Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations

Obesity is a disorder with a complex genetic etiology, and its epidemic is a worldwide problem. Although multiple genetic loci associated with body mass index, the most common measure of obesity, have been identified in European populations, few studies have focused on Asian populations. Here we report a genome-wide association study and replication studies with 62,245 east Asian subjects, which identified two new body mass index–associated loci in the CDKAL1 locus at 6p22 (rs2206734, P = 1.4 × 10−11) and the KLF9 locus at 9q21 (rs11142387, P = 1.3 × 10−9), as well as several previously reported loci (the SEC16B, BDNF, FTO, MC4R and GIPR loci, P < 5.0 × 10−8). We subsequently performed gene-gene interaction analyses and identified an interaction (P = 2.0 × 10−8) between a SNP in the KLF9 locus (rs11142387) and one in the MSTN (also known as GDF8) locus at 2q32 (rs13034723). These findings should provide useful insights into the etiology of obesity.

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

[2]  K. Burgdorf,et al.  Variation in the gene encoding Krüppel-like factor 7 influences body fat: studies of 14 818 Danes. , 2009, European journal of endocrinology.

[3]  M. Hamrick,et al.  Myostatin (GDF-8) as a key factor linking muscle mass and bone structure. , 2010, Journal of musculoskeletal & neuronal interactions.

[4]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[5]  H Toyoshima,et al.  Validity of self-reported height and weight in a Japanese workplace population , 2005, International Journal of Obesity.

[6]  Yusuke Nakamura,et al.  Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus. , 2011, Human molecular genetics.

[7]  K. Liao,et al.  Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis , 2011, Cell Death and Differentiation.

[8]  S. Akira,et al.  Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. , 2005, Cell metabolism.

[9]  T. Kadowaki,et al.  Adiponectin and adiponectin receptors. , 2005, Endocrine reviews.

[10]  Gary K. Chen,et al.  Meta-analysis identifies common variants associated with body mass index in East Asians , 2012, Nature Genetics.

[11]  Philippe Froguel,et al.  Genome-wide association scans identified CTNNBL1 as a novel gene for obesity. , 2008, Human molecular genetics.

[12]  E. Bonifacio,et al.  BMI at Age 8 Years Is Influenced by the Type 2 Diabetes Susceptibility Genes HHEX-IDE and CDKAL1 , 2010, Diabetes.

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

[14]  S. Gabriel,et al.  Assessing the impact of population stratification on genetic association studies , 2004, Nature Genetics.

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

[16]  Taesung Park,et al.  A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits , 2009, Nature Genetics.

[17]  Alex Doney,et al.  Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge , 2010, Nature Genetics.

[18]  T. Hansen,et al.  Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight , 2010, Diabetologia.

[19]  Yusuke Nakamura,et al.  A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B , 2010, Nature Genetics.

[20]  Barbara Heude,et al.  Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations , 2009, Nature Genetics.

[21]  Kazutoshi Nakamura,et al.  RELIABILITY OF SELF-REPORTED BODY HEIGHT AND WEIGHT OF ADULT JAPANESE WOMEN , 1999, Journal of Biosocial Science.

[22]  P. Kopelman.  Obesity as a medical problem , 2000, Nature.

[23]  S. Dietrich,et al.  An evolutionarily conserved Myostatin proximal promoter/enhancer confers basal levels of transcription and spatial specificity in vivo , 2009, Development Genes and Evolution.

[24]  H. Cordell.  Detecting gene–gene interactions that underlie human diseases , 2009, Nature Reviews Genetics.

[25]  Tanya M. Teslovich,et al.  Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index , 2010 .

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

[27]  C. Nishida,et al.  Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies , 2004, The Lancet.

[28]  Marc S. Williams.  Myostatin mutation associated with gross muscle hypertrophy in a child. , 2004, The New England journal of medicine.

[29]  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.

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

[31]  Ellen Kampman,et al.  Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity , 2009, Nature Genetics.

[32]  Shengjie Li,et al.  Recent Advances , 2018, Journal of Optimization Theory and Applications.

[33]  S. Levy,et al.  Genome-wide association and replication studies identified TRHR as an important gene for lean body mass. , 2009, American journal of human genetics.

[34]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[35]  Yusuke Nakamura,et al.  Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. , 2008, American journal of human genetics.

[36]  J. Hebebrand,et al.  From monogenic to polygenic obesity: recent advances , 2010, European Child & Adolescent Psychiatry.

[37]  Yusuke Nakamura,et al.  The BioBank Japan Project. , 2007, Clinical advances in hematology & oncology : H&O.

[38]  P. Deurenberg,et al.  Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship , 2002, Obesity reviews : an official journal of the International Association for the Study of Obesity.