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

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 SilaniJohn A Hardy, Henry Houlden, Michael J Owen, Martin R Turner, Mina Ryten, Ammar Al-Chalabi^*

^*Corresponding author for this work

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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.

Original language	English
Article number	106082
Number of pages	8
Journal	Neurobiology of Disease
Volume	180
Early online date	15 Mar 2023
DOIs	https://doi.org/10.1016/j.nbd.2023.106082
Publication status	Published - May 2023

Keywords

Alzheimer's disease
Amyotrophic lateral sclerosis
Evolution
Genetics
Natural selection
Neanderthal
Neurodegenerative diseases
Parkinson's disease

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Chen, Z., Reynolds, R. H., Pardiñas, A. F., Gagliano Taliun, S. A., van Rheenen, W., Lin, K., Shatunov, A., Gustavsson, E. K., Fogh, I., Jones, A. R., Robberecht, W., Corcia, P., Chiò, A., Shaw, P. J., Morrison, K. E., Veldink, J. H., van den Berg, L. H., Shaw, C. E., Powell, J. F., ... Al-Chalabi, A. (2023). The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases. Neurobiology of Disease, 180, Article 106082. https://doi.org/10.1016/j.nbd.2023.106082

@article{1895c1832435414698c324e61b15f560,

title = "The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases",

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",

author = "Zhongbo Chen and Reynolds, {Regina H} and Pardi{\~n}as, {Antonio F} and {Gagliano Taliun}, {Sarah A} and {van Rheenen}, Wouter and Kuang Lin and Aleksey Shatunov and Gustavsson, {Emil K} and Isabella Fogh and Jones, {Ashley R} and Wim Robberecht and Philippe Corcia and Adriano Chi{\`o} and Shaw, {Pamela J} and Morrison, {Karen E} and Veldink, {Jan H} and {van den Berg}, {Leonard H} and Shaw, {Christopher E} and Powell, {John F} and Vincenzo Silani and Hardy, {John A} and Henry Houlden and Owen, {Michael J} and Turner, {Martin R} and Mina Ryten and Ammar Al-Chalabi",

note = "Funding Information: Z.C. is funded by a Leonard Wolfson Foundation clinical research fellowship in neurodegeneration. I.F. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. I.F. is also funded by the Motor Neurone Disease Association (Grant number 905-793, 6058). W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the Laevers Fund for ALS Research, the ALS Liga Belgi{\"e}, the fund {\textquoteleft}Een Hart voor ALS{\textquoteright} and the fund {\textquoteleft}Opening the Future{\textquoteright}. MRT is supported by the Motor Neurone Disease Association. AAC is an NIHR Senior Investigator (NIHR202421). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)) and through the Motor Neurone Disease Association, My Name{\textquoteright}5 Doddie Foundation, and Alan Davidson Foundation. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College Londona. The work leading up to this publication was funded by the European Community's Health Seventh Framework Programme (FP7/2007–2013; grant agreement number 259867 and 340429). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. MR is supported through the award of a Tenure Track Medical Research Council (MRC) Clinician Scientist Fellowship (MR/N008324/1). Funding Information: Z.C. is funded by a Leonard Wolfson Foundation clinical research fellowship in neurodegeneration. I.F. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London . I.F. is also funded by the Motor Neurone Disease Association (Grant number 905-793, 6058 ). W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the Laevers Fund for ALS Research , the ALS Liga Belgi{\"e} , the fund {\textquoteleft}Een Hart voor ALS{\textquoteright} and the fund {\textquoteleft}Opening the Future{\textquoteright} . MRT is supported by the Motor Neurone Disease Association . AAC is an NIHR Senior Investigator ( NIHR202421 ). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council ( MR/L501529/1 ; MR/R024804/1 ) and Economic and Social Research Council ( ES/L008238/1 )) and through the Motor Neurone Disease Association , My Name{\textquoteright}5 Doddie Foundation , and Alan Davidson Foundation . This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College Londona . The work leading up to this publication was funded by the European Community's Health Seventh Framework Programme (FP7/2007–2013; grant agreement number 259867 and 340429 ). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. MR is supported through the award of a Tenure Track Medical Research Council (MRC) Clinician Scientist Fellowship (MR/N008324/1). Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = may,

doi = "10.1016/j.nbd.2023.106082",

language = "English",

volume = "180",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Academic Press Inc.",

