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.