Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes

Dannemann, Michael; Milaneschi, Yuri; Yermakovich, Danat; Stiglbauer, Victoria; Kariis, Hanna; Krebs, Kristi; Friese, Manuel A.; Otte, Christian; Esko, Tõnu; Metspalu, Andres; Milani, Lili; Mägi, Reedik; Nelis, Mari; Lehto, Kelli; Penninx, Brenda W. J. H.; Kelso, Janet; Gold, Stefan M.

doi:10.1038/s41398-022-02196-2

Cited by 12 publications

(13 citation statements)

References 65 publications

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“…Second, recent genetic modifications in the modern-day human genome reveal a particular enrichment for psychiatric traits (e.g. depression, alcohol intake; SI Appendix ), in line with recent evidence showing that introgressed variants from Neanderthals (variants relatively recent in human evolution) are linked to smoking, alcohol consumption, and mood-related traits (48); and with findings of an overrepresentation of alleles conferring risk for mood-related traits specifically in ancient farmers genome (∼11,000 years old) but not in evolutionary previous hunter-gatherer genome (49). Third, genes related to neuropsychiatric conditions (SCZ, BD, and AD) were found to contain more recent genetic modifications compared to other genes.…”

Section: Discussionsupporting

confidence: 67%

Mapping the genetic evolutionary timeline of human neural and cognitive traits

Libedinsky

Wei

Leeuw

et al. 2023

Preprint

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Humans have undergone several anatomical adaptations throughout evolution. Paleontological records are a prime method of studying these adaptations, but they can unfortunately provide only a limited view of how modifications of 'soft traits' such as brain and cognition have contributed to the emergence of Homo sapiens. An additional approach includes the examination of when genetic variations associated with human phenotypes emerged in our history. Combining data from genome-wide association studies (GWAS) with dating data on the human genome, we systematically analysed the temporal emergence of single-nucleotide polymorphisms (SNPs) associated with modern-day human phenotypes over the last five million years. We show the genetic timeline of human-characteristic phenotypes to follow a distinct pattern with two bursts of genetic variation that co-emerge with milestones in the human lineage. Our findings suggest that SNPs associated with neocortical, neuropsychiatric, and ophthalmological traits appeared relatively recently in hominin evolution, with genes containing recently emerged SNPs linked to intelligence and neocortical area.

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Section: Discussionsupporting

confidence: 67%

Mapping the genetic evolutionary timeline of human neural and cognitive traits

Libedinsky

Wei

Leeuw

et al. 2023

Preprint

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“…This observation is consistent with recent studies using UK Biobank data that showed introgressed variants were depleted for contribution to the heritability of most complex traits or at least not enriched. 21,22 These studies did not specifically focus on neurodegenerative diseases. Our findings suggest that Neanderthal admixture is unlikely to have maintained the common genetic variant architecture of these neurodegenerative diseases in modern humans.…”

Section: Discussionmentioning

confidence: 99%

“…20 More recently, two studies aimed to address the complex nature of medically-relevant traits and the genome-wide influence of Neanderthal admixture using UK Biobank data. 21,22 The former study found that Neanderthal introgression did not significantly contribute to neurological and psychiatric traits and the latter found that introgressed variants were depleted for heritability of high-level cognitive traits. 22 However, neither looked specifically at neurodegenerative diseases of interest.…”

Section: Introductionmentioning

confidence: 99%

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Chen

Reynolds

Pardiñas

et al. 2022

Preprint

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BackgroundHumans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions.MethodsWe used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.ResultsWe found a significant depletion of positively-selected SNPs in the heritability of Parkinson’s disease, raising the possibility that these variants may modulate disease risk, in addition to conferring an evolutionary advantage. For Alzheimer’s disease and amyotrophic lateral sclerosis, common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk.ConclusionsThese findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.

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“…This observation is consistent with recent studies using UK Biobank data that showed introgressed variants were depleted for contribution to the heritability of most complex traits or at least not enriched. (Dannemann et al, 2022;McArthur et al, 2021) These studies did not specifically focus on neurodegenerative diseases. Our findings suggest that Neanderthal admixture is unlikely to have maintained the common genetic variant architecture of these neurodegenerative diseases in modern humans.…”

Section: Discussionmentioning

confidence: 99%

“…(Simonti et al, 2016) More recently, two studies aimed to address the complex nature of medically-relevant traits and the genomewide influence of Neanderthal admixture using UK Biobank data. (Dannemann et al, 2022;McArthur et al, 2021) The former study found that Neanderthal introgression did not significantly contribute to neurological and psychiatric traits and the latter found that introgressed variants were depleted for heritability of high-level cognitive traits. (McArthur et al, 2021) However, neither looked specifically at neurodegenerative diseases of interest.…”

Section: Introductionmentioning

confidence: 99%