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The lingering effects of Neanderthal introgression on human complex traits

View ORCID ProfileXinzhu Wei, Christopher R. Robles, Ali Pazokitoroudi, Andrea Ganna, Alexander Gusev, Arun Durvasula, Steven Gazal, Po-Ru Loh, David Reich, Sriram Sankararaman
doi: https://doi.org/10.1101/2022.06.07.495223
Xinzhu Wei
1Department of Computational Biology, Cornell University, UCLA, Los Angeles, CA 90095
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  • ORCID record for Xinzhu Wei
Christopher R. Robles
2Department of Human Genetics, UCLA, Los Angeles, CA 90095
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Ali Pazokitoroudi
3Department of Computer Science, UCLA, Los Angeles, CA 90095
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Andrea Ganna
4Analytical and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Alexander Gusev
7Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
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Arun Durvasula
8Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
9Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
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Steven Gazal
10Center for Genetic Epidemiology, Department of Public and Population Health Sciences, USC Keck School of Medicine, Los Angeles, CA 90033
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Po-Ru Loh
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
11Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
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David Reich
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
8Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
9Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
12Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Sriram Sankararaman
2Department of Human Genetics, UCLA, Los Angeles, CA 90095
3Department of Computer Science, UCLA, Los Angeles, CA 90095
13Department of Computational Medicine, UCLA, Los Angeles, CA 90095
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  • For correspondence: sriram@cs.ucla.edu
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Abstract

The mutations 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 mutations. We developed rigorous methods to assess the contribution of introgressed Neanderthal mutations to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal mutations and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal mutations have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.1% of heritable variation averaged across phenotypes; p = 9.59×10-9). However, the contribution of introgressed mutations tends to be significantly depleted relative to modern human mutations matched for allele frequency and linkage disequilibrium (about 57% depletion on average), consistent with purifying selection on introgressed mutations. 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 mutations with 64 phenotypes (p < 1 ×10-10). Previous work (Skov 2021) 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 mutations 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 mutations are highly likely to have a phenotypic effect. Examination of these mutations 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/AprilWei001/NIM

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 08, 2022.
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The lingering effects of Neanderthal introgression on human complex traits
Xinzhu Wei, Christopher R. Robles, Ali Pazokitoroudi, Andrea Ganna, Alexander Gusev, Arun Durvasula, Steven Gazal, Po-Ru Loh, David Reich, Sriram Sankararaman
bioRxiv 2022.06.07.495223; doi: https://doi.org/10.1101/2022.06.07.495223
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The lingering effects of Neanderthal introgression on human complex traits
Xinzhu Wei, Christopher R. Robles, Ali Pazokitoroudi, Andrea Ganna, Alexander Gusev, Arun Durvasula, Steven Gazal, Po-Ru Loh, David Reich, Sriram Sankararaman
bioRxiv 2022.06.07.495223; doi: https://doi.org/10.1101/2022.06.07.495223

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