, Stefan A %A Chakravarti, Aravinda %A Ehret, Georg %A Coresh, Josef %A Li, Man %A Prineas, Ronald J %A Franco, Oscar H %A Kwok, Pui-Yan %A Lumley, Thomas %A Dumas, Florence %A McKnight, Barbara %A Rotter, Jerome I %A Lemaitre, Rozenn N %A Heckbert, Susan R %A O'Donnell, Christopher J %A Hwang, Shih-Jen %A Tardif, Jean-Claude %A VanDenburgh, Martin %A Uitterlinden, André G %A Hofman, Albert %A Stricker, Bruno H C %A de Bakker, Paul I W %A Franks, Paul W %A Jansson, Jan-Håkan %A Asselbergs, Folkert W %A Halushka, Marc K %A Maleszewski, Joseph J %A Tfelt-Hansen, Jacob %A Engstrøm, Thomas %A Salomaa, Veikko %A Virmani, Renu %A Kolodgie, Frank %A Wilde, Arthur A M %A Tan, Hanno L %A Bezzina, Connie R %A Eijgelsheim, Mark %A Rioux, John D %A Jouven, Xavier %A Kääb, Stefan %A Psaty, Bruce M %A Siscovick, David S %A Arking, Dan E %A Sotoodehnia, Nona %X

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.

Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.

Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

%B Eur Heart J %8 2018 Aug 28 %G eng %R 10.1093/eurheartj/ehy474 %0 Journal Article %J Blood %D 2018 %T DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis. %A Ward-Caviness, Cavin K %A Huffman, Jennifer E %A Evertt, Karl %A Germain, Marine %A van Dongen, Jenny %A Hill, W David %A Jhun, Min A %A Brody, Jennifer A %A Ghanbari, Mohsen %A Du, Lei %A Roetker, Nicholas S %A de Vries, Paul S %A Waldenberger, Melanie %A Gieger, Christian %A Wolf, Petra %A Prokisch, Holger %A Koenig, Wolfgang %A O'Donnell, Christopher J %A Levy, Daniel %A Liu, Chunyu %A Truong, Vinh %A Wells, Philip S %A Trégouët, David-Alexandre %A Tang, Weihong %A Morrison, Alanna C %A Boerwinkle, Eric %A Wiggins, Kerri L %A McKnight, Barbara %A Guo, Xiuqing %A Psaty, Bruce M %A Sotoodenia, Nona %A Boomsa, Dorret I %A Willemsen, Gonneke %A Ligthart, Lannie %A Deary, Ian J %A Zhao, Wei %A Ware, Erin B %A Kardia, Sharon L R %A van Meurs, Joyce B J %A Uitterlinden, André G %A Franco, Oscar H %A Eriksson, Per %A Franco-Cereceda, Anders %A Pankow, James S %A Johnson, Andrew D %A Gagnon, France %A Morange, Pierre-Emmanuel %A de Geus, Eco J C %A Starr, John M %A Smith, Jennifer A %A Dehghan, Abbas %A Björck, Hanna M %A Smith, Nicholas L %A Peters, Annette %X

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

%B Blood %8 2018 Jul 24 %G eng %R 10.1182/blood-2018-02-831347 %0 Journal Article %J Nat Genet %D 2018 %T Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Boerwinkle, Eric %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A Borst, Martin H de %A Geus, Eco J de %A Deary, Ian J %A Deelen, Joris %A del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Asa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %X

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.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %R 10.1038/s41588-018-0205-x %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

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.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J Circulation %D 2018 %T Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. %A Sabater-Lleal, Maria %A Huffman, Jennifer E %A de Vries, Paul S %A Marten, Jonathan %A Mastrangelo, Michael A %A Song, Ci %A Pankratz, Nathan %A Ward-Caviness, Cavin K %A Yanek, Lisa R %A Trompet, Stella %A Delgado, Graciela E %A Guo, Xiuqing %A Bartz, Traci M %A Martinez-Perez, Angel %A Germain, Marine %A de Haan, Hugoline G %A Ozel, Ayse B %A Polasek, Ozren %A Smith, Albert V %A Eicher, John D %A Reiner, Alex P %A Tang, Weihong %A Davies, Neil M %A Stott, David J %A Rotter, Jerome I %A Tofler, Geoffrey H %A Boerwinkle, Eric %A de Maat, Moniek P M %A Kleber, Marcus E %A Welsh, Paul %A Brody, Jennifer A %A Chen, Ming-Huei %A Vaidya, Dhananjay %A Soria, José Manuel %A Suchon, Pierre %A van Hylckama Vlieg, Astrid %A Desch, Karl C %A Kolcic, Ivana %A Joshi, Peter K %A Launer, Lenore J %A Harris, Tamara B %A Campbell, Harry %A Rudan, Igor %A Becker, Diane M %A Li, Jun Z %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Cushman, Mary %A Psaty, Bruce M %A Morange, Pierre-Emmanuel %A McKnight, Barbara %A Chong, Michael R %A Fernandez-Cadenas, Israel %A Rosand, Jonathan %A Lindgren, Arne %A Gudnason, Vilmundur %A Wilson, James F %A Hayward, Caroline %A Ginsburg, David %A Fornage, Myriam %A Rosendaal, Frits R %A Souto, Juan Carlos %A Becker, Lewis C %A Jenny, Nancy S %A März, Winfried %A Jukema, J Wouter %A Dehghan, Abbas %A Trégouët, David-Alexandre %A Morrison, Alanna C %A Johnson, Andrew D %A O'Donnell, Christopher J %A Strachan, David P %A Lowenstein, Charles J %A Smith, Nicholas L %X

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant (p≤2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

%B Circulation %8 2018 Nov 20 %G eng %R 10.1161/CIRCULATIONAHA.118.034532 %0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Boerwinkle, Eric %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

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.

%B Nat Commun %V 9 %P 5141 %8 2018 12 03 %G eng %N 1 %R 10.1038/s41467-018-07340-5 %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stephanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %X

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 Mar 01 %G eng %N 3 %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J Nephrol Dial Transplant %D 2018 %T Low thyroid function is not associated with an accelerated deterioration in renal function. %A Meuwese, Christiaan L %A van Diepen, Merel %A Cappola, Anne R %A Sarnak, Mark J %A Shlipak, Michael G %A Bauer, Douglas C %A Fried, Linda P %A Iacoviello, Massimo %A Vaes, Bert %A Degryse, Jean %A Khaw, Kay-Tee %A Luben, Robert N %A Asvold, Bjørn O %A Bjøro, Trine %A Vatten, Lars J %A de Craen, Anton J M %A Trompet, Stella %A Iervasi, Giorgio %A Molinaro, Sabrina %A Ceresini, Graziano %A Ferrucci, Luigi %A Dullaart, Robin P F %A Bakker, Stephan J L %A Jukema, J Wouter %A Kearney, Patricia M %A Stott, David J %A Peeters, Robin P %A Franco, Oscar H %A Völzke, Henry %A Walsh, John P %A Bremner, Alexandra %A Sgarbi, José A %A Maciel, Rui M B %A Imaizumi, Misa %A Ohishi, Waka %A Dekker, Friedo W %A Rodondi, Nicolas %A Gussekloo, Jacobijn %A den Elzen, Wendy P J %X

Background: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.

Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.

Results: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.

Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

%B Nephrol Dial Transplant %8 2018 Apr 18 %G eng %R 10.1093/ndt/gfy071 %0 Journal Article %J Nat Genet %D 2018 %T Multi-ethnic genome-wide association study for atrial fibrillation. %A Roselli, Carolina %A Chaffin, Mark D %A Weng, Lu-Chen %A Aeschbacher, Stefanie %A Ahlberg, Gustav %A Albert, Christine M %A Almgren, Peter %A Alonso, Alvaro %A Anderson, Christopher D %A Aragam, Krishna G %A Arking, Dan E %A Barnard, John %A Bartz, Traci M %A Benjamin, Emelia J %A Bihlmeyer, Nathan A %A Bis, Joshua C %A Bloom, Heather L %A Boerwinkle, Eric %A Bottinger, Erwin B %A Brody, Jennifer A %A Calkins, Hugh %A Campbell, Archie %A Cappola, Thomas P %A Carlquist, John %A Chasman, Daniel I %A Chen, Lin Y %A Chen, Yii-Der Ida %A Choi, Eue-Keun %A Choi, Seung Hoan %A Christophersen, Ingrid E %A Chung, Mina K %A Cole, John W %A Conen, David %A Cook, James %A Crijns, Harry J %A Cutler, Michael J %A Damrauer, Scott M %A Daniels, Brian R %A Darbar, Dawood %A Delgado, Graciela %A Denny, Joshua C %A Dichgans, Martin %A Dörr, Marcus %A Dudink, Elton A %A Dudley, Samuel C %A Esa, Nada %A Esko, Tõnu %A Eskola, Markku %A Fatkin, Diane %A Felix, Stephan B %A Ford, Ian %A Franco, Oscar H %A Geelhoed, Bastiaan %A Grewal, Raji P %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gupta, Namrata %A Gustafsson, Stefan %A Gutmann, Rebecca %A Hamsten, Anders %A Harris, Tamara B %A Hayward, Caroline %A Heckbert, Susan R %A Hernesniemi, Jussi %A Hocking, Lynne J %A Hofman, Albert %A Horimoto, Andrea R V R %A Huang, Jie %A Huang, Paul L %A Huffman, Jennifer %A Ingelsson, Erik %A Ipek, Esra Gucuk %A Ito, Kaoru %A Jimenez-Conde, Jordi %A Johnson, Renee %A Jukema, J Wouter %A Kääb, Stefan %A Kähönen, Mika %A Kamatani, Yoichiro %A Kane, John P %A Kastrati, Adnan %A Kathiresan, Sekar %A Katschnig-Winter, Petra %A Kavousi, Maryam %A Kessler, Thorsten %A Kietselaer, Bas L %A Kirchhof, Paulus %A Kleber, Marcus E %A Knight, Stacey %A Krieger, Jose E %A Kubo, Michiaki %A Launer, Lenore J %A Laurikka, Jari %A Lehtimäki, Terho %A Leineweber, Kirsten %A Lemaitre, Rozenn N %A Li, Man %A Lim, Hong Euy %A Lin, Henry J %A Lin, Honghuang %A Lind, Lars %A Lindgren, Cecilia M %A Lokki, Marja-Liisa %A London, Barry %A Loos, Ruth J F %A Low, Siew-Kee %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Macfarlane, Peter W %A Magnusson, Patrik K %A Mahajan, Anubha %A Malik, Rainer %A Mansur, Alfredo J %A Marcus, Gregory M %A Margolin, Lauren %A Margulies, Kenneth B %A März, Winfried %A McManus, David D %A Melander, Olle %A Mohanty, Sanghamitra %A Montgomery, Jay A %A Morley, Michael P %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Natale, Andrea %A Nazarian, Saman %A Neumann, Benjamin %A Newton-Cheh, Christopher %A Niemeijer, Maartje N %A Nikus, Kjell %A Nilsson, Peter %A Noordam, Raymond %A Oellers, Heidi %A Olesen, Morten S %A Orho-Melander, Marju %A Padmanabhan, Sandosh %A Pak, Hui-Nam %A Paré, Guillaume %A Pedersen, Nancy L %A Pera, Joanna %A Pereira, Alexandre %A Porteous, David %A Psaty, Bruce M %A Pulit, Sara L %A Pullinger, Clive R %A Rader, Daniel J %A Refsgaard, Lena %A Ribasés, Marta %A Ridker, Paul M %A Rienstra, Michiel %A Risch, Lorenz %A Roden, Dan M %A Rosand, Jonathan %A Rosenberg, Michael A %A Rost, Natalia %A Rotter, Jerome I %A Saba, Samir %A Sandhu, Roopinder K %A Schnabel, Renate B %A Schramm, Katharina %A Schunkert, Heribert %A Schurman, Claudia %A Scott, Stuart A %A Seppälä, Ilkka %A Shaffer, Christian %A Shah, Svati %A Shalaby, Alaa A %A Shim, Jaemin %A Shoemaker, M Benjamin %A Siland, Joylene E %A Sinisalo, Juha %A Sinner, Moritz F %A Slowik, Agnieszka %A Smith, Albert V %A Smith, Blair H %A Smith, J Gustav %A Smith, Jonathan D %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stricker, Bruno H %A Sun, Albert %A Sun, Han %A Svendsen, Jesper H %A Tanaka, Toshihiro %A Tanriverdi, Kahraman %A Taylor, Kent D %A Teder-Laving, Maris %A Teumer, Alexander %A Thériault, Sébastien %A Trompet, Stella %A Tucker, Nathan R %A Tveit, Arnljot %A Uitterlinden, André G %A van der Harst, Pim %A Van Gelder, Isabelle C %A Van Wagoner, David R %A Verweij, Niek %A Vlachopoulou, Efthymia %A Völker, Uwe %A Wang, Biqi %A Weeke, Peter E %A Weijs, Bob %A Weiss, Raul %A Weiss, Stefan %A Wells, Quinn S %A Wiggins, Kerri L %A Wong, Jorge A %A Woo, Daniel %A Worrall, Bradford B %A Yang, Pil-Sung %A Yao, Jie %A Yoneda, Zachary T %A Zeller, Tanja %A Zeng, Lingyao %A Lubitz, Steven A %A Lunetta, Kathryn L %A Ellinor, Patrick T %X

