%0 Journal Article %J Hum Mol Genet %D 2013 %T Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. %A Guo, Yiran %A Lanktree, Matthew B %A Taylor, Kira C %A Hakonarson, Hakon %A Lange, Leslie A %A Keating, Brendan J %K Body Mass Index %K Cohort Studies %K Ethnic Groups %K Humans %K Polymorphism, Single Nucleotide %X

Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ~2100 metabolic and cardiovascular-related loci to genotype up to 108 912 individuals of European ancestry (EA), African-Americans, Hispanics and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P < 2.40E-06), we identify novel BMI associations in loci translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (MC4R) regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics.

%B Hum Mol Genet %V 22 %P 184-201 %8 2013 Jan 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23001569?dopt=Abstract %R 10.1093/hmg/dds396 %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 Hum Mol Genet %D 2014 %T Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. %A Yoneyama, Sachiko %A Guo, Yiran %A Lanktree, Matthew B %A Barnes, Michael R %A Elbers, Clara C %A Karczewski, Konrad J %A Padmanabhan, Sandosh %A Bauer, Florianne %A Baumert, Jens %A Beitelshees, Amber %A Berenson, Gerald S %A Boer, Jolanda M A %A Burke, Gregory %A Cade, Brian %A Chen, Wei %A Cooper-Dehoff, Rhonda M %A Gaunt, Tom R %A Gieger, Christian %A Gong, Yan %A Gorski, Mathias %A Heard-Costa, Nancy %A Johnson, Toby %A Lamonte, Michael J %A McDonough, Caitrin %A Monda, Keri L %A Onland-Moret, N Charlotte %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Ordovas, Jose %A Peter, Inga %A Peters, Annette %A Shaffer, Jonathan %A Shen, Haiqinq %A Smith, Erin %A Speilotes, Liz %A Thomas, Fridtjof %A Thorand, Barbara %A Monique Verschuren, W M %A Anand, Sonia S %A Dominiczak, Anna %A Davidson, Karina W %A Hegele, Robert A %A Heid, Iris %A Hofker, Marten H %A Huggins, Gordon S %A Illig, Thomas %A Johnson, Julie A %A Kirkland, Susan %A König, Wolfgang %A Langaee, Taimour Y %A McCaffery, Jeanne %A Melander, Olle %A Mitchell, Braxton D %A Munroe, Patricia %A Murray, Sarah S %A Papanicolaou, George %A Redline, Susan %A Reilly, Muredach %A Samani, Nilesh J %A Schork, Nicholas J %A van der Schouw, Yvonne T %A Shimbo, Daichi %A Shuldiner, Alan R %A Tobin, Martin D %A Wijmenga, Cisca %A Yusuf, Salim %A Hakonarson, Hakon %A Lange, Leslie A %A Demerath, Ellen W %A Fox, Caroline S %A North, Kari E %A Reiner, Alex P %A Keating, Brendan %A Taylor, Kira C %K Adiposity %K Adult %K Aged %K Aged, 80 and over %K Body Mass Index %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Waist Circumference %K Waist-Hip Ratio %K Young Adult %X

