Comprehensive gene heritability estimation reveals the genetic architecture of rare coding variants underlying complex traits.

Whole-exome sequencing (WES) enables high-resolution interrogation of the contribution of rare coding variants to complex trait variation. However, existing methods for heritability estimation attributed to rare-coding variants are often limited by the effects of linkage disequilibrium (LD) and by the sparse nature of rare variant data. We introduce FLEX (Fast, LD-aware Estimation of eXome-wide and gene-level heritability), a scalable and flexible framework for estimating and partitioning heritability across genes or sets of genes using WES data. FLEX integrates all coding variants- from common to ultra-rare - within a unified model and corrects for LD-induced effects to improve the accuracy of heritability estimates. In addition, FLEX supports both individual-level and summary statistic data and is computationally efficient for biobank-scale datasets. Through extensive simulations, we show that FLEX is well-calibrated while providing accurate heritability estimates. We applied FLEX to WES data across N = 153 , 351 unrelated European ancestry individuals and 20 quantitative traits in the UK Biobank. We identified 64 gene-trait pairs with significant gene-level heritability ( p < 0.05 / 18 , 624 accounting for the number of protein-coding genes tested), among which rare coding variants explained 38% of gene-level heritability, on average. Compared to heritability estimates from genome-wide imputed SNPs, incorporation of rare and ultra-rare coding variants led to a 24.8% increase in heritability on average, while effect sizes at rare and ultra-rare variants are substantially larger ≈ 18 x on average). Partitioning across variant effect annotations, we find that predicted loss-of-function variants had stronger individual effects than missense variants (24% on average) while missense variants accounted for a greater share of rare coding heritability. Together, FLEX provides an adaptable and accurate approach for quantifying gene-level heritability, advancing our understanding of the genetic architecture of complex traits, and facilitating the discovery of trait-relevant genes.