Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals - PubMed (original) (raw)

Meta-Analysis

. 2013 Jan 1;22(1):184-201.

doi: 10.1093/hmg/dds396. Epub 2012 Sep 21.

Collaborators, Affiliations

Meta-Analysis

Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals

Yiran Guo et al. Hum Mol Genet. 2013.

Abstract

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.

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Figures

Figure 1.

Figure 1.

Schematic design of study for genetic association between BMI and genetic markers in the ITMAT-Broad-CARe (IBC) array. The work flow includes three parts, which are within study procedures, primary analyses and secondary analyses. Details can be found in the text.

Figure 2.

Figure 2.

Forest plots for the novel finding rs2075650 at the translocase of outer mitochondrial membrane 40 homolog (yeast)-apolipoprotein E-apolipoprotein C-I (TOMM40-APOE-APOC1) locus of genetic association between BMI and ITMAT-Broad-CARe (IBC) SNPs. Name of participating study, number of samples entering the meta-analysis, minor allele frequency (MAF) and effect size together with 95% confidence interval (CI) are shown as indicated by the header line of each plot. Effect sizes of meta-analysis results are shown at the bottom of each plot. Studies are sorted by sample size and are grouped according to ethnicities and data-contributing type (individual level or summary level). Sub-meta-analysis results are also shown where applicable.

Figure 3.

Figure 3.

Regional plots for the melanocortin 4 receptor (MC4R) and brain-derived neurotrophic factor (BDNF) region before and after doing conditional analysis. Two MC4R sub-figures are to the left panel and two BDNF sub-figures are to the right. For each locus, the top part shows unconditional meta-analysis results for individual-level samples of European ancestry (EA) and the bottom part shows meta-analysis results conditioning on lead SNP, rs2229616 in MC4R and rs10767664 in BDNF, respectively. Figures were generated using LocusZoom (31).

Figure 4.

Figure 4.

Regional plots of the TOMM40-APOE-APOC1 region for multi-ethnic association between BMI and ITMAT-Broad-CARe (IBC) array SNPs. Meta-analysis regional results of overall European ancestry individuals (top left), African-American (bottom left), East Asians (top right) and Hispanics (bottom right) are shown using LocusZoom (31). In each sub-figure, each spot represents one IBC SNP and its _y_-axis coordinate indicates significance level in association. For each SNP, linkage disequilibrium (LD) measure _r_2 with the lead SNP can be determined from the inset color scheme. Genome recombination rates (in cM/Mb) are shown by blue lines and gene annotation information can be found at the bottom.

References

    1. Ogden C.L., Carroll M.D., Curtin L.R., McDowell M.A., Tabak C.J., Flegal K.M. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA. 2006;295:1549–1555. doi:10.1001/jama.295.13.1549. - DOI - PubMed
    1. International Association for Study of Obesity (IASO) Global prevalence of adult obesity. IASO; 2011. http://www.iaso.org/site_media/uploads/Prevalence_of_Adult_Obesity_April.... (date last accessed September 2012)
    1. World Health Organization (WHO) Obesity and overweight fact sheet. WHO; 2011. http://www.who.int/mediacentre/factsheets/fs311/en/index.html. (date last accessed September 2012)
    1. Center for Disease Control and Prevention (CDC) Heart Disease Facts. CDC; 2010. http://www.cdc.gov/heartdisease/facts.htm. (date last accessed September 2012)
    1. Wormser D., Kaptoge S., Di Angelantonio E., Wood A.M., Pennells L., Thompson A., Sarwar N., Kizer J.R., Lawlor D.A., Nordestgaard B.G., et al. Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. Lancet. 2011;377:1085–1095. - PMC - PubMed

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