Department of Computer Science, University of California, Los Angeles, Los Angeles, United States
Andrea Ganna
Analytical and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States
Alexander Gusev
Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
Department of Genetics, Harvard Medical School, Boston, United States; Department of Human Evolutionary Biology, Harvard University, Cambridge, United States
Steven Gazal
Center for Genetic Epidemiology, Department of Public and Population Health Sciences, University of Southern California, Los Angeles, United States; Division of Genetics,Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Po-Ru Loh
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States; Department of Genetics, Harvard Medical School, Boston, United States; Department of Human Evolutionary Biology, Harvard University, Cambridge, United States; Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States; Department of Computer Science, University of California, Los Angeles, Los Angeles, United States; Department of Computational Medicine, University of California, Los Angeles, Los Angeles, United States
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 and 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 make a significant contribution to trait variation (explaining 0.12% of trait variation on average). 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 et al., 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 et al., 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. Applying a customized fine-mapping led us to identify 112 regions across 47 phenotypes containing 4303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveals their substantial impact on genes that are important for the immune system, development, and metabolism.