Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 × 10−7. This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.

[1]  S. Sookoian,et al.  Meta-analysis on the G-308A tumor necrosis factor alpha gene variant and phenotypes associated with the metabolic syndrome. , 2005, Obesity research.

[2]  Xiang Hu,et al.  Characterization and expression of a human KCTD1 gene containing the BTB domain, which mediates transcriptional repression and homomeric interactions. , 2008, DNA and cell biology.

[3]  M. Olivier A haplotype map of the human genome. , 2003, Nature.

[4]  M. Olivier A haplotype map of the human genome , 2003, Nature.

[5]  H. Stefánsson,et al.  Genetics of gene expression and its effect on disease , 2008, Nature.

[6]  Yuan Hong Yu,et al.  Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells. , 2008, Cancer research.

[7]  E. Gordon,et al.  BDNF Val66Met Polymorphism Is Associated with Body Mass Index in Healthy Adults , 2006, Neuropsychobiology.

[8]  Hiroaki Kitano,et al.  The PANTHER database of protein families, subfamilies, functions and pathways , 2004, Nucleic Acids Res..

[9]  Kári Stefánsson,et al.  Protection of privacy by third-party encryption in genetic research in Iceland , 2000, European Journal of Human Genetics.

[10]  C. Baile,et al.  Leptin-induced adipose apoptosis: Implications for body weight regulation , 2003, Apoptosis.

[11]  T. Spector,et al.  The SH2B Gene is Associated with Serum Leptin and Body Fat in Normal Female Twins , 2007, Obesity.

[12]  Friedrich Buck,et al.  Neurotractin, A Novel Neurite Outgrowth-promoting Ig-like Protein that Interacts with CEPU-1 and LAMP , 1999, The Journal of cell biology.

[13]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[14]  L. Chouchane,et al.  Genetic variation in the stress protein hsp70-2 gene is highly associated with obesity , 2001, International Journal of Obesity.

[15]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[16]  Kathryn Roeder,et al.  Genomic Control to the extreme , 2004, Nature Genetics.

[17]  Charlotte Glümer,et al.  A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99 (1) , 2003, European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology.

[18]  Christian Gieger,et al.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation , 2009, Nature Genetics.

[19]  J. González,et al.  Brain-Derived Neurotrophic Factor Val66Met and Psychiatric Disorders: Meta-Analysis of Case-Control Studies Confirm Association to Substance-Related Disorders, Eating Disorders, and Schizophrenia , 2007, Biological Psychiatry.

[20]  M. Neale,et al.  Genetic and Environmental Factors in Relative Body Weight and Human Adiposity , 1997, Behavior genetics.

[21]  T. Hansen,et al.  The common T60N polymorphism of the lymphotoxin-α gene is associated with type 2 diabetes and other phenotypes of the metabolic syndrome , 2005, Diabetologia.

[22]  Subhajyoti De,et al.  Common variants near MC4R are associated with fat mass, weight and risk of obesity , 2008, Nature Genetics.

[23]  T. Brümmendorf,et al.  Neurotractin/kilon promotes neurite outgrowth and is expressed on reactive astrocytes after entorhinal cortex lesion , 2005, Molecular and Cellular Neuroscience.

[24]  K. Clément,et al.  Unraveling the Genetics of Human Obesity , 2006, PLoS genetics.

[25]  F. Collins,et al.  Screening of 134 Single Nucleotide Polymorphisms (SNPs) Previously Associated With Type 2 Diabetes Replicates Association With 12 SNPs in Nine Genes , 2007, Diabetes.

[26]  M. Jarvelin,et al.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2007, Science.

[27]  Philippe Froguel,et al.  Common genetic variation near MC4R is associated with waist circumference and insulin resistance , 2008, Nature Genetics.

[28]  E. Koonin,et al.  Fold prediction and evolutionary analysis of the POZ domain: structural and evolutionary relationship with the potassium channel tetramerization domain. , 1999, Journal of molecular biology.

[29]  Claude Bouchard,et al.  The Human Obesity Gene Map: The 2005 Update , 2006, Obesity.

[30]  E. Lukhtanov,et al.  A novel endonuclease IV post-PCR genotyping system , 2006, Nucleic acids research.

[31]  Robert Plomin,et al.  Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. , 2008, The American journal of clinical nutrition.

[32]  T Lauritzen,et al.  The ADDITION study: proposed trial of the cost-effectiveness of an intensive multifactorial intervention on morbidity and mortality among people with Type 2 diabetes detected by screening , 2000, International Journal of Obesity.

[33]  K. Flegal,et al.  Prevalence of overweight and obesity in the United States, 1999-2004. , 2006, JAMA.

[34]  M. Pencina,et al.  Increasing trends in incidence of overweight and obesity over 5 decades. , 2007, The American journal of medicine.

[35]  Bjarni V. Halldórsson,et al.  Many sequence variants affecting diversity of adult human height , 2008, Nature Genetics.