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

%B Nat Genet %V 50 %P 1225-1233 %8 2018 Sep %G eng %N 9 %R 10.1038/s41588-018-0133-9 %0 Journal Article %J PLoS One %D 2018 %T Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. %A Feitosa, Mary F %A Kraja, Aldi T %A Chasman, Daniel I %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Bentley, Amy R %A Brown, Michael R %A Schwander, Karen %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Wojczynski, Mary K %A Alver, Maris %A Boissel, Mathilde %A Cai, Qiuyin %A Campbell, Archie %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Luan, Jian'an %A Matoba, Nana %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Riaz, Muhammad %A Rueedi, Rico %A Robino, Antonietta %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Vitart, Veronique %A Wang, Yajuan %A Ware, Erin B %A Warren, Helen R %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Boerwinkle, Eric %A Borecki, Ingrid %A Broeckel, Ulrich %A Brown, Morris %A Brumat, Marco %A Burke, Gregory L %A Canouil, Mickaël %A Chakravarti, Aravinda %A Charumathi, Sabanayagam %A Ida Chen, Yii-Der %A Connell, John M %A Correa, Adolfo %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Deng, Xuan %A Ding, Jingzhong %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Eppinga, Ruben N %A Evangelou, Evangelos %A Faul, Jessica D %A Felix, Stephan B %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gigante, Bruna %A Gu, C Charles %A Gu, Dongfeng %A Hagenaars, Saskia P %A Hallmans, Göran %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Howard, Barbara V %A Ikram, M Arfan %A John, Ulrich %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lin, Shiow %A Liu, Jianjun %A Liu, Jingmin %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Nalls, Mike A %A Nelson, Christopher P %A Sotoodehnia, Nona %A Norris, Jill M %A O'Connell, Jeff R %A Palmer, Nicholette D %A Perls, Thomas %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Roll, Kathryn %A Rose, Lynda M %A Rosendaal, Frits R %A Rotter, Jerome I %A Schmidt, Carsten O %A Schreiner, Pamela J %A Schupf, Nicole %A Scott, William R %A Sever, Peter S %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Turner, Stephen T %A Uitterlinden, André G %A Vollenweider, Peter %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Williams, Christine %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Kutalik, Zoltán %A Laakso, Markku %A Laurie, Cathy C %A Leander, Karin %A Lehtimäki, Terho %A Study, Lifelines Cohort %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Polasek, Ozren %A Porteous, David J %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Bouchard, Claude %A Christensen, Kaare %A Evans, Michele K %A Gudnason, Vilmundur %A Horta, Bernardo L %A Kardia, Sharon L R %A Liu, Yongmei %A Pereira, Alexandre C %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Gauderman, W James %A Zhu, Xiaofeng %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Rotimi, Charles N %A Cupples, L Adrienne %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Kooperberg, Charles %A Palmas, Walter %A Rice, Kenneth %A Morrison, Alanna C %A Elliott, Paul %A Caulfield, Mark J %A Munroe, Patricia B %A Rao, Dabeeru C %A Province, Michael A %A Levy, Daniel %X

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

%B PLoS One %V 13 %P e0198166 %8 2018 %G eng %N 6 %R 10.1371/journal.pone.0198166 %0 Journal Article %J Nat Commun %D 2018 %T PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. %A van Setten, Jessica %A Brody, Jennifer A %A Jamshidi, Yalda %A Swenson, Brenton R %A Butler, Anne M %A Campbell, Harry %A Del Greco, Fabiola M %A Evans, Daniel S %A Gibson, Quince %A Gudbjartsson, Daniel F %A Kerr, Kathleen F %A Krijthe, Bouwe P %A Lyytikäinen, Leo-Pekka %A Müller, Christian %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Ritchie, Marylyn D %A Robino, Antonietta %A Smith, Albert V %A Steri, Maristella %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A Ulivi, Sheila %A Verweij, Niek %A Yin, Xiaoyan %A Arnar, David O %A Asselbergs, Folkert W %A Bader, Joel S %A Barnard, John %A Bis, Josh %A Blankenberg, Stefan %A Boerwinkle, Eric %A Bradford, Yuki %A Buckley, Brendan M %A Chung, Mina K %A Crawford, Dana %A den Hoed, Marcel %A Denny, Josh C %A Dominiczak, Anna F %A Ehret, Georg B %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Felix, Stephan B %A Franco, Oscar H %A Franke, Lude %A Harris, Tamara B %A Holm, Hilma %A Ilaria, Gandin %A Iorio, Annamaria %A Kähönen, Mika %A Kolcic, Ivana %A Kors, Jan A %A Lakatta, Edward G %A Launer, Lenore J %A Lin, Honghuang %A Lin, Henry J %A Loos, Ruth J F %A Lubitz, Steven A %A Macfarlane, Peter W %A Magnani, Jared W %A Leach, Irene Mateo %A Meitinger, Thomas %A Mitchell, Braxton D %A Münzel, Thomas %A Papanicolaou, George J %A Peters, Annette %A Pfeufer, Arne %A Pramstaller, Peter P %A Raitakari, Olli T %A Rotter, Jerome I %A Rudan, Igor %A Samani, Nilesh J %A Schlessinger, David %A Silva Aldana, Claudia T %A Sinner, Moritz F %A Smith, Jonathan D %A Snieder, Harold %A Soliman, Elsayed Z %A Spector, Timothy D %A Stott, David J %A Strauch, Konstantin %A Tarasov, Kirill V %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Jan Westra, Harm %A Wild, Philipp S %A Zeller, Tanja %A Alonso, Alvaro %A Avery, Christy L %A Bandinelli, Stefania %A Benjamin, Emelia J %A Cucca, Francesco %A Dörr, Marcus %A Ferrucci, Luigi %A Gasparini, Paolo %A Gudnason, Vilmundur %A Hayward, Caroline %A Heckbert, Susan R %A Hicks, Andrew A %A Jukema, J Wouter %A Kääb, Stefan %A Lehtimäki, Terho %A Liu, Yongmei %A Munroe, Patricia B %A Parsa, Afshin %A Polasek, Ozren %A Psaty, Bruce M %A Roden, Dan M %A Schnabel, Renate B %A Sinagra, Gianfranco %A Stefansson, Kari %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Wilson, James F %A Gharib, Sina A %A de Bakker, Paul I W %A Isaacs, Aaron %A Arking, Dan E %A Sotoodehnia, Nona %X

