title: A method for gene-based pathway analysis using genomewide association study summary statistics reveals nine new type 1 diabetes associations.
abstract: Pathway analysis can complement point-wise single nucleotide polymorphism (SNP) analysis in exploring genomewide association study (GWAS) data to identify specific disease-associated genes that can be candidate causal genes. We propose a straightforward methodology that can be used for conducting a gene-based pathway analysis using summary GWAS statistics in combination with widely available reference genotype data. We used this method to perform a gene-based pathway analysis of a type 1 diabetes (T1D) meta-analysis GWAS (of 7,514 cases and 9,045 controls). An important feature of the conducted analysis is the removal of the major histocompatibility complex gene region, the major genetic risk factor for T1D. Thirty-one of the 1,583 (2%) tested pathways were identified to be enriched for association with T1D at a 5% false discovery rate. We analyzed these 31 pathways and their genes to identify SNPs in or near these pathway genes that showed potentially novel association with T1D and attempted to replicate the association of 22 SNPs in additional samples. Replication P-values were skewed (P=9.85×10-11) with 12 of the 22 SNPs showing P<0.05. Support, including replication evidence, was obtained for nine T1D associated variants in genes ITGB7 (rs11170466, P=7.86×10-9), NRP1 (rs722988, 4.88×10-8), BAD (rs694739, 2.37×10-7), CTSB (rs1296023, 2.79×10-7), FYN (rs11964650, P=5.60×10-7), UBE2G1 (rs9906760, 5.08×10-7), MAP3K14 (rs17759555, 9.67×10-7), ITGB1 (rs1557150, 1.93×10-6), and IL7R (rs1445898, 2.76×10-6). The proposed methodology can be applied to other GWAS datasets for which only summary level data are available.
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Evangelou
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.forename: Mary D
authors.initials: MD
authors.lastname: Fortune
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Burren
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results
keywords: genomewide association data; meta-analysis; pathway analysis