Refining fine-mapping: Effect sizes and regional heritability

Recent statistical approaches have shown that the set of all available genetic variants explains considerably more phenotypic variance of complex traits and diseases than the individual variants that are robustly associated with these phenotypes. However, rapidly increasing sample sizes constantly improve detection and prioritization of individual variants driving the associations between genomic regions and phenotypes. Therefore, it is useful to routinely estimate how much phenotypic variance the detected variants explain for each region by taking into account the correlation structure of variants and the uncertainty in their causal status. Here we extend the FINEMAP software to estimate the effect sizes and regional heritability under the probabilistic model that assumes a handful of causal variants per region. Using the UK Biobank (UKB) data to simulate genomic regions, we demonstrate that FINEMAP provides higher precision and enables more detailed decomposition of regional heritability into individual variants than the variance component model implemented in BOLT or the fixed-effect model implemented in HESS, particularly when there are only a few causal variants in the fine-mapped region. Using data from 2,940 plasma proteins from the UKB study, we observed that on average FINEMAP identified 2.5 causal variants at an association signal and captured 36% more regional heritability than the variant with the lowest P-value. We estimate that in genomic regions with notable contribution to the total heritability, FINEMAP captures on average 13% and 40% more heritability than BOLT and HESS respectively. Our analysis shows how FINEMAP, BOLT and HESS relate to each other in cases where inference of a variant-level picture of the regional genetic architecture is possible.Author summary: Advancements in statistical methodologies to analyze Genome-Wide Association Studies (GWAS) have revealed that numerous genetic variants across the whole genome significantly contribute to the phenotypic variation in quantitative traits and disease risk. As sample sizes in GWAS grow, there is a continuous improvement in identifying and prioritizing individual variants that drive associations between genomic regions and phenotypes. To better understand both the individual and joint contribution of these variants to phenotypic variation, we extend the FINEMAP software to simultaneously estimate effect sizes of individual variants and heritability of genomic regions. Using simulations, we study how regional heritability estimates of FINEMAP and existing heritability approaches relate to each other and when a fine-mapping model is able to accurately narrow down the regional heritability into contributions from individual variants. In the analysis of plasma biomarkers, we demonstrate that FINEMAP offers more precise regional heritability estimates than existing heritability approaches in genomic regions that contribute notably to the total heritability. These new features in FINEMAP enable routine comparisons between the regional heritability estimates originating from different modeling assumptions, and inform us about the genetic architecture of each genomic region.