Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets.Our data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute to pathology in modern day humans
Highlanders and lowlanders of Papua New Guinea (PNG) have faced distinct environmental conditions. These environmental differences lead to specific stress on PNG highlanders and lowlanders, such as hypoxia and environment-specific pathogen exposure, respectively. We hypothesise that these constraints induced specific selective pressures that shaped the genomes of both populations. In this study, we explored signatures of selection in newly sequenced whole genomes of 54 PNG highlanders and 74 PNG lowlanders. Based on multiple methods to detect selection, we investigated the 21 and 23 genomic top candidate regions for positive selection in PNG highlanders and PNG lowlanders, respectively. To identify the most likely candidate SNP driving selection in each of these regions, we computationally reconstructed allele frequency trajectories of variants in each of these regions and chose the SNP with the highest likelihood of being under selection with CLUES. We show that regions with signatures of positive selection in PNG highlanders genomes encompass genes associated with the hypoxia-inducible factors pathway, brain development, blood composition, and immunity, while selected genomic regions in PNG lowlanders contain genes related to immunity and blood composition. We found that several candidate driver SNPs are associated with haematological phenotypes in the UK biobank. Moreover, using phenotypes measured from the sequenced Papuans, we found that two candidate SNPs are significantly associated with altered heart rates in PNG highlanders and lowlanders. Furthermore, we found that 16 of the 44 selection candidate regions harboured archaic introgression. In four of these regions, the selection signal might be driven by the introgressed archaic haplotypes, suggesting a significant role of archaic admixture in local adaptation in PNG populations.
The admixture between modern humans and Neandertals has resulted in ∼2% of the genomes of present-day non-Africans being composed of Neandertal DNA. Introgressed Neandertal DNA has been demonstrated to significantly affect the transcriptomic landscape in people today and via this molecular mechanism influence phenotype variation as well. However, little is known about how much of that regulatory impact is mediated through long-range regulatory effects that have been shown to explain ∼20% of expression variation. Here we identified 60 transcription factors (TFs) with their top cis-eQTL SNP in GTEx being of Neandertal ancestry and predicted long-range Neandertal DNA-induced regulatory effects by screening for the predicted target genes of those TFs. We show that the TFs form a significantly connected protein-protein interaction network. Among them are JUN and PRDM5, two brain-expressed TFs that have their predicted target genes enriched in regions devoid of Neandertal DNA. Archaic cis-eQTLs for the 60 TFs include multiple candidates for local adaptation, some of which show significant allele frequency increases over the last ∼10,000 years. A large proportion of the cis-eQTL-associated archaic SNPs have additional associations with various immune traits, schizophrenia, blood cell type composition and anthropometric measures. Finally, we demonstrate that our results are consistent with those of Neandertal-DNA-associated empirical trans-eQTLs. Our results suggest that Neandertal DNA significantly influences regulatory networks, that its regulatory reach goes beyond the 40% of genomic sequence that it still covers in present-day non-Africans and that via the investigated mechanism Neandertal DNA influences the phenotypic variation in people today.
We present the results of the depression Genome-wide association studies study performed on a cohort of Russian-descent individuals, which identified a novel association at chromosome 7q21 locus. Gene prioritization analysis based on already known depression risk genes indicated MAGI2 (S-SCAM) as the most probable gene from the locus and potential susceptibility gene for the disease. Brain and gut expression patterns were the main features highlighting functional relatedness of MAGI2 to the previously known depression risk genes. Local genetic covariance analysis, analysis of gene expression, provided initial suggestive evidence of hospital anxiety and depression scale and diagnostic and statistical manual of mental disorders scales having a different relationship with gut-brain axis disturbance. It should be noted, that while several independent methods successfully in silico validate the role of MAGI2, we were unable to replicate genetic association for the leading variant in the MAGI2 locus, therefore the role of rs521851 in depression should be interpreted with caution.
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