Abstract
We have performed exome-wide association studies to identify genetic variants that influence body mass index or confer susceptibility to obesity or metabolic syndrome in Japanese. The exome-wide association study for body mass index included 12,890 subjects, and those for obesity and metabolic syndrome included 12,968 subjects (3954 individuals with obesity, 9014 controls) and 6817 subjects (3998 individuals with MetS, 2819 controls), respectively. Exome-wide association studies were performed with Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of genotypes of single nucleotide polymorphisms to body mass index was examined by linear regression analysis, and that of allele frequencies of single nucleotide polymorphisms to obesity or metabolic syndrome was evaluated with Fisher's exact test. The exome-wide association studies identified six, 11, and 40 single nucleotide polymorphisms as being significantly associated with body mass index, obesity (P <1.21 × 10−6), or metabolic syndrome (P <1.20 × 10−6), respectively. Subsequent multivariable logistic regression analysis with adjustment for age and sex revealed that three and five single nucleotide polymorphisms were related (P < 0.05) to obesity or metabolic syndrome, respectively, with one of these latter polymorphisms—rs7350481 (C/T) at chromosome 11q23.3—also being significantly (P < 3.13 × 10−4) associated with metabolic syndrome. The polymorphism rs7350481 may thus be a novel susceptibility locus for metabolic syndrome in Japanese. In addition, single nucleotide polymorphisms in three genes (CROT, TSC1, RIN3) and at four loci (ANKK1, ZNF804B, CSRNP3, 17p11.2) were implicated as candidate determinants of obesity and metabolic syndrome, respectively.
Highlights
Obesity is a major risk factor for coronary artery disease, hypertension, diabetes mellitus, dyslipidemia, and several types of cancer [1, 2]
We examined the relation of genotypes of 41,327 single nucleotide polymorphisms (SNPs) that passed quality control to body mass index (BMI) in 12,890 subjects by linear regression analysis
We examined the relation of allele frequencies of 41,327 SNPs to obesity with Fisher’s exact test
Summary
Obesity is a major risk factor for coronary artery disease, hypertension, diabetes mellitus, dyslipidemia, and several types of cancer [1, 2]. Genetic variants identified in previous GWASs typically have a minor allele frequency (MAF) of ≥5% and a small individual effect size Given that these common variants explain only a fraction of the heritability, it is expected that low-frequency (0.5% ≤ MAF < 5%) or rare (MAF < 0.5%) variants with larger effect sizes contribute to the genetic architecture of obesity or MetS [26]. Several polymorphisms have been found to be significantly associated with BMI in East Asian populations [15,16,17], genetic variants, including low-frequency and rare variants, that influence BMI or contribute to predisposition to obesity or MetS in Japanese remain to be identified definitively. We used Illumina arrays that provide coverage of functional single nucleotide polymorphisms (SNPs) in entire exons including low-frequency and rare variants
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