Genetic mapping of a 17q chromosomal region linked to obesity phenotypes in the IRAS family study

Abstract

Objective: Obesity is widely accepted to be influenced by both environmental and genetic factors. Several recent studies have used the positional cloning approach in an attempt to discover genes contributing to obesity. In the IRAS Family Study a genomewide scan was performed on 1425 individuals of Hispanic descent (90 extended pedigree families) to identify regions of the genome linked to obesity phenotypes. Methods: Nonparametric QTL linkage analysis was performed using a variance components approach. The genome scan was performed in two phases: an initial genome scan in 45 families and a replication scan in 45 families. Fine mapping and candidate gene analyses were also performed. General estimating equations (GEE1) and quantitative pedigree disequilibrium tests (QPDT) were used for association analysis of single SNP and haplotype data. Results: Evidence for linkage to obesity traits was observed in each scan on the long arm of chromosome 17. When data from both scans was combined, a region on chromosome 17q was identified with evidence of linkage to visceral adipose tissue (VAT; LOD 3.11), waist circumference (WAIST) (LOD 2.5) and body mass index (BMI) (LOD 2.81). Nine additional microsatellite markers were identified and genotyped on all Hispanic individuals, with a mean marker density of approximately 1 marker/3 cM. Evidence of linkage remained significant with LOD 3.05 for VAT, LOD 2.44 for BMI and LOD 1.92 for WAIST. Fine mapping analyses suggest the possibility of two different obesity loci. In addition, the LOD -1 interval of the major VAT peak decreased from 83-108 to 95-111 cM. Three positional candidate genes under the peak: somatostatin receptor 2 (SSTR2), galanin receptor 2 (GALR2), and growth hormone bound protein receptor 2 (GRB2) were chosen for detailed evaluation. Multiple polymorphisms within each candidate were genotyped and tested for association with the obesity phenotypes. Little evidence of association was detected between polymorphisms and obesity traits. Conclusion: In conclusion, replication of linkage and fine mapping suggest that a region on chromosome 17q contains a gene (or genes) that contributes to the genetic etiology of obesity with the strongest evidence for linkage to VAT. Candidate genes in the region do not appear to account for the evidence of linkage. Additional studies are necessary to identify the obesity-related polymorphisms.

The rs1466113 Polymorphism in the Somatostatin Receptor 2 Gene Is Associated with Obesity and Food Intake in a Mediterranean Population

“…However, supporting our results, a genome-wide scan carried out in the Insulin Resistance Atherosclerosis Study (IRAS) family study [10] identified the region on chromosome 17q, where the SSTR2 gene is located, with evidence of linkage to visceral adipose tissue, waist circumference and BMI. Some years later [16] , researchers of the IRAS family study investigated the influence of 10 polymorphisms at the SSTR2 locus on insulin resistance.…”

“…Its gene is located in 17q24 and the SSTR2 gene is the one that contains at least 1 intron, in contrast to other members of the somatostatin receptor family that are intronless [9] . In a genome-wide scan [10] , performed on 1,425 individuals of Hispanic descent to identify regions of the genome linked to obesity phenotypes, evidence for linkage to obesity traits was observed at 17q. Additional fine mapping identified the SSTR2 gene as a positional candidate for obesity.…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…Indeed, the actions of central and peripheral galanin and its receptors in the regulation of metabolism, obesity, and appetite, including galanin receptor-linked mechanisms in experimental obesity, were recently reviewed in detail (Fang et al, 2012a), with the authors recommending development of GAL 1 antagonism as a novel antiobesity strategy. However, in early clinical studies, there was no strong association reported between GAL or GAL 1 genetic variants and obesity or dietary fat intake in obese children and adolescents (Schauble et al, 2005) and no evidence for a GAL 2 linkage to obesity (Sutton et al, 2006) (Table 6). …”

“…Indeed, despite the widely reported and diverse effects of galanin on consummatory behavior, genetic linkage studies have to date revealed no strong impact of the galanin or galanin receptor genes on obesity Lapsys et al, 1999;Schauble et al, 2005;Sutton et al, 2006; section VII.C). However, it has become clear over recent years that common neural circuits can be involved in mediating different behaviors such as the regulation of feeding and fear/ anxiety.…”

Will family studies return to prominence in human genetics and genomics? Rare variants and linkage analysis of complex traits

“…These participants were from 80 different families with an average family size of 12. In prior years extensive linkage analysis studies were performed (Rich, 2004;Sutton, 2006;Palmer 2006). Especially notable for the strength of the linkage evidence was analysis of the adipocytokine adiponectin, coded for by the ADIPOQ gene (Guo, 2006).…”