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

doi:10.1016/j.nbd.2023.106082

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Neurobiol Dis. 2023 May:180:106082. doi: 10.1016/j.nbd.2023.106082. Epub 2023 Mar 15.

Authors

Zhongbo Chen¹, Regina H Reynolds², Antonio F Pardiñas³, Sarah A Gagliano Taliun⁴, Wouter van Rheenen⁵, Kuang Lin⁶, Aleksey Shatunov⁷, Emil K Gustavsson², Isabella Fogh⁷, Ashley R Jones⁷, Wim Robberecht⁸, Philippe Corcia⁹, Adriano Chiò¹⁰, Pamela J Shaw¹¹, Karen E Morrison¹², Jan H Veldink⁵, Leonard H van den Berg⁵, Christopher E Shaw⁷, John F Powell⁷, Vincenzo Silani¹³, John A Hardy¹⁴, Henry Houlden¹⁵, Michael J Owen³, Martin R Turner¹⁶, Mina Ryten², Ammar Al-Chalabi¹⁷

Affiliations

¹ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK; Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK. Electronic address: zhongbo.chen@ucl.ac.uk.
² Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK.
³ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁴ Department of Medicine & Department of Neurosciences, Université de Montréal, Montréal, Québec, Canada; Montréal Heart Institute, Montréal, Québec, Canada.
⁵ Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands.
⁶ Nuffield Department of Population Health, Oxford University, Oxford, UK.
⁷ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Department of Neurology, University Hospital Leuven, Leuven, Belgium; Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, Leuven, Belgium; Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium.
⁹ ALS Center, Department of Neurology, CHRU Bretonneau, Tours, France.
¹⁰ Rita Levi Montalcini Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy; Azienda Ospedaliera Universitaria Città della Salute e della Scienza, Torino, Italy.
¹¹ Academic Neurology Unit, Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK.
¹² School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
¹³ Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, 20122 Milano, Italy.
¹⁴ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK; Reta Lila Weston Institute, Queen Square Institute of Neurology, UCL, London, UK; UK Dementia Research Institute, Queen Square Institute of Neurology, UCL, London, UK; NIHR University College London Hospitals Biomedical Research Centre, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, SAR, China.
¹⁵ Department of Neuromuscular Disease, Queen Square Institute of Neurology, UCL, London, UK.
¹⁶ Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.
¹⁷ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address: ammar.al-chalabi@kcl.ac.uk.

PMID: 36925053
DOI: 10.1016/j.nbd.2023.106082

Abstract

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. 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, amyotrophic lateral sclerosis and Parkinson's disease. We found no evidence for enrichment of positively-selected SNPs in the heritability of Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, suggesting that 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. 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.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Evolution; Genetics; Natural selection; Neanderthal; Neurodegenerative diseases; Parkinson's disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease*
Amyotrophic Lateral Sclerosis*
Animals
Humans
Neanderthals* / genetics
Neurodegenerative Diseases* / genetics
Parkinson Disease*
Selection, Genetic

Abstract

Publication types

MeSH terms

Grants and funding