The lingering effects of Neanderthal introgression on human complex traits.

The genetic variants introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed variants. We developed rigorous methods to assess the contribution of introgressed Neanderthal variants to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal variants and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal variants have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.12% of heritable variation averaged across phenotypes). However, the contribution of introgressed variants tends to be significantly depleted relative to modern human variants matched for allele frequency and linkage disequilibrium (about 59% depletion on average), consistent with purifying selection on introgressed variants. Different from previous studies (McArthur 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal variants with 64 phenotypes . Previous work (Skov 2020) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. We therefore developed a customized statistical fine-mapping methodology for introgressed variants that led us to identify 112 regions (at a false discovery proportion of 16%) across 47 phenotypes containing 4,303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveal their substantial impact on genes that are important for the immune system, development, and metabolism. Our results provide the first rigorous basis for understanding how Neanderthal introgression modulates complex trait variation in present-day humans.