The genetic overlap between Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease

Douglas P. Wightman; Jeanne E. Savage; Elleke Tissink; Cato Romero; Iris E. Jansen; Danielle Posthuma

doi:10.1016/j.neurobiolaging.2023.03.004

The genetic overlap between Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease

Douglas P. Wightman^*, Jeanne E. Savage, Elleke Tissink, Cato Romero, Iris E. Jansen, Danielle Posthuma

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Neurodegenerative diseases are a group of disorders characterized by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterized by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. The majority of previous genetic evidence for overlap between neurodegenerative diseases has been pairwise. In this study, we aimed to identify overlap between the 4 investigated neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between 3 or more diseases. Using local genetic correlation, we found 2 loci (TMEM175 and HLA) that were shared across 3 disorders. We also highlighted genes, genomic loci, gene sets, cell types, and tissue types which may be important to 2 or more disorders by analyzing the association of variants with a common factor estimated from the 4 disorders. Our study successfully highlighted genetic loci and tissues associated with 2 or more neurodegenerative diseases.

Original language	English
Pages (from-to)	99-112
Number of pages	14
Journal	Neurobiology of Aging
Volume	127
DOIs	https://doi.org/10.1016/j.neurobiolaging.2023.03.004
Publication status	Published - Jul 2023

Bibliographical note

Funding Information:
DP was funded by The Netherlands Organization for Scientific Research ( NWO 453–14-005 ), NWO Gravitation : BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ), and a European Research Council advanced grant (Grant No. ERC-2018-AdG GWAS2FUNC 834057 ). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). JES was supported by funding from the Amsterdam Neuroscience Alliance Project . CR was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA.

Funding Information:
DP was funded by The Netherlands Organization for Scientific Research (NWO 453–14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No. ERC-2018-AdG GWAS2FUNC 834057). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). JES was supported by funding from the Amsterdam Neuroscience Alliance Project. CR was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA. DPW and ET analyzed the data. DPW wrote the manuscript. DPW, IEJ, JES, CR, ET, and DP designed the analysis plan. IEJ, JES, and DP supervised the project. Authors declare that data contained in the manuscript being submitted have not been previously published, have not been submitted elsewhere and will not be submitted elsewhere while under consideration at Neurobiology of Aging. All authors have reviewed the contents of the manuscript being submitted, approve of its contents and validate the accuracy of the data.

Publisher Copyright:
© 2023 The Author(s)

Funding

DP was funded by The Netherlands Organization for Scientific Research ( NWO 453–14-005 ), NWO Gravitation : BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ), and a European Research Council advanced grant (Grant No. ERC-2018-AdG GWAS2FUNC 834057 ). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). JES was supported by funding from the Amsterdam Neuroscience Alliance Project . CR was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA. DP was funded by The Netherlands Organization for Scientific Research (NWO 453–14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No. ERC-2018-AdG GWAS2FUNC 834057). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). JES was supported by funding from the Amsterdam Neuroscience Alliance Project. CR was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA. DPW and ET analyzed the data. DPW wrote the manuscript. DPW, IEJ, JES, CR, ET, and DP designed the analysis plan. IEJ, JES, and DP supervised the project. Authors declare that data contained in the manuscript being submitted have not been previously published, have not been submitted elsewhere and will not be submitted elsewhere while under consideration at Neurobiology of Aging. All authors have reviewed the contents of the manuscript being submitted, approve of its contents and validate the accuracy of the data.

Funders	Funder number
Dutch National Computing and Networking Services
European Research Council	ERC-2018-AdG GWAS2FUNC 834057
European Research Council
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	NWO 453–14-005, 024.004.012
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Keywords

Alzheimer's disease
Amyotrophic lateral sclerosis
Genetic overlap
Global genetic correlation
Lewy body dementia
Local genetic correlation
Parkinson's disease

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neurobiolaging.2023.03.004

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Cite this

@article{83a1e281b3af4c4a8cccf6cb3fa2d589,

title = "The genetic overlap between Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease",

abstract = "Neurodegenerative diseases are a group of disorders characterized by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterized by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. The majority of previous genetic evidence for overlap between neurodegenerative diseases has been pairwise. In this study, we aimed to identify overlap between the 4 investigated neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between 3 or more diseases. Using local genetic correlation, we found 2 loci (TMEM175 and HLA) that were shared across 3 disorders. We also highlighted genes, genomic loci, gene sets, cell types, and tissue types which may be important to 2 or more disorders by analyzing the association of variants with a common factor estimated from the 4 disorders. Our study successfully highlighted genetic loci and tissues associated with 2 or more neurodegenerative diseases.",

keywords = "Alzheimer's disease, Amyotrophic lateral sclerosis, Genetic overlap, Global genetic correlation, Lewy body dementia, Local genetic correlation, Parkinson's disease",

author = "Wightman, {Douglas P.} and Savage, {Jeanne E.} and Elleke Tissink and Cato Romero and Jansen, {Iris E.} and Danielle Posthuma",

note = "Funding Information: DP was funded by The Netherlands Organization for Scientific Research ( NWO 453–14-005 ), NWO Gravitation : BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ), and a European Research Council advanced grant (Grant No. ERC-2018-AdG GWAS2FUNC 834057 ). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). JES was supported by funding from the Amsterdam Neuroscience Alliance Project . CR was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 ). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA. Funding Information: DP was funded by The Netherlands Organization for Scientific Research (NWO 453–14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No. ERC-2018-AdG GWAS2FUNC 834057). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). JES was supported by funding from the Amsterdam Neuroscience Alliance Project. CR was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA. DPW and ET analyzed the data. DPW wrote the manuscript. DPW, IEJ, JES, CR, ET, and DP designed the analysis plan. IEJ, JES, and DP supervised the project. Authors declare that data contained in the manuscript being submitted have not been previously published, have not been submitted elsewhere and will not be submitted elsewhere while under consideration at Neurobiology of Aging. All authors have reviewed the contents of the manuscript being submitted, approve of its contents and validate the accuracy of the data. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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doi = "10.1016/j.neurobiolaging.2023.03.004",

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AU - Romero, Cato

AU - Jansen, Iris E.

AU - Posthuma, Danielle

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N2 - Neurodegenerative diseases are a group of disorders characterized by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterized by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. The majority of previous genetic evidence for overlap between neurodegenerative diseases has been pairwise. In this study, we aimed to identify overlap between the 4 investigated neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between 3 or more diseases. Using local genetic correlation, we found 2 loci (TMEM175 and HLA) that were shared across 3 disorders. We also highlighted genes, genomic loci, gene sets, cell types, and tissue types which may be important to 2 or more disorders by analyzing the association of variants with a common factor estimated from the 4 disorders. Our study successfully highlighted genetic loci and tissues associated with 2 or more neurodegenerative diseases.

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KW - Lewy body dementia

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The genetic overlap between Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

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