Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies

Abstract

Linkage disequilibrium (LD) is the correlation among nearby genetic variants. In genetic association studies, LD is often modeled using massive local correlation matrices, but this approach is slow, especially in ancestrally diverse studies. Here, we introduce LD graphical models (LDGMs), which are an extremely sparse and efficient representation of LD. LDGMs are derived from genome-wide genealogies; statistical relationships among alleles in the LDGM correspond to genealogical relationships among haplotypes. We publish LDGMs and ancestry specific LDGM precision matrices for 18 million common SNPs (MAF>1%) in five ancestry groups, validate their accuracy, and demonstrate order-of-magnitude improvements in runtime for commonly used LD matrix computations. We implement an extremely fast multi-ancestry polygenic prediction method, BLUPx-ldgm, which performs better than a similar method based on the reference LD correlation matrix. LDGMs will enable sophisticated methods that scale to ancestrally genetic association data across millions of variants and individuals.