title: Risk and information evaluation of prioritized genes for complex traits: application to bipolar disorder.
abstract: Many susceptibility genes for complex traits were identified without conclusive findings. There is a strong need to integrate rapidly accumulated genomic data from multi-dimensional platforms, and to conduct risk evaluation for potential therapeutic and diagnostic usages. We set up an algorithm to computationally search for optimal weight-vector for various data sources, while minimized potential noises. Through gene-prioritization framework, combined scores for the resulting prioritized gene-set were calculated using a genome-wide association (GWA) dataset, following with evaluation using weighted genetic risk score and risk-attributed information using an independent GWA dataset. The significance of association of GWA data was corrected for gene length. Enriched functional pathways were identified for the prioritized gene-set using the Gene Ontology analysis. We illustrated our framework with bipolar disorder. 233 prioritized genes were identified from 10,830 candidates that curated from six platforms. The prioritized genes were significantly enriched (P(adjusted) < 1 × 10(-5)) in 18 biological functions and molecular mechanisms including membrane, synaptic transmission, transmission of nerve impulse, integral to membrane, and plasma membrane. Our risk evaluation demonstrated higher weighted genetic risk score in bipolar patients than controls (P-values ranged from 0.002 to 3.8 × 10(-6)). Substantial risk-information (71%) was extracted from prioritized genes for bipolar illness than other candidate-gene sets. Our evidence-based prioritized gene-set provides opportunity to explore the complex network and to conduct follow-up basic and clinical studies for complex traits.
authors.affiliation: Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Chung-Feng
authors.initials: CF
authors.lastname: Kao
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Chuang
authors.forename: Po-Hsiu
authors.initials: PH
authors.lastname: Kuo
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors
chemical_list: D015415:Biomarkers
keywords: bipolar; gene prioritization; genomic data integration; risk-attributed information; weighted genetic risk score