Network-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia.
With the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia; these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had P(meta)<1 × 10⁻⁴, including the gene HLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available.
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
Peilin
P
Jia
Lily
L
Wang
Ayman H
AH
Fanous
Carlos N
CN
Pato
Todd L
TL
Edwards
Zhongming
Z
Zhao
D000465:Algorithms; D030541:Databases, Genetic; D055106:Genome-Wide Association Study / Q000379:methods*; D023281:Genomics; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000235:genetics*