Joint modeling of whole-genome sequencing data for human height via approximate message passing

Human height is a model for the genetic analysis of complex traits, and recent studies suggest the presence of thousands of common genetic variant associations and hundreds of low-frequency/rare variants. Here, we develop a new algorithmic paradigm based on approximate message passing (genomic vector approximate message passing [gVAMP]) for identifying DNA sequence variants associated with complex traits and common diseases in large-scale whole-genome sequencing (WGS) data. We show that gVAMP accurately localizes associations to variants with the correct frequency and position in the DNA, outperforming existing fine-mapping methods in selecting the appropriate genetic variants within WGS data. We then apply gVAMP to jointly model the relationship of tens of millions of WGS variants with human height in hundreds of thousands of UK Biobank individuals. We identify 59 rare variants and gene burden scores alongside many hundreds of DNA regions containing common variant associations and show that understanding the genetic basis of complex traits will require the joint analysis of hundreds of millions of variables measured on millions of people. The polygenic risk scores obtained from gVAMP have high accuracy (including a prediction accuracy of ∼46% for human height) and outperform current methods for downstream tasks such as mixed linear model association testing across 13 UK Biobank traits. In conclusion, gVAMP offers a scalable foundation for a wider range of analyses in WGS data.