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

%B Nat Commun %V 9 %P 2904 %8 2018 Jul 25 %G eng %N 1 %R 10.1038/s41467-018-04766-9 %0 Journal Article %J PLoS One %D 2018 %T 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. %A Lorenz, Matthias W %A Gao, Lu %A Ziegelbauer, Kathrin %A Norata, Giuseppe Danilo %A Empana, Jean Philippe %A Schmidtmann, Irene %A Lin, Hung-Ju %A McLachlan, Stela %A Bokemark, Lena %A Ronkainen, Kimmo %A Amato, Mauro %A Schminke, Ulf %A Srinivasan, Sathanur R %A Lind, Lars %A Okazaki, Shuhei %A Stehouwer, Coen D A %A Willeit, Peter %A Polak, Joseph F %A Steinmetz, Helmuth %A Sander, Dirk %A Poppert, Holger %A Desvarieux, Moïse %A Ikram, M Arfan %A Johnsen, Stein Harald %A Staub, Daniel %A Sirtori, Cesare R %A Iglseder, Bernhard %A Beloqui, Oscar %A Engström, Gunnar %A Friera, Alfonso %A Rozza, Francesco %A Xie, Wuxiang %A Parraga, Grace %A Grigore, Liliana %A Plichart, Matthieu %A Blankenberg, Stefan %A Su, Ta-Chen %A Schmidt, Caroline %A Tuomainen, Tomi-Pekka %A Veglia, Fabrizio %A Völzke, Henry %A Nijpels, Giel %A Willeit, Johann %A Sacco, Ralph L %A Franco, Oscar H %A Uthoff, Heiko %A Hedblad, Bo %A Suarez, Carmen %A Izzo, Raffaele %A Zhao, Dong %A Wannarong, Thapat %A Catapano, Alberico %A Ducimetiere, Pierre %A Espinola-Klein, Christine %A Chien, Kuo-Liong %A Price, Jackie F %A Bergström, Göran %A Kauhanen, Jussi %A Tremoli, Elena %A Dörr, Marcus %A Berenson, Gerald %A Kitagawa, Kazuo %A Dekker, Jacqueline M %A Kiechl, Stefan %A Sitzer, Matthias %A Bickel, Horst %A Rundek, Tatjana %A Hofman, Albert %A Mathiesen, Ellisiv B %A Castelnuovo, Samuela %A Landecho, Manuel F %A Rosvall, Maria %A Gabriel, Rafael %A de Luca, Nicola %A Liu, Jing %A Baldassarre, Damiano %A Kavousi, Maryam %A de Groot, Eric %A Bots, Michiel L %A Yanez, David N %A Thompson, Simon G %K Aged %K Cardiovascular Diseases %K Carotid Intima-Media Thickness %K Female %K Humans %K Intersectoral Collaboration %K Male %K Middle Aged %K Prognosis %K Risk Factors %X

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.

%B PLoS One %V 13 %P e0191172 %8 2018 %G eng %N 4 %R 10.1371/journal.pone.0191172 %0 Journal Article %J Nat Genet %D 2018 %T Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. %A Mahajan, Anubha %A Wessel, Jennifer %A Willems, Sara M %A Zhao, Wei %A Robertson, Neil R %A Chu, Audrey Y %A Gan, Wei %A Kitajima, Hidetoshi %A Taliun, Daniel %A Rayner, N William %A Guo, Xiuqing %A Lu, Yingchang %A Li, Man %A Jensen, Richard A %A Hu, Yao %A Huo, Shaofeng %A Lohman, Kurt K %A Zhang, Weihua %A Cook, James P %A Prins, Bram Peter %A Flannick, Jason %A Grarup, Niels %A Trubetskoy, Vassily Vladimirovich %A Kravic, Jasmina %A Kim, Young Jin %A Rybin, Denis V %A Yaghootkar, Hanieh %A Müller-Nurasyid, Martina %A Meidtner, Karina %A Li-Gao, Ruifang %A Varga, Tibor V %A Marten, Jonathan %A Li, Jin %A Smith, Albert Vernon %A An, Ping %A Ligthart, Symen %A Gustafsson, Stefan %A Malerba, Giovanni %A Demirkan, Ayse %A Tajes, Juan Fernandez %A Steinthorsdottir, Valgerdur %A Wuttke, Matthias %A Lecoeur, Cécile %A Preuss, Michael %A Bielak, Lawrence F %A Graff, Marielisa %A Highland, Heather M %A Justice, Anne E %A Liu, Dajiang J %A Marouli, Eirini %A Peloso, Gina Marie %A Warren, Helen R %A Afaq, Saima %A Afzal, Shoaib %A Ahlqvist, Emma %A Almgren, Peter %A Amin, Najaf %A Bang, Lia B %A Bertoni, Alain G %A Bombieri, Cristina %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Burtt, Noel P %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Cho, Yoon Shin %A Christensen, Cramer %A Eastwood, Sophie V %A Eckardt, Kai-Uwe %A Fischer, Krista %A Gambaro, Giovanni %A Giedraitis, Vilmantas %A Grove, Megan L %A de Haan, Hugoline G %A Hackinger, Sophie %A Hai, Yang %A Han, Sohee %A Tybjærg-Hansen, Anne %A Hivert, Marie-France %A Isomaa, Bo %A Jäger, Susanne %A Jørgensen, Marit E %A Jørgensen, Torben %A Käräjämäki, AnneMari %A Kim, Bong-Jo %A Kim, Sung Soo %A Koistinen, Heikki A %A Kovacs, Peter %A Kriebel, Jennifer %A Kronenberg, Florian %A Läll, Kristi %A Lange, Leslie A %A Lee, Jung-Jin %A Lehne, Benjamin %A Li, Huaixing %A Lin, Keng-Hung %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jun %A Loh, Marie %A Mägi, Reedik %A Mamakou, Vasiliki %A McKean-Cowdin, Roberta %A Nadkarni, Girish %A Neville, Matt %A Nielsen, Sune F %A Ntalla, Ioanna %A Peyser, Patricia A %A Rathmann, Wolfgang %A Rice, Kenneth %A Rich, Stephen S %A Rode, Line %A Rolandsson, Olov %A Schönherr, Sebastian %A Selvin, Elizabeth %A Small, Kerrin S %A Stančáková, Alena %A Surendran, Praveen %A Taylor, Kent D %A Teslovich, Tanya M %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tin, Adrienne %A Tönjes, Anke %A Varbo, Anette %A Witte, Daniel R %A Wood, Andrew R %A Yajnik, Pranav %A Yao, Jie %A Yengo, Loic %A Young, Robin %A Amouyel, Philippe %A Boeing, Heiner %A Boerwinkle, Eric %A Bottinger, Erwin P %A Chowdhury, Rajiv %A Collins, Francis S %A Dedoussis, George %A Dehghan, Abbas %A Deloukas, Panos %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Frossard, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Heckbert, Susan R %A Howson, Joanna M M %A Ingelsson, Martin %A Kathiresan, Sekar %A Kee, Frank %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lindgren, Cecilia M %A Männistö, Satu %A Meitinger, Thomas %A Melander, Olle %A Mohlke, Karen L %A Moitry, Marie %A Morris, Andrew D %A Murray, Alison D %A de Mutsert, Renée %A Orho-Melander, Marju %A Owen, Katharine R %A Perola, Markus %A Peters, Annette %A Province, Michael A %A Rasheed, Asif %A Ridker, Paul M %A Rivadineira, Fernando %A Rosendaal, Frits R %A Rosengren, Anders H %A Salomaa, Veikko %A Sheu, Wayne H-H %A Sladek, Rob %A Smith, Blair H %A Strauch, Konstantin %A Uitterlinden, André G %A Varma, Rohit %A Willer, Cristen J %A Blüher, Matthias %A Butterworth, Adam S %A Chambers, John Campbell %A Chasman, Daniel I %A Danesh, John %A van Duijn, Cornelia %A Dupuis, Josée %A Franco, Oscar H %A Franks, Paul W %A Froguel, Philippe %A Grallert, Harald %A Groop, Leif %A Han, Bok-Ghee %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Ingelsson, Erik %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal Singh %A Köttgen, Anna %A Kuulasmaa, Kari %A Laakso, Markku %A Lin, Xu %A Lind, Lars %A Liu, Yongmei %A Loos, Ruth J F %A Marchini, Jonathan %A Metspalu, Andres %A Mook-Kanamori, Dennis %A Nordestgaard, Børge G %A Palmer, Colin N A %A Pankow, James S %A Pedersen, Oluf %A Psaty, Bruce M %A Rauramaa, Rainer %A Sattar, Naveed %A Schulze, Matthias B %A Soranzo, Nicole %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Thorsteinsdottir, Unnur %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wareham, Nicholas J %A Wilson, James G %A Zeggini, Eleftheria %A Scott, Robert A %A Barroso, Inês %A Frayling, Timothy M %A Goodarzi, Mark O %A Meigs, James B %A Boehnke, Michael %A Saleheen, Danish %A Morris, Andrew P %A Rotter, Jerome I %A McCarthy, Mark I %X

