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The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

View ORCID ProfileZhongbo Chen, Regina H. Reynolds, Antonio F. Pardiñas, Sarah A. Gagliano Taliun, View ORCID ProfileWouter van Rheenen, Kuang Lin, Aleksey Shatunov, View ORCID ProfileEmil K. Gustavsson, Isabella Fogh, Ashley R. Jones, Wim Robberecht, Philippe Corcia, Adriano Chiò, Pamela J. Shaw, Karen E. Morrison, View ORCID ProfileJan H. Veldink, Leonard H. van den Berg, Christopher E. Shaw, John F. Powell, View ORCID ProfileVincenzo Silani, John A. Hardy, Henry Houlden, Michael J. Owen, Martin R. Turner, Mina Ryten, View ORCID ProfileAmmar Al-Chalabi
doi: https://doi.org/10.1101/2022.04.29.490053
Zhongbo Chen
1Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
2Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK
3NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK
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Regina H. Reynolds
2Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK
3NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK
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Antonio F. Pardiñas
4MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
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Sarah A. Gagliano Taliun
5Department of Medicine & Department of Neurosciences, Université de Montréal, Montréal, Québec, Canada
6Montréal Heart Institute, Montréal, Québec, Canada
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Wouter van Rheenen
7Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands
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Kuang Lin
8Nuffield Department of Population Health, Oxford University, Oxford, UK
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Aleksey Shatunov
9Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Emil K. Gustavsson
2Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK
3NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK
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Isabella Fogh
9Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Ashley R. Jones
9Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Wim Robberecht
10Department of Neurology, University Hospital Leuven, Leuven, Belgium
11Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, Leuven, Belgium
12Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium
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Philippe Corcia
13ALS Center, Department of Neurology, CHRU Bretonneau, Tours, France
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Adriano Chiò
14Rita Levi Montalcini Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy
15Azienda Ospedaliera Universitaria Città della Salute e della Scienza, Torino, Italy
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Pamela J. Shaw
16Academic Neurology Unit, Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK
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Karen E. Morrison
17School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
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Jan H. Veldink
7Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands
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Leonard H. van den Berg
7Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands
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Christopher E. Shaw
9Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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John F. Powell
9Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Vincenzo Silani
18Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy
19Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, 20122 Milano, Italy
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John A. Hardy
1Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
20Reta Lila Weston Institute, Queen Square Institute of Neurology, UCL, London, UK
21UK Dementia Research Institute, Queen Square Institute of Neurology, UCL, London, UK
22NIHR University College London Hospitals Biomedical Research Centre, London, UK
23Institute for Advanced Study, The Hong Kong University of Science and Technology, The Hong Kong University of Science and Technology, Hong Kong SAR, China
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Henry Houlden
24Department of Neuromuscular Disease, Queen Square Institute of Neurology, UCL, London, UK
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Michael J. Owen
4MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
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Martin R. Turner
25Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK
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Mina Ryten
2Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK
3NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK
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Ammar Al-Chalabi
9Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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  • For correspondence: ammar.al-chalabi@kcl.ac.uk
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Abstract

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 Statement

AAC reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Brainstorm, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, and Wave Pharmaceuticals.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 30, 2022.
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The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases
Zhongbo Chen, Regina H. Reynolds, Antonio F. Pardiñas, Sarah A. Gagliano Taliun, Wouter van Rheenen, Kuang Lin, Aleksey Shatunov, Emil K. Gustavsson, Isabella Fogh, Ashley R. Jones, Wim Robberecht, Philippe Corcia, Adriano Chiò, Pamela J. Shaw, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Christopher E. Shaw, John F. Powell, Vincenzo Silani, John A. Hardy, Henry Houlden, Michael J. Owen, Martin R. Turner, Mina Ryten, Ammar Al-Chalabi
bioRxiv 2022.04.29.490053; doi: https://doi.org/10.1101/2022.04.29.490053
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The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases
Zhongbo Chen, Regina H. Reynolds, Antonio F. Pardiñas, Sarah A. Gagliano Taliun, Wouter van Rheenen, Kuang Lin, Aleksey Shatunov, Emil K. Gustavsson, Isabella Fogh, Ashley R. Jones, Wim Robberecht, Philippe Corcia, Adriano Chiò, Pamela J. Shaw, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Christopher E. Shaw, John F. Powell, Vincenzo Silani, John A. Hardy, Henry Houlden, Michael J. Owen, Martin R. Turner, Mina Ryten, Ammar Al-Chalabi
bioRxiv 2022.04.29.490053; doi: https://doi.org/10.1101/2022.04.29.490053

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