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

%B Hum Mol Genet %V 23 %P 2498-510 %8 2014 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract %R 10.1093/hmg/ddt626 %0 Journal Article %J Lancet %D 2015 %T HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. %A Swerdlow, Daniel I %A Preiss, David %A Kuchenbaecker, Karoline B %A Holmes, Michael V %A Engmann, Jorgen E L %A Shah, Tina %A Sofat, Reecha %A Stender, Stefan %A Johnson, Paul C D %A Scott, Robert A %A Leusink, Maarten %A Verweij, Niek %A Sharp, Stephen J %A Guo, Yiran %A Giambartolomei, Claudia %A Chung, Christina %A Peasey, Anne %A Amuzu, Antoinette %A Li, KaWah %A Palmen, Jutta %A Howard, Philip %A Cooper, Jackie A %A Drenos, Fotios %A Li, Yun R %A Lowe, Gordon %A Gallacher, John %A Stewart, Marlene C W %A Tzoulaki, Ioanna %A Buxbaum, Sarah G %A van der A, Daphne L %A Forouhi, Nita G %A Onland-Moret, N Charlotte %A van der Schouw, Yvonne T %A Schnabel, Renate B %A Hubacek, Jaroslav A %A Kubinova, Ruzena %A Baceviciene, Migle %A Tamosiunas, Abdonas %A Pajak, Andrzej %A Topor-Madry, Roman %A Stepaniak, Urszula %A Malyutina, Sofia %A Baldassarre, Damiano %A Sennblad, Bengt %A Tremoli, Elena %A de Faire, Ulf %A Veglia, Fabrizio %A Ford, Ian %A Jukema, J Wouter %A Westendorp, Rudi G J %A de Borst, Gert Jan %A de Jong, Pim A %A Algra, Ale %A Spiering, Wilko %A Maitland-van der Zee, Anke H %A Klungel, Olaf H %A de Boer, Anthonius %A Doevendans, Pieter A %A Eaton, Charles B %A Robinson, Jennifer G %A Duggan, David %A Kjekshus, John %A Downs, John R %A Gotto, Antonio M %A Keech, Anthony C %A Marchioli, Roberto %A Tognoni, Gianni %A Sever, Peter S %A Poulter, Neil R %A Waters, David D %A Pedersen, Terje R %A Amarenco, Pierre %A Nakamura, Haruo %A McMurray, John J V %A Lewsey, James D %A Chasman, Daniel I %A Ridker, Paul M %A Maggioni, Aldo P %A Tavazzi, Luigi %A Ray, Kausik K %A Seshasai, Sreenivasa Rao Kondapally %A Manson, JoAnn E %A Price, Jackie F %A Whincup, Peter H %A Morris, Richard W %A Lawlor, Debbie A %A Smith, George Davey %A Ben-Shlomo, Yoav %A Schreiner, Pamela J %A Fornage, Myriam %A Siscovick, David S %A Cushman, Mary %A Kumari, Meena %A Wareham, Nick J %A Verschuren, W M Monique %A Redline, Susan %A Patel, Sanjay R %A Whittaker, John C %A Hamsten, Anders %A Delaney, Joseph A %A Dale, Caroline %A Gaunt, Tom R %A Wong, Andrew %A Kuh, Diana %A Hardy, Rebecca %A Kathiresan, Sekar %A Castillo, Berta A %A van der Harst, Pim %A Brunner, Eric J %A Tybjaerg-Hansen, Anne %A Marmot, Michael G %A Krauss, Ronald M %A Tsai, Michael %A Coresh, Josef %A Hoogeveen, Ronald C %A Psaty, Bruce M %A Lange, Leslie A %A Hakonarson, Hakon %A Dudbridge, Frank %A Humphries, Steve E %A Talmud, Philippa J %A Kivimaki, Mika %A Timpson, Nicholas J %A Langenberg, Claudia %A Asselbergs, Folkert W %A Voevoda, Mikhail %A Bobak, Martin %A Pikhart, Hynek %A Wilson, James G %A Reiner, Alex P %A Keating, Brendan J %A Hingorani, Aroon D %A Sattar, Naveed %K Aged %K Body Mass Index %K Body Weight %K Cholesterol, HDL %K Cholesterol, LDL %K Diabetes Mellitus, Type 2 %K Female %K Genetic Testing %K Humans %K Hydroxymethylglutaryl CoA Reductases %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Randomized Controlled Trials as Topic %K Risk Factors %X

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.

FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).

INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.

FUNDING: The funding sources are cited at the end of the paper.

%B Lancet %V 385 %P 351-61 %8 2015 Jan 24 %G eng %N 9965 %1 http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract %R 10.1016/S0140-6736(14)61183-1