title: Network-based analysis of genome wide association data provides novel candidate genes for lipid and lipoprotein traits.
abstract: 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 Malmö 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 × 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.
authors.affiliation: Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Genetic Epidemiology, Lund University, University Hospital Malmö, Malmö, Sweden;
authors.forename: Amitabh
authors.initials: A
authors.lastname: Sharma
authors.forename: Natali
authors.initials: N
authors.lastname: Gulbahce
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Pevzner
authors.forename: Jörg
authors.initials: J
authors.lastname: Menche
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Albert-László
authors.initials: AL
authors.lastname: Barabási
mesh_terms: D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000235:genetics*; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics; D012307:Risk Factors
chemical_list: D008055:Lipids; D008074:Lipoproteins; D003541:Cystathionine beta-Synthase