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. 2009 Apr 15;18(8):1489-96.
doi: 10.1093/hmg/ddp041. Epub 2009 Jan 22.

Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden

Frida Renström  1 , Felicity Payne, Anna Nordström, Ema C Brito, Olov Rolandsson, Göran Hallmans, Ines Barroso, Peter Nordström, Paul W Franks; GIANT Consortium
Affiliations

Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden

Frida Renström et al. Hum Mol Genet. .

Abstract

Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1 and PCSK1). Here we extend those studies by examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3885 non-diabetic and 1038 diabetic individuals with available measures of height, weight and body mass index (BMI). Adipose mass and distribution were objectively assessed using dual-energy X-ray absorptiometry in a sub-group of non-diabetics (n = 2206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P < 0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752 and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the score were heavier (+2.6 kg) and had more total (+2.4 kg), gynoid (+191 g) and abdominal (+136 g) adipose tissue than those in the lowest quintile (all P < 0.001). The genetic burden score significantly increased diabetes risk, with those in the highest quintile (n = 193/594 cases/controls) being at 1.55-fold (95% CI 1.21-1.99; P < 0.0001) greater risk of type 2 diabetes than those in the lowest quintile (n = 130/655 cases/controls). In summary, we have statistically replicated six of the previously associated obese-risk loci and our results suggest that the weight-inducing effects of these variants are explained largely by increased adipose accumulation.

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Figures

Figure 1.
Figure 1.
Differences in weight (kg) and total, abdominal and gynoid adipose mass (kg) between major and minor allele homozygotes at each of the seven nominally associated loci (P < 0.1) and between the first and fifth quintiles of the genetic burden score. Data are adjusted for age and sex (n = 2206). As described in the results, nominal gene–sex interactions were observed for total and abdominal adipose mass at the MC4R locus.
Figure 2.
Figure 2.
Associations between the genetic burden score (expressed in quintiles) and obesity indices. Error bars are 95% confidence intervals. P-values are derived from linear regression models adjusted for age and sex. (A) P = 2.32 × 10−5; (B) P = 3.69 × 10−6; (C) P = 0.0001; (D) P = 0.0004; (E) P = 0.0002; (F) P = 0.099).
Figure 3.
Figure 3.
Unadjusted receiver-operating characteristic curve showing the combined ability of the genetic burden score to discriminate between 353 obese (BMI >30 kg/m2) and 1370 normal weight (BMI 18.5–24.9 kg/m2) individuals.
See this image and copyright information in PMC

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