Funmap: integrating high-dimensional functional annotations to improve fine-mapping

Abstract

Motivation: Fine-mapping aims to prioritize causal variants underlying complex traits by accounting for the linkage disequilibrium of genome-wide association study risk locus. The expanding resources of functional annotations serve as auxiliary evidence to improve the power of fine-mapping. However, existing fine-mapping methods tend to generate many false positive results when integrating a large number of annotations. Results: In this study, we propose a unified method to integrate high-dimensional functional annotations with fine-mapping (Funmap). Funmap can effectively improve the power of fine-mapping by borrowing information from hundreds of functional annotations. Meanwhile, it relates the annotation to the causal probability with a random effects model that avoids the over-fitting issue, thereby producing a well-controlled false positive rate. Paired with a fast algorithm, Funmap enables scalable integration of a large number of annotations to facilitate prioritizing multiple causal single nucleotide polymorphisms. Our comprehensive simulations across a wide range of annotation relevance settings demonstrate that Funmap is the only method that produces well-calibrated false discovery rate under the setting of high-dimensional annotations while achieving better or comparable power gains as compared to existing methods. By integrating genome-wide association studies of 4 lipid traits with 187 functional annotations, Funmap consistently identified more variants that can be replicated in an independent cohort, achieving 15.5%-26.2% improvement over the runner-up in terms of replication rate.