Dataset Information

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.

ABSTRACT: 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 (? ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (? = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (? = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (? = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (? = 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.

SUBMITTER: Yoneyama S

PROVIDER: S-EPMC3988452 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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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.

Yoneyama Sachiko S Guo Yiran Y Lanktree Matthew B MB Barnes Michael R MR Elbers Clara C CC Karczewski Konrad J KJ Karczewski Konrad J KJ Padmanabhan Sandosh S Bauer Florianne F Baumert Jens J Beitelshees Amber A Berenson Gerald S GS Boer Jolanda M A JM Burke Gregory G Cade Brian B Chen Wei W Cooper-Dehoff Rhonda M RM Gaunt Tom R TR Gieger Christian C Gong Yan Y Gorski Mathias M Heard-Costa Nancy N Johnson Toby T Lamonte Michael J MJ McDonough Caitrin C Monda Keri L KL Onland-Moret N Charlotte NC Nelson Christopher P CP O'Connell Jeffrey R JR Ordovas Jose J Peter Inga I Peters Annette A Shaffer Jonathan J Shen Haiqinq H Smith Erin E Speilotes Liz L Thomas Fridtjof F Thorand Barbara B Monique Verschuren W M WM Anand Sonia S SS Dominiczak Anna A Davidson Karina W KW Hegele Robert A RA Heid Iris I Hofker Marten H MH Huggins Gordon S GS Illig Thomas T Johnson Julie A JA Kirkland Susan S König Wolfgang W Langaee Taimour Y TY McCaffery Jeanne J Melander Olle O Mitchell Braxton D BD Munroe Patricia P Murray Sarah S SS Papanicolaou George G Redline Susan S Reilly Muredach M Samani Nilesh J NJ Schork Nicholas J NJ Van Der Schouw Yvonne T YT Shimbo Daichi D Shuldiner Alan R AR Tobin Martin D MD Wijmenga Cisca C Yusuf Salim S Hakonarson Hakon H Lange Leslie A LA Demerath Ellen W EW Fox Caroline S CS North Kari E KE Reiner Alex P AP Keating Brendan B Taylor Kira C KC

Human molecular genetics 20131217 9

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 Gen ...[more]

PMID: 24345515

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Project description: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.

Project description:ImportanceIndividuals of African descent have been reported to be at higher risk for becoming visually impaired from glaucoma compared with individuals of European descent.ObjectiveTo investigate racial differences in longitudinal visual field variability and their impact on time to detect visual field progression.Design, setting, and participantsThis multicenter prospective observational cohort study included 236 eyes of 173 individuals of European descent and 235 eyes of 171 individuals of African descent followed up for a mean (SD) time of 7.5 (3.4) years.Main outcomes and measuresDifferences in test-retest variability and simulated time to detect progression in individuals of African descent and of European descent with glaucoma. Standard automated perimetry mean deviation values were regressed over time for each eye, and SD of the residuals was used as a measure of variability. Distributions of residuals were used in computer simulations to reconstruct "real-world" standard automated perimetry mean deviation trajectories under different assumptions about rate of change and frequency of testing. Times to detect progression were obtained for the simulated visual fields.ResultsAmong the 344 patients, the mean (SD) age at baseline was 60.2 (10.0) and 60.6 (9.0) years for individuals of African descent and of European descent, respectively; 94 (52%) and 86 (48%) of individuals of African descent and of European descent were women, respectively. The mean SD of the residuals was larger in eyes of individuals of African descent vs those of European descent (1.45 [0.83] dB vs 1.12 [0.48] dB; mean difference: 0.33 dB; 95% CI of the difference, 0.21-0.46; P < .001). The eyes in individuals of African descent had a larger increase in variability with worsening disease (P < .001). When simulations were performed assuming common progression scenarios, there was a delay to detect progression in eyes of individuals of African descent compared with those of European descent. For a scenario with baseline mean deviation of -10 dB and rate of change of -0.5 dB/y, detection of progression in individuals of African descent was delayed by 3.1 (95% CI, 2.9-3.2) years, when considered 80% power and annual tests.Conclusions and relevancePatients of African descent with glaucoma showed increased visual field variability compared with those of European descent, resulting in delayed detection of progression that may contribute to explain higher rates of glaucoma-related visual impairment in individuals of African descent compared with those of European descent with glaucoma.

Dataset Information

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.

Publications

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.

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