biostudies-literatureKoller DNCATS NIH HHSNIDA NIH HHSMedical Research CouncilNIDCD NIH HHSNIMH NIH HHSNational Institute on Deafness and Other Communication DisordersNational Institute of Mental HealthNational Institute on Drug AbuseH2020 Marie Skłodowska-Curie Actions249https://www.ebi.ac.uk/biostudies/studies/S-EPMC9641937biostudies-literatureUnknown20(1)<h4>Background</h4>Introgression from extinct Neanderthal and Denisovan human species has been shown to contribute to the genetic pool of modern human populations and their phenotypic spectrum. Evidence of how Neanderthal introgression shaped the genetics of human traits and diseases has been extensively studied in populations of European descent, with signatures of admixture reported for instance in genes associated with pigmentation, immunity, and metabolic traits. However, limited information is currently available about the impact of archaic introgression on other ancestry groups. Additionally, to date, no study has been conducted with respect to the impact of Denisovan introgression on the health and disease of modern populations. Here, we compare the way evolutionary pressures shaped the genetics of complex traits in East Asian and European populations, and provide evidence of the impact of Denisovan introgression on the health of East Asian and Central/South Asian populations.<h4>Results</h4>Leveraging genome-wide association statistics from the Biobank Japan and UK Biobank, we assessed whether Denisovan and Neanderthal introgression together with other evolutionary genomic signatures were enriched for the heritability of physiological and pathological conditions in populations of East Asian and European descent. In EAS, Denisovan-introgressed loci were enriched for coronary artery disease heritability (1.69-fold enrichment, p=0.003). No enrichment for archaic introgression was observed in EUR. We also performed a phenome-wide association study of Denisovan and Neanderthal alleles in six ancestry groups available in the UK Biobank. In EAS, the Denisovan-introgressed SNP rs62391664 in the major histocompatibility complex region was associated with albumin/globulin ratio (beta=-0.17, p=3.57×10^-7). Neanderthal-introgressed alleles were associated with psychiatric and cognitive traits in EAS (e.g., "No Bipolar or Depression"-rs79043717 beta=-1.5, p=1.1×10^-7), and with blood biomarkers (e.g., alkaline phosphatase-rs11244089 beta=0.1, p=3.69×10^-116) and red hair color (rs60733936 beta=-0.86, p=4.49×10^-165) in EUR. In the other ancestry groups, Neanderthal alleles were associated with several traits, also including the use of certain medications (e.g., Central/South East Asia: indapamide - rs732632 beta=-2.38, p=5.22×10^-7).<h4>Conclusions</h4>Our study provides novel evidence regarding the impact of archaic introgression on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in EAS populations.BMC biologyDenisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations.PMC9641937MC_PC_17228F32 MH122058R21 DC018098R33 DA047527MC_QA137853UL1 TR001863De Lillo ADe Angelis FWendt FRPathak GAKoller DCabrera-Mendoza BPolimanti RTucci SfalseDenisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations.<h4>Background</h4>Introgression from extinct Neanderthal and Denisovan human species has been shown to contribute to the genetic pool of modern human populations and their phenotypic spectrum. Evidence of how Neanderthal introgression shaped the genetics of human traits and diseases has been extensively studied in populations of European descent, with signatures of admixture reported for instance in genes associated with pigmentation, immunity, and metabolic traits. However, limited information is currently available about the impact of archaic introgression on other ancestry groups. Additionally, to date, no study has been conducted with respect to the impact of Denisovan introgression on the health and disease of modern populations. Here, we compare the way evolutionary pressures shaped the genetics of complex traits in East Asian and European populations, and provide evidence of the impact of Denisovan introgression on the health of East Asian and Central/South Asian populations.<h4>Results</h4>Leveraging genome-wide association statistics from the Biobank Japan and UK Biobank, we assessed whether Denisovan and Neanderthal introgression together with other evolutionary genomic signatures were enriched for the heritability of physiological and pathological conditions in populations of East Asian and European descent. In EAS, Denisovan-introgressed loci were enriched for coronary artery disease heritability (1.69-fold enrichment, p=0.003). No enrichment for archaic introgression was observed in EUR. We also performed a phenome-wide association study of Denisovan and Neanderthal alleles in six ancestry groups available in the UK Biobank. In EAS, the Denisovan-introgressed SNP rs62391664 in the major histocompatibility complex region was associated with albumin/globulin ratio (beta=-0.17, p=3.57×10^-7). Neanderthal-introgressed alleles were associated with psychiatric and cognitive traits in EAS (e.g., "No Bipolar or Depression"-rs79043717 beta=-1.5, p=1.1×10^-7), and with blood biomarkers (e.g., alkaline phosphatase-rs11244089 beta=0.1, p=3.69×10^-116) and red hair color (rs60733936 beta=-0.86, p=4.49×10^-165) in EUR. In the other ancestry groups, Neanderthal alleles were associated with several traits, also including the use of certain medications (e.g., Central/South East Asia: indapamide - rs732632 beta=-2.38, p=5.22×10^-7).<h4>Conclusions</h4>Our study provides novel evidence regarding the impact of archaic introgression on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in EAS populations.2022-01-01T00:00:00Z2022 Nov2024-11-09T07:09:22.691Z2024-11-09T07:09:22.691ZS-EPMC96419373634498210.1186/s12915-022-01449-2