The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

被引：2

作者：

Chen, Zhongbo ^{[1
,2
,3
]}

Reynolds, Regina H. ^{[2
,3
]}

Pardinas, Antonio F. ^{[4
]}

Taliun, Sarah A. Gagliano ^{[5
,6
,7
]}

van Rheenen, Wouter ^{[8
]}

Lin, Kuang ^{[9
]}

Shatunov, Aleksey ^{[10
]}

Gustavsson, Emil K. ^{[2
,3
]}

Fogh, Isabella ^{[10
]}

Jones, Ashley R. ^{[10
]}

Robberecht, Wim ^{[11
,12
,13
,14
]}

Corcia, Philippe ^{[15
]}

Chio, Adriano ^{[16
,17
]}

Shaw, Pamela J. ^{[18
]}

Morrison, Karen E. ^{[19
]}

Veldink, Jan H. ^{[8
]}

van den Berg, Leonard H. ^{[8
]}

Shaw, Christopher E. ^{[10
]}

Powell, John F. ^{[10
]}

Silani, Vincenzo ^{[20
,21
,22
]}

Hardy, John A. ^{[1
,23
,24
,25
,26
]}

Houlden, Henry ^{[27
]}

Owen, Michael J. ^{[4
]}

Turner, Martin R. ^{[28
]}

Ryten, Mina ^{[2
,3
]}

Al-Chalabi, Ammar ^{[10
]}

机构：

[1] UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London WC1N 3BG, England

[2] UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England

[3] UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England

[4] Cardiff Univ, Div Psychol Med & Clin Neurosci, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff, Wales

[5] Univ Montreal, Dept Med, Montreal, PQ, Canada

[6] Univ Montreal, Dept Neurosci, Montreal, PQ, Canada

[7] Montreal Heart Inst, Montreal, PQ, Canada

[8] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands

[9] Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England

[10] Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Clin Neurosci Inst, Dept Basic & Clin Neurosci, London, England

[11] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium

[12] Dept Neurosci, Expt Neurol, Leuven, Belgium

[13] Leuven Res Inst Neurosci & Dis, Leuven, Belgium

[14] Vesalius Res Ctr, Neurobiol Lab, Leuven, Belgium

[15] CHRU Bretonneau, Dept Neurol, ALS Ctr, Tours, France

[16] Univ Torino, ALS Ctr, Rita Levi Montalcini Dept Neurosci, Turin, Italy

[17] Azienda Osped Univ Citta Salute & Sci, Turin, Italy

[18] Univ Sheffield, Fac Med Dent & Hlth, Dept Neurosci, Acad Neurol Unit, Sheffield, S Yorkshire, England

[19] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland

[20] IRCCS Ist Auxol Italiano, Dept Neurol, Milan, Italy

[21] IRCCS Ist Auxol Italiano, Lab Neurosci, Milan, Italy

[22] Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, I-20122 Milan, Italy

[23] UCL, Queen Sq Inst Neurol, Reta Lila Weston Inst, London, England

[24] UCL, Queen Sq Inst Neurol, UK Dementia Res Inst, London, England

[25] NIHR Univ Coll London Hosp Biomed Res Ctr, London, England

[26] Hong Kong Univ Sci & Technol, Inst Adv Study, Hong Kong, Peoples R China

[27] UCL, Queen Sq Inst Neurol, Dept Neuromuscular Dis, London, England

[28] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England

来源：

NEUROBIOLOGY OF DISEASE | 2023年 / 180卷

基金：

英国医学研究理事会; 英国经济与社会研究理事会;

关键词：

Alzheimer?s disease; Parkinson?s disease; Amyotrophic lateral sclerosis; Genetics; Natural selection; Evolution; Neanderthal; Neurodegenerative diseases; GENETIC-VARIATION; RISK LOCI; GENOME; HERITABILITY; ASSOCIATION; EVOLUTION; VARIANTS; REPEAT; COMPOSITE; ADMIXTURE;

D O I：

10.1016/j.nbd.2023.106082

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 un-clear 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 neurodegenera-tive 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 contrib-uted to common genetic risk of neurodegeneration in anatomically-modern humans.

引用

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