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.

%B Nat Genet %V 50 %P 559-571 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0084-1 %0 Journal Article %J J Clin Endocrinol Metab %D 2018 %T The relation between thyroid function and anemia: a pooled analysis of individual participant data. %A Wopereis, Daisy M %A Du Puy, Robert S %A van Heemst, Diana %A Walsh, John P %A Bremner, Alexandra %A Bakker, Stephan J L %A Bauer, Douglas C %A Cappola, Anne R %A Ceresini, Graziano %A Degryse, Jean %A Dullaart, Robin P F %A Feller, Martin %A Ferrucci, Luigi %A Floriani, Carmen %A Franco, Oscar H %A Iacoviello, Massimo %A Iervasi, Georgio %A Imaizumi, Misa %A Jukema, J Wouter %A Khaw, Kay-Tee %A Luben, Robert N %A Molinaro, Sabrina %A Nauck, Matthias %A Patel, Kushang V %A Peeters, Robin P %A Psaty, Bruce M %A Razvi, Salman %A Schindhelm, Roger K %A van Schoor, Natasja M %A Stott, David J %A Vaes, Bert %A Vanderpump, Mark P J %A Völzke, Henry %A Westendorp, Rudi G J %A Rodondi, Nicolas %A Cobbaert, Christa M %A Gussekloo, Jacobijn %A den Elzen, Wendy P J %X

Context: Anemia and thyroid dysfunction often co-occur and both increase with age. Human data on the relationship between thyroid disease and anemia are scarce.

Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia.

Design: Individual participant data meta-analysis.

Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n=42 162).

Main outcome measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women).

Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants (overt hypothyroidism, pooled odds ratio 1.84 [95% CI: 1.35-2.50], subclinical hypothyroidism 1.21 [1.02-1.43], subclinical hyperthyroidism 1.27 [1.03-1.57], overt hyperthyroidism 1.69 [1.00-2.87]). Hemoglobin levels were lower in all groups compared to participants with euthyroidism. In the longitudinal analyses (n=25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 [95% CI: 0.86-2.20] for overt hypothyroidism, 1.18 [1.00-1.38] for subclinical hypothyroidism, 1.15 [0.94-1.42] for subclinical hyperthyroidism and 1.47 [0.91-2.38] for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.

Conclusion: Higher odds of having anemia were observed in both participants with hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

%B J Clin Endocrinol Metab %8 2018 Aug 02 %G eng %R 10.1210/jc.2018-00481 %0 Journal Article %J Lancet %D 2018 %T Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. %A Wood, Angela M %A Kaptoge, Stephen %A Butterworth, Adam S %A Willeit, Peter %A Warnakula, Samantha %A Bolton, Thomas %A Paige, Ellie %A Paul, Dirk S %A Sweeting, Michael %A Burgess, Stephen %A Bell, Steven %A Astle, William %A Stevens, David %A Koulman, Albert %A Selmer, Randi M %A Verschuren, W M Monique %A Sato, Shinichi %A Njølstad, Inger %A Woodward, Mark %A Salomaa, Veikko %A Nordestgaard, Børge G %A Yeap, Bu B %A Fletcher, Astrid %A Melander, Olle %A Kuller, Lewis H %A Balkau, Beverley %A Marmot, Michael %A Koenig, Wolfgang %A Casiglia, Edoardo %A Cooper, Cyrus %A Arndt, Volker %A Franco, Oscar H %A Wennberg, Patrik %A Gallacher, John %A de la Cámara, Agustin Gómez %A Völzke, Henry %A Dahm, Christina C %A Dale, Caroline E %A Bergmann, Manuela M %A Crespo, Carlos J %A van der Schouw, Yvonne T %A Kaaks, Rudolf %A Simons, Leon A %A Lagiou, Pagona %A Schoufour, Josje D %A Boer, Jolanda M A %A Key, Timothy J %A Rodriguez, Beatriz %A Moreno-Iribas, Conchi %A Davidson, Karina W %A Taylor, James O %A Sacerdote, Carlotta %A Wallace, Robert B %A Quiros, J Ramon %A Tumino, Rosario %A Blazer, Dan G %A Linneberg, Allan %A Daimon, Makoto %A Panico, Salvatore %A Howard, Barbara %A Skeie, Guri %A Strandberg, Timo %A Weiderpass, Elisabete %A Nietert, Paul J %A Psaty, Bruce M %A Kromhout, Daan %A Salamanca-Fernandez, Elena %A Kiechl, Stefan %A Krumholz, Harlan M %A Grioni, Sara %A Palli, Domenico %A Huerta, José M %A Price, Jackie %A Sundström, Johan %A Arriola, Larraitz %A Arima, Hisatomi %A Travis, Ruth C %A Panagiotakos, Demosthenes B %A Karakatsani, Anna %A Trichopoulou, Antonia %A Kühn, Tilman %A Grobbee, Diederick E %A Barrett-Connor, Elizabeth %A van Schoor, Natasja %A Boeing, Heiner %A Overvad, Kim %A Kauhanen, Jussi %A Wareham, Nick %A Langenberg, Claudia %A Forouhi, Nita %A Wennberg, Maria %A Després, Jean-Pierre %A Cushman, Mary %A Cooper, Jackie A %A Rodriguez, Carlos J %A Sakurai, Masaru %A Shaw, Jonathan E %A Knuiman, Matthew %A Voortman, Trudy %A Meisinger, Christa %A Tjønneland, Anne %A Brenner, Hermann %A Palmieri, Luigi %A Dallongeville, Jean %A Brunner, Eric J %A Assmann, Gerd %A Trevisan, Maurizio %A Gillum, Richard F %A Ford, Ian %A Sattar, Naveed %A Lazo, Mariana %A Thompson, Simon G %A Ferrari, Pietro %A Leon, David A %A Smith, George Davey %A Peto, Richard %A Jackson, Rod %A Banks, Emily %A Di Angelantonio, Emanuele %A Danesh, John %X

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.

METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies.

FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.

INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

%B Lancet %V 391 %P 1513-1523 %8 2018 04 14 %G eng %N 10129 %R 10.1016/S0140-6736(18)30134-X %0 Journal Article %J Diabetologia %D 2018 %T Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis. %A McKeown, Nicola M %A Dashti, Hassan S %A Ma, Jiantao %A Haslam, Danielle E %A Kiefte-de Jong, Jessica C %A Smith, Caren E %A Tanaka, Toshiko %A Graff, Mariaelisa %A Lemaitre, Rozenn N %A Rybin, Denis %A Sonestedt, Emily %A Frazier-Wood, Alexis C %A Mook-Kanamori, Dennis O %A Li, Yanping %A Wang, Carol A %A Leermakers, Elisabeth T M %A Mikkilä, Vera %A Young, Kristin L %A Mukamal, Kenneth J %A Cupples, L Adrienne %A Schulz, Christina-Alexandra %A Chen, Tzu-An %A Li-Gao, Ruifang %A Huang, Tao %A Oddy, Wendy H %A Raitakari, Olli %A Rice, Kenneth %A Meigs, James B %A Ericson, Ulrika %A Steffen, Lyn M %A Rosendaal, Frits R %A Hofman, Albert %A Kähönen, Mika %A Psaty, Bruce M %A Brunkwall, Louise %A Uitterlinden, André G %A Viikari, Jorma %A Siscovick, David S %A Seppälä, Ilkka %A North, Kari E %A Mozaffarian, Dariush %A Dupuis, Josée %A Orho-Melander, Marju %A Rich, Stephen S %A de Mutsert, Renée %A Qi, Lu %A Pennell, Craig E %A Franco, Oscar H %A Lehtimäki, Terho %A Herman, Mark A %X

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits.

METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway.

RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant.

CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.

TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).

%B Diabetologia %V 61 %P 317-330 %8 2018 Feb %G eng %N 2 %R 10.1007/s00125-017-4475-0 %0 Journal Article %J Nat Genet %D 2019 %T A catalog of genetic loci associated with kidney function from analyses of a million individuals. %A Wuttke, Matthias %A Li, Yong %A Li, Man %A Sieber, Karsten B %A Feitosa, Mary F %A Gorski, Mathias %A Tin, Adrienne %A Wang, Lihua %A Chu, Audrey Y %A Hoppmann, Anselm %A Kirsten, Holger %A Giri, Ayush %A Chai, Jin-Fang %A Sveinbjornsson, Gardar %A Tayo, Bamidele O %A Nutile, Teresa %A Fuchsberger, Christian %A Marten, Jonathan %A Cocca, Massimiliano %A Ghasemi, Sahar %A Xu, Yizhe %A Horn, Katrin %A Noce, Damia %A van der Most, Peter J %A Sedaghat, Sanaz %A Yu, Zhi %A Akiyama, Masato %A Afaq, Saima %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boehnke, Michael %A Boerwinkle, Eric %A Boissel, Mathilde %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brenner, Hermann %A Brumat, Marco %A Burkhardt, Ralph %A Butterworth, Adam S %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Canouil, Mickaël %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Chee, Miao-Ling %A Chee, Miao-Li %A Chen, Xu %A Cheng, Ching-Yu %A Cheng, Yurong %A Christensen, Kaare %A Cifkova, Renata %A Ciullo, Marina %A Concas, Maria Pina %A Cook, James P %A Coresh, Josef %A Corre, Tanguy %A Sala, Cinzia Felicita %A Cusi, Daniele %A Danesh, John %A Daw, E Warwick %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Degenhardt, Frauke %A Delgado, Graciela %A Demirkan, Ayse %A Di Angelantonio, Emanuele %A Dittrich, Katalin %A Divers, Jasmin %A Dorajoo, Rajkumar %A Eckardt, Kai-Uwe %A Ehret, Georg %A Elliott, Paul %A Endlich, Karlhans %A Evans, Michele K %A Felix, Janine F %A Foo, Valencia Hui Xian %A Franco, Oscar H %A Franke, Andre %A Freedman, Barry I %A Freitag-Wolf, Sandra %A Friedlander, Yechiel %A Froguel, Philippe %A Gansevoort, Ron T %A Gao, He %A Gasparini, Paolo %A Gaziano, J Michael %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Giulianini, Franco %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hartman, Catharina A %A Hayward, Caroline %A Hellwege, Jacklyn N %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hofer, Edith %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Indridason, Olafur S %A Ingelsson, Erik %A Ising, Marcus %A Jaddoe, Vincent W V %A Jakobsdottir, Johanna %A Jonas, Jost B %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kanai, Masahiro %A Kastarinen, Mika %A Kerr, Shona M %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kraja, Aldi T %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A Kuokkanen, Mikko %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lange, Leslie A %A Langefeld, Carl D %A Lee, Jeannette Jen-Mai %A Lehne, Benjamin %A Lehtimäki, Terho %A Lieb, Wolfgang %A Lim, Su-Chi %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Jun %A Liu, Jianjun %A Loeffler, Markus %A Loos, Ruth J F %A Lucae, Susanne %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Magnusson, Patrik K E %A Mahajan, Anubha %A Martin, Nicholas G %A Martins, Jade %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mikaelsdottir, Evgenia K %A Milaneschi, Yuri %A Miliku, Kozeta %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey %A O'Donoghue, Michelle L %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Orho-Melander, Marju %A Ouwehand, Willem H %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Palsson, Runolfur %A Penninx, Brenda W J H %A Perls, Thomas %A Perola, Markus %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Podgornaia, Anna I %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Pramstaller, Peter P %A Preuss, Michael H %A Prins, Bram P %A Province, Michael A %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rizzi, Federica %A Roberts, David J %A Robino, Antonietta %A Rossing, Peter %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Salvi, Erika %A Saum, Kai-Uwe %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Schupf, Nicole %A Shaffer, Christian M %A Shi, Yuan %A Smith, Albert V %A Smith, Blair H %A Soranzo, Nicole %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Svensson, Per O %A Szymczak, Silke %A Tai, E-Shyong %A Tajuddin, Salman M %A Tan, Nicholas Y Q %A Taylor, Kent D %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomsen, Hauke %A Thorleifsson, Gudmar %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Tzoulaki, Ioanna %A Uitterlinden, André G %A Vaccargiu, Simona %A van Dam, Rob M %A van der Harst, Pim %A van Duijn, Cornelia M %A Velez Edward, Digna R %A Verweij, Niek %A Vogelezang, Suzanne %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Wallentin, Lars %A Wang, Ya Xing %A Wang, Chaolong %A Waterworth, Dawn M %A Bin Wei, Wen %A White, Harvey %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Wojczynski, Mary K %A Wong, Charlene %A Wong, Tien-Yin %A Xu, Liang %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Weihua %A Zonderman, Alan B %A Rotter, Jerome I %A Bochud, Murielle %A Psaty, Bruce M %A Vitart, Veronique %A Wilson, James G %A Dehghan, Abbas %A Parsa, Afshin %A Chasman, Daniel I %A Ho, Kevin %A Morris, Andrew P %A Devuyst, Olivier %A Akilesh, Shreeram %A Pendergrass, Sarah A %A Sim, Xueling %A Böger, Carsten A %A Okada, Yukinori %A Edwards, Todd L %A Snieder, Harold %A Stefansson, Kari %A Hung, Adriana M %A Heid, Iris M %A Scholz, Markus %A Teumer, Alexander %A Köttgen, Anna %A Pattaro, Cristian %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Inheritance Patterns %K Kidney Function Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Renal Insufficiency, Chronic %K Uromodulin %X

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.