}

Chen, Z, Reynolds, RH, Pardiñas, AF, Gagliano Taliun, SA, van Rheenen, W, Lin, K, Shatunov, A, Gustavsson, EK, Fogh, I, Jones, AR, Robberecht, W, Corcia, P, Chiò, A, Shaw, PJ, Morrison, KE, Veldink, JH , van den Berg, LH, Shaw, CE, Powell, JF, Silani, V, Hardy, JA, Houlden, H, Owen, MJ, Turner, MR, Ryten, M & Al-Chalabi, A 2023, 'The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases', Neurobiology of Disease, vol. 180, 106082. https://doi.org/10.1016/j.nbd.2023.106082

TY - JOUR

T1 - The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

AU - Chen, Zhongbo

AU - Reynolds, Regina H

AU - Pardiñas, Antonio F

AU - Gagliano Taliun, Sarah A

AU - van Rheenen, Wouter

AU - Lin, Kuang

AU - Shatunov, Aleksey

AU - Gustavsson, Emil K

AU - Fogh, Isabella

AU - Jones, Ashley R

AU - Robberecht, Wim

AU - Corcia, Philippe

AU - Chiò, Adriano

AU - Shaw, Pamela J

AU - Morrison, Karen E

AU - Veldink, Jan H

AU - van den Berg, Leonard H

AU - Shaw, Christopher E

AU - Powell, John F

AU - Silani, Vincenzo

AU - Hardy, John A

AU - Houlden, Henry

AU - Owen, Michael J

AU - Turner, Martin R

AU - Ryten, Mina

AU - Al-Chalabi, Ammar

N1 - Funding Information: Z.C. is funded by a Leonard Wolfson Foundation clinical research fellowship in neurodegeneration. I.F. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. I.F. is also funded by the Motor Neurone Disease Association (Grant number 905-793, 6058). W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the Laevers Fund for ALS Research, the ALS Liga België, the fund ‘Een Hart voor ALS’ and the fund ‘Opening the Future’. MRT is supported by the Motor Neurone Disease Association. AAC is an NIHR Senior Investigator (NIHR202421). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)) and through the Motor Neurone Disease Association, My Name’5 Doddie Foundation, and Alan Davidson Foundation. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College Londona. The work leading up to this publication was funded by the European Community's Health Seventh Framework Programme (FP7/2007–2013; grant agreement number 259867 and 340429). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. MR is supported through the award of a Tenure Track Medical Research Council (MRC) Clinician Scientist Fellowship (MR/N008324/1). Funding Information: Z.C. is funded by a Leonard Wolfson Foundation clinical research fellowship in neurodegeneration. I.F. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London . I.F. is also funded by the Motor Neurone Disease Association (Grant number 905-793, 6058 ). W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the Laevers Fund for ALS Research , the ALS Liga België , the fund ‘Een Hart voor ALS’ and the fund ‘Opening the Future’ . MRT is supported by the Motor Neurone Disease Association . AAC is an NIHR Senior Investigator ( NIHR202421 ). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council ( MR/L501529/1 ; MR/R024804/1 ) and Economic and Social Research Council ( ES/L008238/1 )) and through the Motor Neurone Disease Association , My Name’5 Doddie Foundation , and Alan Davidson Foundation . This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College Londona . The work leading up to this publication was funded by the European Community's Health Seventh Framework Programme (FP7/2007–2013; grant agreement number 259867 and 340429 ). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. MR is supported through the award of a Tenure Track Medical Research Council (MRC) Clinician Scientist Fellowship (MR/N008324/1). Publisher Copyright: © 2023

PY - 2023/5

Y1 - 2023/5

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Amyotrophic lateral sclerosis

KW - Evolution

KW - Genetics

KW - Natural selection

KW - Neanderthal

KW - Neurodegenerative diseases

KW - Parkinson's disease

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DO - 10.1016/j.nbd.2023.106082

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VL - 180

JO - Neurobiology of Disease

JF - Neurobiology of Disease

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ER -

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

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