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Network-based Analysis of Genome Wide Association Data Provides Novel Candidate Genes for Lipid and Lipoprotein Traits

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Author

  • Amitabh Sharma
  • Natali Gulbahce
  • Samuel J. Pevzner
  • Joerg Menche
  • Claes Ladenvall
  • Lasse Folkersen
  • Per Eriksson
  • Marju Orho-Melander
  • Albert-Laszlo Barabasi

Summary, in English

Genome wide association studies (GWAS) identify susceptibility loci for complex traits, but do not identify particular genes of interest. Integration of functional and network information may help in overcoming this limitation and identifying new susceptibility loci. Using GWAS and comorbidity data, we present a network-based approach to predict candidate genes for lipid and lipoprotein traits. We apply a prediction pipeline incorporating interactome, co-expression, and comorbidity data to Global Lipids Genetics Consortium (GLGC) GWAS for four traits of interest, identifying phenotypically coherent modules. These modules provide insights regarding gene involvement in complex phenotypes with multiple susceptibility alleles and low effect sizes. To experimentally test our predictions, we selected four candidate genes and genotyped representative SNPs in the Malmo Diet and Cancer Cardiovascular Cohort. We found significant associations with LDL-C and total-cholesterol levels for a synonymous SNP (rs234706) in the cystathionine beta-synthase (CBS) gene (p = 1 x 10(-5) and adjusted-p = 0.013, respectively). Further, liver samples taken from 206 patients revealed that patients with the minor allele of rs234706 had significant dysregulation of CBS (p = 0.04). Despite the known biological role of CBS in lipid metabolism, SNPs within the locus have not yet been identified in GWAS of lipoprotein traits. Thus, the GWAS-based Comorbidity Module (GCM) approach identifies candidate genes missed by GWAS studies, serving as a broadly applicable tool for the investigation of other complex disease phenotypes.

Publishing year

2013

Language

English

Pages

3398-3408

Publication/Series

Molecular & Cellular Proteomics

Volume

12

Issue

11

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Cardiovascular Disease
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 1535-9484