%B Nat Genet %V 51 %P 957-972 %8 2019 06 %G eng %N 6 %R 10.1038/s41588-019-0407-x %0 Journal Article %J PLoS One %D 2019 %T Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. %A Ward-Caviness, Cavin K %A de Vries, Paul S %A Wiggins, Kerri L %A Huffman, Jennifer E %A Yanek, Lisa R %A Bielak, Lawrence F %A Giulianini, Franco %A Guo, Xiuqing %A Kleber, Marcus E %A Kacprowski, Tim %A Groß, Stefan %A Petersman, Astrid %A Davey Smith, George %A Hartwig, Fernando P %A Bowden, Jack %A Hemani, Gibran %A Müller-Nuraysid, Martina %A Strauch, Konstantin %A Koenig, Wolfgang %A Waldenberger, Melanie %A Meitinger, Thomas %A Pankratz, Nathan %A Boerwinkle, Eric %A Tang, Weihong %A Fu, Yi-Ping %A Johnson, Andrew D %A Song, Ci %A de Maat, Moniek P M %A Uitterlinden, André G %A Franco, Oscar H %A Brody, Jennifer A %A McKnight, Barbara %A Chen, Yii-Der Ida %A Psaty, Bruce M %A Mathias, Rasika A %A Becker, Diane M %A Peyser, Patricia A %A Smith, Jennifer A %A Bielinski, Suzette J %A Ridker, Paul M %A Taylor, Kent D %A Yao, Jie %A Tracy, Russell %A Delgado, Graciela %A Trompet, Stella %A Sattar, Naveed %A Jukema, J Wouter %A Becker, Lewis C %A Kardia, Sharon L R %A Rotter, Jerome I %A März, Winfried %A Dörr, Marcus %A Chasman, Daniel I %A Dehghan, Abbas %A O'Donnell, Christopher J %A Smith, Nicholas L %A Peters, Annette %A Morrison, Alanna C %X

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

%B PLoS One %V 14 %P e0216222 %8 2019 %G eng %N 5 %R 10.1371/journal.pone.0216222 %0 Journal Article %J Am J Epidemiol %D 2019 %T Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. %A de Vries, Paul S %A Brown, Michael R %A Bentley, Amy R %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Schwander, Karen %A Kraja, Aldi T %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Huffman, Jennifer E %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Deng, Xuan %A Dorajoo, Rajkumar %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Evangelou, Evangelos %A Graff, Mariaelisa %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Lee, Joseph H %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Matoba, Nana %A Nolte, Ilja M %A Pietzner, Maik %A Riaz, Muhammad %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Wang, Yajuan %A Ware, Erin B %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Ballantyne, Christie %A Boerwinkle, Eric %A Broeckel, Ulrich %A Campbell, Archie %A Canouil, Mickaël %A Charumathi, Sabanayagam %A Chen, Yii-Der Ida %A Connell, John M %A de Faire, Ulf %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Ding, Jingzhong %A Dominiczak, Anna F %A Duan, Qing %A Eaton, Charles B %A Eppinga, Ruben N %A Faul, Jessica D %A Fisher, Virginia %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Ghanbari, Mohsen %A Giulianini, Franco %A Grabe, Hans J %A Grove, Megan L %A Gu, C Charles %A Harris, Tamara B %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hixson, James E %A Howard, Barbara V %A Ikram, M Arfan %A Jacobs, David R %A Johnson, Craig %A Jonas, Jost Bruno %A Kammerer, Candace M %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooperberg, Charles %A Krieger, Jose E %A Kritchevsky, Steve B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lemaitre, Rozenn N %A Li, Yize %A Liang, Jingjing %A Liu, Jianjun %A Liu, Kiang %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Mosley, Thomas H %A Mukamal, Kenneth J %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A Sotoodehnia, Nona %A O'Connell, Jeff R %A Palmer, Nicholette D %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Reiner, Alex P %A Rice, Treva K %A Rich, Stephen S %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Smith, Blair H %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tan, Nicholas %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A van Heemst, Diana %A Vuckovic, Dragana %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Yujie %A Wang, Zhe %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo L %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Penninx, Brenda %A Pereira, Alexandre C %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wang, Ya Xing %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Zheng, Wei %A Elliott, Paul %A North, Kari E %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Liu, Ching-Ti %A Liu, Yongmei %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Kardia, Sharon L R %A Zhu, Xiaofeng %A Rotimi, Charles N %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Liu, Jingmin %A Rotter, Jerome I %A Gauderman, W James %A Province, Michael A %A Munroe, Patricia B %A Rice, Kenneth %A Chasman, Daniel I %A Cupples, L Adrienne %A Rao, Dabeeru C %A Morrison, Alanna C %X

An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

%B Am J Epidemiol %8 2019 Jan 29 %G eng %R 10.1093/aje/kwz005 %0 Journal Article %J PLoS One %D 2020 %T Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Hahn, Julie %A Fu, Yi-Ping %A Brown, Michael R %A Bis, Joshua C %A de Vries, Paul S %A Feitosa, Mary F %A Yanek, Lisa R %A Weiss, Stefan %A Giulianini, Franco %A Smith, Albert Vernon %A Guo, Xiuqing %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Brody, Jennifer A %A Chen, Yii-Der Ida %A Franco, Oscar H %A Grove, Megan %A Harris, Tamara B %A Hofman, Albert %A Hwang, Shih-Jen %A Kral, Brian G %A Launer, Lenore J %A Markus, Marcello R P %A Rice, Kenneth M %A Rich, Stephen S %A Ridker, Paul M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Sotoodehnia, Nona %A Taylor, Kent D %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Yao, Jie %A Chasman, Daniel I %A Dörr, Marcus %A Gudnason, Vilmundur %A Mathias, Rasika A %A Post, Wendy %A Psaty, Bruce M %A Dehghan, Abbas %A O'Donnell, Christopher J %A Morrison, Alanna C %K Aging %K Coronary Artery Disease %K Cross-Sectional Studies %K Europe %K European Continental Ancestry Group %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

