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

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 nucle...

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Bibliographic Details
Published in:Human Molecular Genetics
Main Authors: Renström, Frida, Payne, Felicity, Nordström, Anna, Brito, Ema C., Rolandsson, Olov, Hallmans, Göran, Barroso, Ines, Nordström, Peter, Franks, Paul W., GIANT Consortium
Format: Text
Language:English
Published: Oxford University Press 2009
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Online Access:http://hmg.oxfordjournals.org/cgi/content/short/18/8/1489
https://doi.org/10.1093/hmg/ddp041
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Summary: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.