Abstract
Genome-wide association studies have identified multiple variants associated with adult obesity, mostly in European-ancestry populations. We aimed to systematically assess the contribution of key loci, which had been previously shown to be associated in East Asian adults, to childhood obesity, related adipokine profiles and metabolic traits in a Chinese pediatric population. Twelve single-nucleotide polymorphisms (SNPs) plus metabolic profiles and levels of five adipokines (leptin, adiponectin, resistin, fibroblast growth factor 21 and retinol binding protein 4) were evaluated in 3,506 Chinese children and adolescents aged 6-18. After correction for multiple comparisons, six of these SNPs were robustly associated with childhood obesity: FTO-rs1558902 (P=5.6×10−5), MC4R-rs2331841 (P=4.4×10−4), GNPDA2-rs16858082 (P = 3.4×10−4), PCSK1-rs261967 (P = 0.001), SEC16B-rs516636 (P = 0.004) and MAP2K5-rs4776970 (P = 0.004), with odds ratios ranging from 1.211 to 1.421; while ITIH4-rs2535633 and BDNF-rs2030323 yielded nominal association with the same trait (P < 0.05). Moreover, the risk alleles of six SNPs displayed significant (P < 0.004) or nominal (P < 0.05) association with leptin levels, namely at in/near PCSK1, MC4R, FTO, MAP2K5, GNPDA2 and BDNF plus their cumulative genetic score yielded stronger association with increased leptin levels (P = 6.2×10−11). Our results reveal that key obesity-associated loci previously reported in Europeans, but also associated with East Asian adults, are also associated with obesity and/or metabolic quantitative traits in Chinese children. These associations coincide with six brain-expressed loci that correlate with leptin levels, thus may point to an important neuronal influence on body weight regulation in the pediatric setting.
Highlights
The worldwide epidemic of obesity poses a major risk for the development of type 2 diabetes (T2D), cardiovascular disease (CVD), hypertension, stroke and certain types of cancer [1, 2]
Recent reports of obesity-related loci enriched in brain-expressed genes such as FTO, MC4R, GNPDA2, and BDNF point to a neuronal influence on body weight regulation in adults [17]
We selected thirteen of the strongest body mass index (BMI)-related loci reported from a recent meta-analysis of genome-wide association studies (GWAS) in adult of East Asian-ancestry populations [12,13,14] to test their associations with obesity in a well-established cohort of Chinese school-aged children, with focus on the single-nucleotide polymorphisms (SNPs) related to brain-expressed loci
Summary
The worldwide epidemic of obesity poses a major risk for the development of type 2 diabetes (T2D), cardiovascular disease (CVD), hypertension, stroke and certain types of cancer [1, 2]. In China, obesity rates have increased sharply over the past 20-30 years, in childhood, rapidly climbing from 0.2% in 1985 to 8.1% in 2012 [3] Both genetic predisposition and lifestyle factors are known to contribute to the risk of obesity [4]. Recent reports of obesity-related loci enriched in brain-expressed genes such as FTO, MC4R, GNPDA2, and BDNF point to a neuronal influence on body weight regulation in adults [17]. We queried whether such an influence existed, or was even more pronounced in children. We selected thirteen of the strongest BMI-related loci reported from a recent meta-analysis of GWAS in adult of East Asian-ancestry populations [12,13,14] to test their associations with obesity in a well-established cohort of Chinese school-aged children, with focus on the single-nucleotide polymorphisms (SNPs) related to brain-expressed loci
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