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Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder.

ABSTRACT: Most pathway and gene-set enrichment methods prioritize genes by their main effect and do not account for variation due to interactions in the pathway. A portion of the presumed missing heritability in genome-wide association studies (GWAS) may be accounted for through gene-gene interactions and additive genetic variability. In this study, we prioritize genes for pathway enrichment in GWAS of bipolar disorder (BD) by aggregating gene-gene interaction information with main effect associations through a machine learning (evaporative cooling) feature selection and epistasis network centrality analysis. We validate this approach in a two-stage (discovery/replication) pathway analysis of GWAS of BD. The discovery cohort comes from the Wellcome Trust Case Control Consortium (WTCCC) GWAS of BD, and the replication cohort comes from the National Institute of Mental Health (NIMH) GWAS of BD in European Ancestry individuals. Epistasis network centrality yields replicated enrichment of Cadherin signaling pathway, whose genes have been hypothesized to have an important role in BD pathophysiology but have not demonstrated enrichment in previous analysis. Other enriched pathways include Wnt signaling, circadian rhythm pathway, axon guidance and neuroactive ligand-receptor interaction. In addition to pathway enrichment, the collective network approach elevates the importance of ANK3, DGKH and ODZ4 for BD susceptibility in the WTCCC GWAS, despite their weak single-locus effect in the data. These results provide evidence that numerous small interactions among common alleles may contribute to the diathesis for BD and demonstrate the importance of including information from the network of gene-gene interactions as well as main effects when prioritizing genes for pathway analysis.

SUBMITTER: Pandey A

PROVIDER: S-EPMC3432194 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder.

Pandey A A Davis N A NA White B C BC Pajewski N M NM Savitz J J Drevets W C WC McKinney B A BA

Translational psychiatry 20120814

Most pathway and gene-set enrichment methods prioritize genes by their main effect and do not account for variation due to interactions in the pathway. A portion of the presumed missing heritability in genome-wide association studies (GWAS) may be accounted for through gene-gene interactions and additive genetic variability. In this study, we prioritize genes for pathway enrichment in GWAS of bipolar disorder (BD) by aggregating gene-gene interaction information with main effect associations thr ...[more]

PMID: 22892719

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Project description:OBJECTIVES:Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD. METHODS:A total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations. RESULTS:Associations of eight a priori GWAS SNPs with BD were replicated with nominal (P?.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5'-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction. CONCLUSIONS:These results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos. Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD.

Dataset Information

Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder.

Publications

Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder.

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