%B PLoS One %V 15 %P e0230035 %8 2020 %G eng %N 11 %R 10.1371/journal.pone.0230035 %0 Journal Article %J Nat Genet %D 2022 %T Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. %A Mahajan, Anubha %A Spracklen, Cassandra N %A Zhang, Weihua %A Ng, Maggie C Y %A Petty, Lauren E %A Kitajima, Hidetoshi %A Yu, Grace Z %A Rüeger, Sina %A Speidel, Leo %A Kim, Young Jin %A Horikoshi, Momoko %A Mercader, Josep M %A Taliun, Daniel %A Moon, Sanghoon %A Kwak, Soo-Heon %A Robertson, Neil R %A Rayner, Nigel W %A Loh, Marie %A Kim, Bong-Jo %A Chiou, Joshua %A Miguel-Escalada, Irene %A Della Briotta Parolo, Pietro %A Lin, Kuang %A Bragg, Fiona %A Preuss, Michael H %A Takeuchi, Fumihiko %A Nano, Jana %A Guo, Xiuqing %A Lamri, Amel %A Nakatochi, Masahiro %A Scott, Robert A %A Lee, Jung-Jin %A Huerta-Chagoya, Alicia %A Graff, Mariaelisa %A Chai, Jin-Fang %A Parra, Esteban J %A Yao, Jie %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Steinthorsdottir, Valgerdur %A Cook, James P %A Kals, Mart %A Grarup, Niels %A Schmidt, Ellen M %A Pan, Ian %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Ahmad, Meraj %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Lecoeur, Cécile %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Jensen, Richard A %A Tajuddin, Salman %A Kabagambe, Edmond K %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Flanagan, Jack %A Abaitua, Fernando %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Akiyama, Masato %A Anand, Sonia S %A Bertoni, Alain %A Bian, Zheng %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Brummett, Chad M %A Buchanan, Thomas A %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Das, Swapan K %A de Silva, H Janaka %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Fuchsberger, Christian %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Goodarzi, Mark O %A Gordon-Larsen, Penny %A Gorkin, David %A Gross, Myron %A Guo, Yu %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Marit E %A Jørgensen, Torben %A Kamatani, Yoichiro %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kohara, Katsuhiko %A Kriebel, Jennifer %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Ligthart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lyssenko, Valeriya %A Mamakou, Vasiliki %A Mani, K Radha %A Meitinger, Thomas %A Metspalu, Andres %A Morris, Andrew D %A Nadkarni, Girish N %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Nongmaithem, Suraj S %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Porneala, Bianca %A Prasad, Gauri %A Preissl, Sebastian %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Kathryn %A Sabanayagam, Charumathi %A Sander, Maike %A Sandow, Kevin %A Sattar, Naveed %A Schönherr, Sebastian %A Schurmann, Claudia %A Shahriar, Mohammad %A Shi, Jinxiu %A Shin, Dong Mun %A Shriner, Daniel %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Stilp, Adrienne M %A Strauch, Konstantin %A Suzuki, Ken %A Takahashi, Atsushi %A Taylor, Kent D %A Thorand, Barbara %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Torres, Jason M %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Vujkovic, Marijana %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Whitsel, Eric A %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamauchi, Toshimasa %A Yengo, Loic %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zhang, Liang %A Zheng, Wei %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Hanis, Craig L %A Peyser, Patricia A %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Zeggini, Eleftheria %A Yokota, Mitsuhiro %A Rich, Stephen S %A Kooperberg, Charles %A Pankow, James S %A Engert, James C %A Chen, Yii-Der Ida %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Kardia, Sharon L R %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Groop, Leif %A Mook-Kanamori, Dennis O %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Bottinger, Erwin P %A Dehghan, Abbas %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Palmer, Colin N A %A Liu, Simin %A Abecasis, Goncalo %A Kooner, Jaspal S %A Loos, Ruth J F %A North, Kari E %A Haiman, Christopher A %A Florez, Jose C %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Mägi, Reedik %A Langenberg, Claudia %A Wareham, Nicholas J %A Maeda, Shiro %A Kadowaki, Takashi %A Lee, Juyoung %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Myers, Simon R %A Ferrer, Jorge %A Gaulton, Kyle J %A Meigs, James B %A Mohlke, Karen L %A Gloyn, Anna L %A Bowden, Donald W %A Below, Jennifer E %A Chambers, John C %A Sim, Xueling %A Boehnke, Michael %A Rotter, Jerome I %A McCarthy, Mark I %A Morris, Andrew P %K Diabetes Mellitus, Type 2 %K Ethnicity %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

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.

%B Nat Genet %V 54 %P 560-572 %8 2022 May %G eng %N 5 %R 10.1038/s41588-022-01058-3 %0 Journal Article %J Hum Mol Genet %D 2022 %T Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. %A Pankratz, Nathan %A Wei, Peng %A Brody, Jennifer A %A Chen, Ming-Huei %A Vries, Paul S %A Huffman, Jennifer E %A Stimson, Mary Rachel %A Auer, Paul L %A Boerwinkle, Eric %A Cushman, Mary %A Maat, Moniek P M %A Folsom, Aaron R %A Franco, Oscar H %A Gibbs, Richard A %A Haagenson, Kelly K %A Hofman, Albert %A Johnsen, Jill M %A Kovar, Christie L %A Kraaij, Robert %A McKnight, Barbara %A Metcalf, Ginger A %A Muzny, Donna %A Psaty, Bruce M %A Tang, Weihong %A Uitterlinden, André G %A Rooij, Jeroen G J %A Dehghan, Abbas %A O'Donnell, Christopher J %A Reiner, Alex P %A Morrison, Alanna C %A Smith, Nicholas L %X

Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

%B Hum Mol Genet %8 2022 May 12 %G eng %R 10.1093/hmg/ddac100 %0 Journal Article %J medRxiv %D 2023 %T Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Rayner, Nigel W %A Bocher, Ozvan %A Ana Luiza de, S V Arruda %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Alaine Broadaway, K %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Danesh, John %A Das, Swapan K %A Janaka de Silva, H %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Torben %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Lithgart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %A Zhang, Liang %A Zheng, Wei %A Project, Biobank Japan %A BioBank, Penn Medicine %A Center, Regeneron Genetics %A Consortium, eMERGE %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Fornage, Myriam %A Hanis, Craig L %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Geoffrey Hayes, M %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

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.

%B medRxiv %8 2023 Mar 31 %G eng %R 10.1101/2023.03.31.23287839 %0 Journal Article %J Nature %D 2024 %T Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Melloni, Giorgio E M %A Kanoni, Stavroula %A Rayner, Nigel W %A Bocher, Ozvan %A Arruda, Ana Luiza %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Broadaway, K Alaine %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Thangam, Manonanthini %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Danesh, John %A Das, Swapan K %A de Silva, H Janaka %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Hakaste, Liisa %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Torben %A Kamanu, Frederick K %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Ligthart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Moura, Filipe A %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %A Zhang, Liang %A Zheng, Wei %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Fornage, Myriam %A Hanis, Craig L %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Ahlqvist, Emma %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Marston, Nicholas A %A Ruff, Christian T %A van Heel, David A %A Finer, Sarah %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

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.

%B Nature %8 2024 Feb 19 %G eng %R 10.1038/s41586-024-07019-6