Olfactory receptor genes cooperate with protocadherin genes in human extreme obesity.

Edwin C M Mariman,Erik E J G Aller,Radek Szklarczyk,Freek G Bouwman,Ping Wang,Marleen A Van Baak

doi:10.1007/s12263-015-0465-3

Edwin C M Mariman, Erik E J G Aller + Show 4 more

Open Access

https://doi.org/10.1007/s12263-015-0465-3

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Journal: Genes & nutrition	Publication Date: May 6, 2015
Citations: 43	License type: CC BY 4.0

Affiliation: Maastricht University Medical Centre

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.

Highlights

Worldwide, the incidence of obesity has increased dramatically over the past decades and all kinds of measures ranging from dietary and lifestyle interventions to bariatric surgery are being taken to revert this situation, albeit with limited success
For the total set of hits of predicted damaging missense variants in the olfactory transduction pathway, and in the three subgroups according to the chromosome location, we tested by v2 analysis whether there might be a higher number of ORvariant hits in PCDH-variant carriers than in non-carriers
Our observations suggest a synergistic effect of genetic variation in genes of the PCDH beta-cluster and of the olfactory transduction pathway on chromosome 1

Summary

Introduction

The incidence of obesity has increased dramatically over the past decades and all kinds of measures ranging from dietary and lifestyle interventions to bariatric surgery are being taken to revert this situation, albeit with limited success. More knowledge about the complex etiology of obesity is needed in order to find additional approaches for treatment and prevention. Obesity and parameters of adiposity are to a considerable extent determined by genetic factors. Heritability estimates for obesity in different studies amount to at least 0.4 (Walley et al 2006; Farooqi and O’Rahilly 2007; Berndt et al 2013). Knowledge of those factors and the processes that they influence provides possibilities for diagnostic testing and counseling in addition to development of novel intervention methods. Using functional clustering analysis of genes with rare variants, we have shown that in people with extreme obesity (BMI 45–65 kg/m2), the protocadherin (PCDH) genes on chromosome 5q31 harbor a surplus of rare variation with a moderate-to-high predicted biological effect (Mariman et al 2014)

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