PT  - JOURNAL ARTICLE
AU  - Zhongbo Chen
AU  - Regina H. Reynolds
AU  - Antonio F. Pardiñas
AU  - Sarah A. Gagliano Taliun
AU  - Wouter van Rheenen
AU  - Kuang Lin
AU  - Aleksey Shatunov
AU  - Emil K. Gustavsson
AU  - Isabella Fogh
AU  - Ashley R. Jones
AU  - Wim Robberecht
AU  - Philippe Corcia
AU  - Adriano Chiò
AU  - Pamela J. Shaw
AU  - Karen E. Morrison
AU  - Jan H. Veldink
AU  - Leonard H. van den Berg
AU  - Christopher E. Shaw
AU  - John F. Powell
AU  - Vincenzo Silani
AU  - John A. Hardy
AU  - Henry Houlden
AU  - Michael J. Owen
AU  - Martin R. Turner
AU  - Mina Ryten
AU  - Ammar Al-Chalabi
TI  - The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases
AID  - 10.1101/2022.04.29.490053
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.04.29.490053
4099  - http://biorxiv.org/content/early/2022/04/30/2022.04.29.490053.short
4100  - http://biorxiv.org/content/early/2022/04/30/2022.04.29.490053.full
AB  - Background Humans 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.Methods We 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.Results We 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.Conclusions These 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.Competing Interest StatementAAC reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Brainstorm, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, and Wave Pharmaceuticals.