Association of common variants identified by recent genome-wide association studies with obesity in Chinese children: a case-control study

Wang et al. BMC Medical Genetics (2016) 17:7 DOI 10.1186/s12881-016-0268-4 RESEARCH ARTICLE Open Access Association of common variants identified by recent genome-wide association studies with obesity in Chinese children: a casecontrol study Hai-Jun Wang1†, Anke Hinney2†, Jie-Yun Song1, André Scherag3, Xiang-Rui Meng1, Harald Grallert4,5, Thomas Illig4,6, Johannes Hebebrand2, Yan Wang7 and Jun Ma1* Abstract Background: Large-scale genome-wide association studies have identified multiple genetic variants that are associated with elevated body mass index (BMI) or the risk of obesity in Caucasian or Asian populations. We examined whether these variants are individually associated with obesity in Chinese children, and also assessed their cumulative effects and predictive value for obesity risk in Chinese children. Methods: We genotyped 40 single nucleotide polymorphisms (SNPs) and conducted association analyses for 32/40 SNPs with an estimated minor allele frequency >1 % in 2 030 unrelated Chinese children, including 607 normal-weight, 718 overweight, and 705 obese individuals from two cross-sectional study groups. Logistic regression and linear regression under the additive model were used to examine associations, and the area under the receiver operating characteristic curve (AUCROC) was reported as prediction summary. Results: We identified obesity association for 6 SNPs near SEC16B, RBJ, CDKAL1, TFAP2B, MAP2K5 and FTO (odds ratios (ORs) ranged from 1.19 to 1.41, nominal two-sided P-values < 0.05). Association (Bonferroni corrected) of rs543874 near SEC16B and rs2241423 near MAP2K5 had presumably stronger effects on obesity in Chinese children than in Caucasian populations. Their risk alleles were also associated with BMI standard deviation score (BMI-SDS) variability. We demonstrated the cumulative effects of the 32 SNPs on obesity risk (per risk allele: OR = 1.06, 95 % CI: 1.03-1.11, P = 4.84 × 10-4) and BMI-SDS (β = 0.04, 95 % CI: 0.02-0.06, P = 3.69 × 10-7). The difference in AUCROC for a model with covariates (age, age square, sex and study group) and the model including covariates and all 32 SNPs was 2.8 % (P = 0.0002). Conclusion: While six SNPs were individually associated with obesity in Chinese children, the 32 common variants identified by recent GWA studies had cumulative effects and resulted in a limited increase in the AUCROC predictive value for childhood obesity. Keywords: Obesity, BMI, Gene, Variant, Children * Correspondence: † Equal contributors 1 Institute of Child and Adolescent Health, Peking University, Beijing, China Full list of author information is available at the end of the article © 2016 Wang et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. BMC Medical Genetics (2016) 17:7 Background The rapid increase of obesity prevalence has been a major public health challenge in both developed and developing countries. Obesity is a major risk factor for many common chronic diseases such as type 2 diabetes mellitus, cardiovascular disease, and many forms of cancer [1]. Although the reason for the increase in obesity prevalence has been largely attributed to environmental factors, including changes in dietary patterns and lifestyle, genetic factors play an important role in obesity susceptibility [2]. The heritability of the variance of body mass index (BMI) ranged from 40 % to 70 % [3]. In 2010, a meta-analysis of genome-wide association (GWA) studies for BMI was conducted in 249,796 adult individuals of European ancestry by the Genetic Investigation of Anthropometric Traits (GIANT) consortium. They confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with BMI at a genomewide significance level (P < 5 × 10-8) [4]. Heritability estimations for BMI or obesity are higher in children, compared with adults [5]. Although the currently known major common variants related to obesity overlap to a substantial degree between children and adults, a GWA study in French and German populations identified 2 new loci for childhood obesity including rs121458332 in SDCCAG8 and rs13278851 near TNKS/ MSRA. The latter locus had an effect in children and adolescents only [6]. In 2012, another meta-analysis of GWA studies identified 2 new loci for childhood obesity in populations of European ancestry (rs9568856 of OLFM4, rs9299 of HOXB5) [5]. Asians account for 60 % of the world’s population and have higher percentages of body fat and increased metabolic disease risk than individuals of European ancestry with the same BMI. Thus, a genetic study in an Asian population can not only facilitate the dissection of genetic architecture of obesity, but also identify genetic variants of particular importance in Asians [7]. Recently, two GWA studies in East Asian populations reported 4 new loci (rs2206734 of CDKAL1, rs11142387 of KLF9, rs261967 of PCSK1, rs12597579 of GP2) associated with BMI [7, 8]. Many replication studies for the 32 loci identified by GIANT have been performed in multiple ethnic populations, including Asians [9-14]. Studies on the SNPs near SDCCAG8 and TNKS/MSRA have led to mixed results [9,12,13]. Similarly, the 2 loci for childhood obesity (OLFM4 and HOXB5) and the 4 loci found in East Asians (CDKAL1, KLF9, PCSK1 and GP2) were not among the top hits of a large scale GWA studies meta-analysis which focused on the tails of the adult BMI distribution [13]. Recently, 28 SNPs from the 32 loci reported by GIANT and 4 additional loci identified in East Asians were studied in Chinese adults [15], but only 4 SNPs near Page 2 of 10 TMEM18, PCSK1, BDNF and MAP2K5 were confirmed (nominal P-values < 0.05). The effects of these SNPs in Chinese children were unclear. In the present study, we genotyped 40 single nucleotide polymorphism (SNPs) and conducted association analyses of the 32 variants that had an estimated minor allele frequency >1 % in 2 030 unrelated Chinese children, including 607 normal-weight, 718 overweight, and 705 obese individuals. The purpose of this case-control study was to (a) examine whether the common variants are individually associated with obesity in Chinese children and (b) assess the cumulative effects and predictive value for obesity in Chinese children. Methods Subjects We conducted an association study in two independent study groups, recruited from the urban regions of Beijing, China. The first study group, including 386 obese, 400 overweight and 151 norm (...truncated)