Unified Sequence Based Association Tests Allowing for Multiple Functional Annotation Scores, and Applications to Meta-Analysis of Noncoding Variation in Metabochip Data

• Activity Number: 13 - Integrative Approaches for Analysis of Complex Phenotype and DNA Sequence Data
• Type: Invited
• Date/Time: Sunday, July 29, 2018 : 2:00 PM to 3:50 PM
• Sponsor: ENAR
• Author(s): Iuliana Ionita-Laza*
• Companies: Columbia University

Abstract

Substantial progress has been made in the functional annotation of genetic variation in the human genome. Integrative analysis that incorporates such functional annotations into sequencing studies may aid the discovery of disease associated genetic variants, especially those in noncoding regions. Direct incorporation of one functional annotation as weights in existing dispersion/burden tests can lead to substantial loss of power when the functional annotation is not predictive of the risk status of a variant. We develop unified tests that can utilize multiple functional annotations at once for integrative association analysis with efficient computational techniques. We show that the proposed tests significantly improve power when variant risk status can be predicted by functional annotations. Importantly, when functional annotations are not predictive of risk status, the proposed tests incur only minimal loss of power relative to existing dispersion/burden tests. We apply the proposed tests to a meta-analysis of noncoding rare variants in Metabochip data on 12,281 individuals.