Olfactory receptor genes cooperate with protocadherin genes in human extreme obesity

Abstract

Worldwide, the incidence of obesity has increased dramatically over the past decades. More knowledge about the complex etiology of obesity is needed in order to find additional approaches for treatment and prevention. Investigating the exome sequencing data of 30 extremely obese subjects (BMI 45–65 kg/m2) shows that predicted damaging missense variants in olfactory receptor genes on chromosome 1q and rare predicted damaging variants in the protocadherin (PCDH) beta-cluster genes on chromosome 5q31, reported in our previous work, co-localize in subjects with extreme obesity. This implies a synergistic effect between genetic variation in these gene clusters in the predisposition to extreme obesity. Evidence for a general involvement of the olfactory transduction pathway on itself could not be found. Bioinformatic analysis indicates a specific involvement of the PCDH beta-cluster genes in controlling tissue development. Further mechanistic insight needs to await the identification of the ligands of the 1q olfactory receptors. Eventually, this may provide the possibility to manipulate food flavor in a way to reduce the risk of overeating and of extreme obesity in genetically predisposed subjects.Electronic supplementary materialThe online version of this article (doi:10.1007/s12263-015-0465-3) contains supplementary material, which is available to authorized users.

Genetics of Obesity Traits: A Bivariate Genome-Wide Association Analysis

“…Besides, OR2AK2 , a member of olfactory receptor genes family which located in chromosome 1q, involved in both GPCR signaling pathway and olfactory signaling pathway. It has been found that the predicted damaging missense variants in olfactory receptor genes on chromosome 1q and rare damaging variants in protocadherin beta-cluster genes on chromosome 5q31 co-localized in subjects with extreme obesity (Mariman et al, 2015 ). The functions of other genes in terms of obesity were unknown, whereas they may be interesting potential candidates for future research.…”

The diversified function and potential therapy of ectopic olfactory receptors in non‐olfactory tissues

“…Smell perception of food affects food choices and consumption, as well as appetite and satiety signals (Yeomans, ). Mariman et al () demonstrate that there is synergistic effect between the genetic variation of OR and the predisposition of extreme obesity. Thus, the manipulation of food flavor may reduce the risk of extreme obesity by controlling overeating in genetically predisposed subject.…”

The cilium: a cellular antenna with an influence on obesity risk

“…We recently reported a relationship between genetic variation in the clustered protocadherin genes on chromosome 5q and extreme obesity (134) . Moreover, a genetic interaction between OR genes on chromosome 1q and the protocadherin-β genes has been observed in this extreme obesity cohort (135) . Notably, food odour can stimulate appetite, food-seeking behaviour and food ingestion, but strong or prolonged exposure to a food odour can have a satiating effect (183) .…”

“…Possibly, the penetrance of BBS gene mutations with regard to obesity is limited and/or the contribution to obesity risk depends more on rare alleles. Previously, we sequenced thirty subjects with extreme obesity (134,135) . We checked for relatively rare variants (frequency < 0·01) with a predicted damaging impact on protein function in sixty-six genes that code for proteins, which are needed for proper cilia function (online Supplementary Table S1), including the genes mentioned in Tables 1 and 2. This resulted in the identification of twenty-four variants in seventeen subjects (Table 3).…”