Gao Chuan, Wang Nan, Guo Xiuqing, Ziegler Julie T, Taylor Kent D, Xiang Anny H, Hai Yang, Kridel Steven J, Nadler Jerry L, Kandeel Fouad, Raffel Leslie J, Chen Yii-Der I, Norris Jill M, Rotter Jerome I, Watanabe Richard M, Wagenknecht Lynne E, Bowden Donald W, Speliotes Elizabeth K, Goodarzi Mark O, Langefeld Carl D, Palmer Nicholette D
Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
PLoS One. 2015 Nov 24;10(11):e0134649. doi: 10.1371/journal.pone.0134649. eCollection 2015.
Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (nmax = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (IDH1) was associated with WAIST (rs34218846, MAF = 6.8%, PDOM = 1.62x10-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (ZGRF1; SNP rs1471880, MAF = 48.1%, PDOM = 1.00x10-8) were strongly associated with WHR. The exact biological function of ZGRF1 and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (nmax = 4156) and the strongest signal was rs1471880 (PDOM = 8.38x10-6) in ZGRF1 with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (IDH1 and ZGRF1) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, IDH1 and ZGRF1 warrant further evaluation.
肥胖症正日益流行，影响着美国35%的成年人。此前的全基因组关联研究（GWAS）已确定了许多与肥胖相关的基因座。然而，大多数研究是在白种人中完成的，重点是全身肥胖指标。在此，我们报告了来自全基因组和外显子芯片关联研究的结果，该研究聚焦于全身肥胖指标，包括体重指数（BMI）、体脂百分比（PBF）以及脂肪沉积指标，如腰围（WAIST）、腰臀比（WHR）、皮下脂肪组织（SAT）和内脏脂肪组织（VAT），研究对象为胰岛素抵抗动脉粥样硬化家族研究（IRASFS）中的西班牙裔美国人（最大样本量n = 1263）。来自两个新基因座的5个单核苷酸多态性（SNP）在IRASFS中达到全基因组显著性水平（P<5.00x10-8）。异柠檬酸脱氢酶1基因（IDH1）中的一个错义SNP与腰围相关（rs34218846，最小等位基因频率MAF = 6.8%，P值分布PDOM = 1.62x10-8）。在细胞和基因敲除动物模型中已证明，该蛋白在脂肪和胆固醇生物合成中起重要作用。锌指、含GRF型1基因（ZGRF1；SNP rs1471880，MAF = 48.1%，PDOM = 1.00x10-8）中的4个相关内含子SNP与腰臀比密切相关。ZGRF1的确切生物学功能及其与肥胖的关联尚不清楚。从IRASFS中选择P值小于5.00x10-6的SNP进行重复验证。对7个独立的西班牙裔美国人队列（最大样本量n = 4156）进行荟萃分析，最强信号是ZGRF1中的rs1471880与腰围相关（PDOM = 8.38x10-6）。总之，我们进行了一项全基因组和外显子芯片关联研究，确定了两个与肥胖相关的新基因座（IDH1和ZGRF1）。虽然重复验证的结果尚无定论，但结合已知生物学信息，IDH1和ZGRF1值得进一步评估。
