Copy number variant analysis and expression profiling of the olfactory receptor-rich 11q11 region in obesity predisposition

Abstract

Genome-wide copy number surveys associated chromosome 11q11 with obesity. As this is an olfactory receptor-rich region, we hypothesize that genetic variation in olfactory receptor genes might be implicated in the pathogenesis of obesity. Multiplex Amplicon Quantification analysis was applied to screen for copy number variants at chromosome 11q11 in 627 patients with obesity and 330 healthy-weight individuals. A ± 80 kb deletion with an internally 1.3 kb retained segment was identified, covering the three olfactory receptor genes OR4C11 , OR4P4 , and OR4S2 . A significant increase in copy number loss(es) was perceived in our patient cohort (MAF = 27%; p = 0.02). Gene expression profiling in metabolic relevant tissues was performed to evaluate the functional impact of the obesity susceptible locus. All three 11q11 genes were present in visceral and subcutaneous adipose tissue while no expression was perceived in the liver. These results support the ‘metabolic system’ hypothesis and imply that gene disruption of OR4C11 , OR4P4 , and OR4S2 will negatively influence energy metabolism, ultimately leading to fat accumulation and obesity. Our study thus demonstrates a role for structural variation within olfactory receptor-rich regions in complex diseases and defines the 11q11 deletion as a risk factor for obesity.

Genomic regions underlying positive selection in local, Alpine cattle breeds

“…In addition to three genes from the olfactory receptor gene family, eight other genes with unknown functions are located in this region. Human studies are currently investigating the possible involvement of olfactory receptor genes in the pathogenesis of obesity (Diels et al, 2020). As far as we know, this is the first study reporting ROH islands on chromosome 11 (56.8–57.6 Mb) and 21 (31.3–32.2 Mb).…”

How Smell Regulates Metabolism: The Role Of Ectopically Expressed Olfactory Receptors In Lipid and Glucose Homeostasis

“…Interestingly, three new olfactory receptors (i.e., OR4C11, OR4P4 and OR4S2) have been detected in the adipose tissue and, as demonstrated in different linkage analysis, their disruption (associated to the deletion of the 11q11 region where they are mapped) leads to fat accumulation, confirming them as new risk factors for obesity [165] and corroborating the hypothesis that ORs might have a protective role against fat accumulation in hepatic and adipose tissue [166]. Another genome-wide associated study (GWAS) allowed to confirm the 11q11 region as a copy number variation region (CNVR) associated to early-onset extreme obesity, confirming reduced number of CNV of that region [167].…”

“…Antiobesogenic effect [36], [38] and brown adipose tissue (BAT) thermogenesis [39] Antiobesogenic effect [165] Antiobesogenic effect [165] Antiobesogenic effect [165] - [167] Kidney Mouse OLFR78 OLFR90, OLFR 1373, OLFR1372…”

How smell regulates metabolism: The role of ectopically expressed olfactory receptors in lipid and glucose homeostasis

“…In-vitro decrease of intracellular triglycerides levels and lipid accumulation was furthermore confirmed by in-vivo reduction of hepatic steatosis [61], together with reduced expression of lipogenic genes such as PPAR-γ and SCD1 [62]. Besides recognizing (-)-carvone, it has been established OR43/OR1A1 binding ability towards about 30 different compounds among esters, terpenes (e.g., citral), alcohols (e.g., nerol), aldehydes and ketones (e.g., 3-Methyl-2,4-nonanedione) [63,164] (Figure 4). Interestingly, three new olfactory receptors (i.e., OR4C11, OR4P4 and OR4S2) have been detected in the adipose tissue and, as demonstrated in different linkage analysis, their disruption (associated to the deletion of the 11q11 region where they are mapped) leads to fat accumulation, confirming them as new risk factors for obesity [165] and corroborating the hypothesis that ORs might have a protective role against fat accumulation in hepatic and adipose tissue [166].…”