The Human Nature of Psychosis: How Neanderthal Admixture is Related to Schizophrenia Diagnosis, Psychotic Symptoms, and Dopamine Functioning

Gregory, Michael D.; Kippenhan, J. Shane; Eisenberg, Daniel; Hamborg, Madeline; Kohn, Philip D.; Kolachana, Bhaskar; Dickinson, Dwight; Berman, Karen F.

doi:10.1016/j.biopsych.2021.02.224

Cited by 2 publications

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“…As a result, current modern human genome contains a small amount (∼2%) of segments derived from Neanderthal introgression (Green et al, 2010;Sankararaman et al, 2014). Moreover, this DNA fraction has been proposed to be associated with multiple human phenotypes or diseases Dolgova & Lao, 2018;McArthur et al, 2021;Sankararaman et al, 2014;Simonti et al, 2016), including lipid catabolism (Khrameeva et al, 2014), skin pigmentation (Ding, Hu, Xu, Wang, Li et al, 2014;Hu et al, 2015;Vernot & Akey, 2014), type 2 diabetes (Williams et al, 2014), schizophrenia (Gregory et al, 2021), pain sensitivity , vitamin B1 metabolism (Ma & Xu, 2022), and environmental (Findley et al, 2021) or immune response (Abi-Rached et al, 2011;Dannemann et al, 2016;Mendez et al, 2012;Quach et al, 2016;Temme et al, 2014), especially COVID-19 susceptibility Zhou et al, 2021). However, the contribution of Neanderthal introgression to cancer, a leading cause of death in contemporary human populations, has been hardly reported.…”

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confidence: 99%

An indel introduced by Neanderthal introgression, rs3835124:ATTTATT > ATT, might contribute to prostate cancer risk by regulating PDK1 expression

Chen,

Yu,

et al. 2023

Annals of Human Genetics

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IntroductionProstate cancer is one of the most common cancer types in males and rs12621278:A > G has been suggested to be associated with this disease by previous genome‐wide association studies. One thousand genomes project data analysis indicated that rs12621278:A > G is within two long‐core haplotypes. However, the origin, causal variant(s), and molecular function of these haplotypes were remaining unclear.Materials and MethodsPopulation genetics analysis and functional genomics work was performed for this locus.ResultsPhylogeny analysis verified that the rare haplotype is derived from Neanderthal introgression. Genome annotation suggested that three genetic variants in the core haplotypes, rs116108611:G > A, rs139972066:AAAAAAAA > AAAAAAAAA, and rs3835124:ATTTATT > ATT, are located in functional regions. Luciferase assay indicated that rs139972066:AAAAAAAA > AAAAAAAAA and rs116108611:G > A are not able to alter ITGA6 (integrin alpha 6) and ITGA6 antisense RNA 1 expression, respectively. In contrast, rs3835124:ATTTATT > ATT can significantly influence PDK1 (pyruvate dehydrogenase kinase 1) expression, which was verified by expression quantitative trait locus analysis. This genetic variant can alter transcription factor cut like homeobox 1 interaction efficiency. The introgressed haplotype was observed to be subject to positive selection in East Asian populations. The molecular function of the haplotype suggested that Neanderthal should be with lower PDK1 expression and further different energy homeostasis from modern human.ConclusionThis study provided new insight into the contribution of Neanderthal introgression to human phenotypes.

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