Introduction

Childhood obesity is one of the most serious public health challenges worldwide. With a high estimated heritability(Elks et al., 2012), it increases the risk of many physical and mental conditions and contributes to the global burden of chronic diseases including type 2 diabetes, cardiovascular diseases, and several types of cancer(Levi et al., 2017; Twig et al., 2016; Twig et al., 2018). Over the past four decades, the number of obese children and adolescents (aged 5 to 19 years) worldwide has risen more than tenfold, from 11 million in 1975 to 124 million in 2016(Collaboration, 2017). Childhood obesity prevalence in China rocketed up since the 90s due to its rapid economic growth and industrialization. According to the Global Burden of Disease study, China has the highest number of obese children (15.3 million), and the second highest number of obese adults (57.3 million) in the world after US in 2015(Collaborators et al., 2017). About 70% of obese adolescents become obese adults, and they are more likely to develop diabetes and cardiovascular diseases at a younger age(Simmonds, Llewellyn, Owen, & Woolacott, 2016; Zhao & Grant, 2011).
Obesity results from a complex interplay of various genetic and environmental factors. Over the past decade, genome-wide association studies (GWASs) have successfully identified numerous common variants associated with obesity-related traits, such as body mass index (BMI), waist-to-hip ratio, and body fat index(Akiyama et al., 2017; Locke et al., 2015; Shungin et al., 2015). Despite the progress, much of the obesity heritability remains yet to be explored. So far the identified single-nucleotide variants (SNVs) associated with obesity tend to be common, non-coding variants with small effect sizes, and the function and pathophysiology of these genetic variants are largely uncertain. Low-frequency or rare variants with large effects that may account for unexplained heritability in common obesity have not been systematically investigated in Chinese population. Exome sequencing has recently identified several large effects coding variants associated with obesity. Two SNVs, rs7238987 (CYB5A ) and chr12:120990399 (RNF10:p.R151H), were identified as obesity-associated variants in American Pima Indians(Huang et al., 2014). SNVs of rs62623713 (SYPL2 ) and rs2076349 (LAMB3 ) were identified in morbidly obese European adults(Jiao et al., 2015; Jiao et al., 2016). A family-based association study in Hispanic children identified rs141510219 (PEX1 ) which was associated with several obesity traits(Sabo et al., 2017). However, most studies were carried out in adults, for whom the genetic influence of obesity-related genes might be compromised by diet, age, pregnancy, lifestyle and other factors. Studies on children were, on the other hand, exempt from the influence of those environmental factors to the utmost extent.
Here, we used whole-exome sequencing (WES) to detect novel obesity-susceptible gene loci in 150 Chinese children and further validated them in 6,334 children. We aim to identify significantly obesity associated coding variants. Association between variants and obesity traits such as BMI, fat mass percentage (FMP), fat mass index (FMI), and fat free mass index (FFMI) were also tested. Transcriptome sequencing were also performed in blood and adipose tissues, and the possible mechanisms of discovered variants in obesity pathology were investigated.