Human Molecular Genetics Advance Access published online on January 22, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp041
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Replication and extension of genome-wide association study results for obesity in 4,923 adults from Northern Sweden
1 Genetic Epidemiology & Clinical Research Group, Department of Public Health & Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå 901 87, Sweden 2 Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK 3 Department of Surgical and Perioperative Sciences, Section for Sports Medicine, Umeå University, Umeå 901 85, Sweden 4 Department of Community Medicine and Rehabilitation, Section for Rehabilitation Medicine, Umeå University Hospital, Umeå 901 87, Sweden 6 Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University Hospital, Umeå 901 85, Sweden 7 Department of Public Health & Clinical Medicine, Section for Nutritional Research, Umeå University, Umeå 901 85, Sweden 8 Department of Community Medicine and Rehabilitation, Section for Geriatric Medicine, Umeå University Hospital, Umeå 901 87, Sweden
* Corresponding author: Dr. Paul W. Franks, Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University Hospital, Umeå 901 87, Sweden. Tel: +46 (0)90 785 33 54, Fax: +46 (0)90 13 76 33, email: paul.franks{at}medicin.umu.se. URL: http://www.umu.se/phmed/medicin/paul.franks/
Received December 17, 2008; Revised January 20, 2009; Accepted January 20, 2009
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 3,885 non-diabetic and 1,038 diabetic individuals with available measures of height, weight and BMI. Adipose mass and distribution was objectively assessed using dual energy X-ray absorptiometry (DEXA) in a sub-group of non-diabetics (n=2,206). 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 (+2.6kg) and had more total (+2.4kg), gynoid (+191g), and abdominal (+136g) 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.
5 See appendix 1 for list of consortium members and their affiliations
These authors contributed equally to this manuscript
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