COAST-SS

COAST-SS implements an allelic series rare variant association test using summary statistics to identify genes where increasingly deleterious mutations have increasingly large phenotypic effects.

Key Features:

• Summary Statistics Input: COAST-SS accepts standard single-variant summary statistics of the type produced by genome-wide association studies as input, eliminating the need for individual-level data.
• LD Robustness: COAST-SS is robust to misspecification of the linkage disequilibrium matrix when LD is low, as expected among rare variants.
• Pathogenicity Annotation Strategies: COAST-SS supports several strategies for annotating variant pathogenicity, which often yield similar power for detecting candidate allelic series.
• Meta-analysis Compatibility: COAST-SS can screen for allelic series in meta-analyzed cohorts, demonstrated in analyses of up to 840,000 subjects.

Scientific Applications:

• Lipid Trait Analysis: COAST-SS identifies allelic series for circulating lipid traits using data from the UK Biobank, the Million Veteran Program, and the Trans-Omics of Precision Medicine Program.
• Therapeutic Target Discovery: COAST-SS detects genes harboring allelic series where dose-response relationships exist between functionality and phenotypic impact, supporting prediction of pharmacological modulation effects from natural genetic variation.

Methodology:

COAST-SS extends the original COAST framework to operate on summary statistics rather than individual-level data, analyzing variants within genes to test for allelic series relationships.