GPA

GPA integrates pleiotropy information and functional annotations into joint analyses of multiple Genome-Wide Association Studies (GWAS) to improve detection and ranking of genetic risk variants for complex diseases.

Key Features:

• Joint GWAS analysis: Performs joint analysis across multiple GWAS datasets to leverage shared genetic signals across traits.
• Pleiotropy integration: Models pleiotropy to detect shared genetic risk factors among different complex diseases.
• Functional annotation integration: Incorporates functional annotations to prioritize variants with biological relevance.
• Expectation-Maximization (EM) algorithm: Employs an EM algorithm to estimate model parameters and to handle genome-wide markers.
• SNP ranking and inference: Provides statistical inference for model parameters and ranks SNPs according to association probabilities.
• Enrichment assessment: Assesses enrichment of functionally annotated variants among significant GWAS findings.
• Integration of external annotation databases: Integrates eQTLs from Genotype-Tissue Expression (GTEx) and DNase-seq data from ENCODE for annotation-driven analyses.
• Detection of weak signals: Increases power to identify weak or modest-effect genetic variants that may be missed by single-dataset analyses.

Scientific Applications:

• Psychiatric disorder genetics: Joint analysis of five psychiatric disorders revealed numerous weak signals, significant pleiotropic effects, and enrichment in central nervous system genes and GTEx eQTLs.
• Bladder cancer genomics: Integration of a bladder cancer GWAS with DNase-seq from 125 ENCODE cell lines identified biologically relevant cell lines associated with bladder cancer.
• Complex disease architecture: Application to diverse complex diseases to uncover shared genetic architecture and annotation-enriched variants.

Methodology:

Performs joint analyses of multiple GWAS datasets while incorporating functional annotations and employs an Expectation-Maximization (EM) algorithm for parameter estimation, genome-wide marker handling, SNP ranking, and assessment of annotation enrichment.