Dissecting the high-resolution genetic architecture of complex phenotypes by accurately estimating gene-based conditional heritability.

Despite extensive research on global heritability estimation for complex traits, few methods accurately dissect local heritability. A precise local heritability estimate is crucial for high-resolution mapping in genetics. Here, we report the effective heritability estimator (EHE) that can use p values from genome-wide association studies (GWASs) for local heritability estimation by directly converting marginal heritability estimates of SNPs to a non-redundant heritability estimate of a gene or a small genomic region. EHE provides higher accuracy and precision for local heritability estimation among seven compared methods. Importantly, EHE can be applied to estimate the conditional heritability of nearby genes, where redundant heritability among the genes can also be removed further. The conditional estimation can be guided by tissue-specific expression profiles (or other functional scores) to prioritize and quantify more functionally important genes of complex phenotypes. Applying EHE to 42 complex phenotypes from the UK Biobank, we revealed the existence of two types of distinct genetic architectures for various complex phenotypes and found that highly pleiotropic genes are not enriched for more heritability compared to other candidate susceptibility genes. EHE provides an accurate and robust way to dissect the genetic architecture of complex phenotypes.