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Whole-genome pathway analysis on 132,497 individuals identifies novel gene-sets associated with body mass index.

ABSTRACT: Whole genome pathway analysis is a powerful tool for the exploration of the combined effects of gene-sets within biological pathways. This study applied Interval Based Enrichment Analysis (INRICH) to perform whole-genome pathway analysis of body-mass index (BMI). We used a discovery set composed of summary statistics from a meta-analysis of 123,865 subjects performed by the GIANT Consortium, and an independent sample of 8,632 subjects to assess replication of significant pathways. We examined SNPs within nominally significant pathways using linear mixed models to estimate their contribution to overall BMI heritability. Six pathways replicated as having significant enrichment for association after correcting for multiple testing, including the previously unknown relationships between BMI and the Reactome regulation of ornithine decarboxylase pathway, the KEGG lysosome pathway, and the Reactome stabilization of P53 pathway. Two non-overlapping sets of genes emerged from the six significant pathways. The clustering of shared genes based on previously identified protein-protein interactions listed in PubMed and OMIM supported the relatively independent biological effects of these two gene-sets. We estimate that the SNPs located in examined pathways explain ?20% of the heritability for BMI that is tagged by common SNPs (3.35% of the 16.93% total).

SUBMITTER: Simonson MA

PROVIDER: S-EPMC3908858 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Whole-genome pathway analysis on 132,497 individuals identifies novel gene-sets associated with body mass index.

Simonson Matthew A MA McQueen Matthew B MB Keller Matthew C MC

PloS one 20140131 1

Whole genome pathway analysis is a powerful tool for the exploration of the combined effects of gene-sets within biological pathways. This study applied Interval Based Enrichment Analysis (INRICH) to perform whole-genome pathway analysis of body-mass index (BMI). We used a discovery set composed of summary statistics from a meta-analysis of 123,865 subjects performed by the GIANT Consortium, and an independent sample of 8,632 subjects to assess replication of significant pathways. We examined SN ...[more]

PMID: 24497910

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Project description:Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics.We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Dataset Information

Whole-genome pathway analysis on 132,497 individuals identifies novel gene-sets associated with body mass index.

Publications

Whole-genome pathway analysis on 132,497 individuals identifies novel gene-sets associated with body mass index.

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