Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants

Abstract

Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available firstdegree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients PLOS Genetics | https://doi

Genetic variation of FTO: rs1421085 T>C, rs8057044 G>A, rs9939609 T>A, and copy number (CNV) in Mexican Mayan school‐aged children with obesity/overweight and with normal weight

“…Glessner et al (2010) found a lack of contribution for common CNVs, including the FTO gene, and proposed CNVs that are exclusive to both European and African ethnicities. None of the studies, including rare CNV in the etiology of severe earlyonset obesity or novel CNV associated with familial obesity, have found CNV of FTO relevant, which supports a lack of CNV contribution to genetic risk for obesity (Serra-Juhé et al, 2017).…”

Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity

“…We performed a literature search to identify genes related to the melanocortin pathway and the development of the hypothalamus (1,5,12,18,19,21,(26)(27)(28)(29)(30)(31)(32)(33). The 24 genes included in the panel were: (1) genes in which variants have previously been reported to cause or associate with obesity (ADCY3, BDNF, CPE, GRPR, LEP, LEPR, LRP2, MC3R, MC4R, MRAP2, MYT1L, NPY, NTRK2, PCSK1, POMC, SH2B1, SIM1, TUB) and (2) genes previously reported in animal models/linkage analysis/CNV studies to be involved in the melanocortin pathway or development of hypothalamus (ARNT2, ISL1, NEUROG3, OTP, OXT, POU3F2).…”

“…For example, common single nucleotide polymorphisms (SNPs) in multiple genes have been shown to modulate the risk of obesity, although each of these have only a minor effect on body mass index (BMI) variation (2,3). We and others have also shown that rare copy number variants (CNVs) are enriched in patients with early-onset severe obesity (4)(5)(6). Recently, it has also been suggested that obesity could be a consequence of rare genetic variants with strong effect (7,8).…”

“…SIM1 and BDNF are transcription and neurotropic factors that control the neuronal differentiation of the hypothalamus and mutations in genes encoding these proteins have been associated with obesity (1). Recently, new obesity related genes involved in hypothalamic development or melanocortin pathway have been identified, such as ADCY3, MYT1L, POU3F2, GRPR, and LRP2 (1,5,(18)(19)(20)(21)(22).…”

Monogenic leptin deficiency in early childhood obesity

“…Early-onset obesity (EOO) is one of the most important global health problems resulting in several comorbidities with predisposition to obesity and related diseases during adulthood. 1 EOO is a heritable disorder with a range of genetic factors interacting with environmental exposures. 2 WHO has estimated that the majority of children with obesity live in developing countries, where the rates are increasing faster than in developed countries.…”