Shared genetic loci between Alzheimer's disease and multiple sclerosis: Crossroads between neurodegeneration and immune system

Vera Fominykh; Alexey A. Shadrin; Piotr P. Jaholkowski; Shahram Bahrami; Lavinia Athanasiu; Douglas P. Wightman; Emil Uffelmann; Danielle Posthuma; Geir Selbæk; Anders M. Dale; Srdjan Djurovic; Oleksandr Frei; Ole A. Andreassen

doi:10.1016/j.nbd.2023.106174

Shared genetic loci between Alzheimer's disease and multiple sclerosis: Crossroads between neurodegeneration and immune system

Vera Fominykh^*, Alexey A. Shadrin, Piotr P. Jaholkowski, Shahram Bahrami, Lavinia Athanasiu, Douglas P. Wightman, Emil Uffelmann, Danielle Posthuma, Geir Selbæk, Anders M. Dale, Srdjan Djurovic, Oleksandr Frei, Ole A. Andreassen

^*Corresponding author for this work

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

Abstract

Background: Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system. Methods: We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets. Results: MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons. Conclusions: Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.

Original language	English
Article number	106174
Pages (from-to)	1-12
Number of pages	12
Journal	Neurobiology of Disease
Volume	183
Early online date	5 Jun 2023
DOIs	https://doi.org/10.1016/j.nbd.2023.106174
Publication status	Published - Jul 2023

Bibliographical note

Funding Information:
This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874 , and EEA grants ( EEA-RO-NO-2018-0535 , EEA-RO-NO-2018-0573 ). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo and operated and developed by the TSD service group at the University of Oslo, IT Department (USIT). Computations were also performed on resources provided by the National Infrastructure for High-Performance Computing and Data Storage in Norway. DP received funding from NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 , to D.P. and D.P.W.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057 , to D.P.).

Funding Information:
All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. The authors thank the researchers of the IMSGC, PGC and ADGC consortia for access to data, and for all participants who provided samples. We gratefully acknowledge support from the American National Institutes of Health ( NS057198 , EB00790 ), the Research Council of Norway (# 229129 , 213837 , 324252 , 326813 , 300309 , 273291 , 223273 , 248980 , 296030 ), the South-East Norway Regional Health Authority ( 2022-073 ), KG Jebsen Stiftelsen ( SKGJ-MED-021 ), Norwegian Health Association ("Nasjonalforeningen for folkehelsen", # 22731 ).

Funding Information:
All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. The authors thank the researchers of the IMSGC, PGC and ADGC consortia for access to data, and for all participants who provided samples. We gratefully acknowledge support from the American National Institutes of Health (NS057198, EB00790), the Research Council of Norway (#229129, 213837, 324252, 326813, 300309, 273291, 223273, 248980, 296030), the South-East Norway Regional Health Authority (2022-073), KG Jebsen Stiftelsen (SKGJ-MED-021), Norwegian Health Association ("Nasjonalforeningen for folkehelsen", #22731). This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874, and EEA grants (EEA-RO-NO-2018-0535, EEA-RO-NO-2018-0573). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo and operated and developed by the TSD service group at the University of Oslo, IT Department (USIT). Computations were also performed on resources provided by the National Infrastructure for High-Performance Computing and Data Storage in Norway. DP received funding from NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012, to D.P. and D.P.W.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057, to D.P.).

Publisher Copyright:
© 2023 The Authors

Funding

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874 , and EEA grants ( EEA-RO-NO-2018-0535 , EEA-RO-NO-2018-0573 ). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo and operated and developed by the TSD service group at the University of Oslo, IT Department (USIT). Computations were also performed on resources provided by the National Infrastructure for High-Performance Computing and Data Storage in Norway. DP received funding from NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 , to D.P. and D.P.W.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057 , to D.P.). All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. The authors thank the researchers of the IMSGC, PGC and ADGC consortia for access to data, and for all participants who provided samples. We gratefully acknowledge support from the American National Institutes of Health ( NS057198 , EB00790 ), the Research Council of Norway (# 229129 , 213837 , 324252 , 326813 , 300309 , 273291 , 223273 , 248980 , 296030 ), the South-East Norway Regional Health Authority ( 2022-073 ), KG Jebsen Stiftelsen ( SKGJ-MED-021 ), Norwegian Health Association ("Nasjonalforeningen for folkehelsen", # 22731 ). All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. The authors thank the researchers of the IMSGC, PGC and ADGC consortia for access to data, and for all participants who provided samples. We gratefully acknowledge support from the American National Institutes of Health (NS057198, EB00790), the Research Council of Norway (#229129, 213837, 324252, 326813, 300309, 273291, 223273, 248980, 296030), the South-East Norway Regional Health Authority (2022-073), KG Jebsen Stiftelsen (SKGJ-MED-021), Norwegian Health Association ("Nasjonalforeningen for folkehelsen", #22731). This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874, and EEA grants (EEA-RO-NO-2018-0535, EEA-RO-NO-2018-0573). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo and operated and developed by the TSD service group at the University of Oslo, IT Department (USIT). Computations were also performed on resources provided by the National Infrastructure for High-Performance Computing and Data Storage in Norway. DP received funding from NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012, to D.P. and D.P.W.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057, to D.P.).

Funders	Funder number
ADGC
American National Institutes of Health	EB00790, NS057198
IMSGC
KG Jebsen Stiftelsen	SKGJ-MED-021
Pennsylvania Game Commission
European Research Council	ERC-2018-AdG GWAS2FUNC 834057
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	024.004.012
Universitetet i Oslo
Norges forskningsråd	296030, 223273, 229129, 248980, 326813, 213837, 324252, 300309, 273291
Helse Sør-Øst RHF	2022-073
Horizon 2020	964874, 847776, EEA-RO-NO-2018-0535
Nasjonalforeningen for Folkehelsen	22731

Keywords

Alzheimer's disease
Dementia
Genetic overlap
Multiple sclerosis
Neurodegeneration
Neuroinflammation
Pleiotropy

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10.1016/j.nbd.2023.106174

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Fominykh, V., Shadrin, A. A., Jaholkowski, P. P., Bahrami, S., Athanasiu, L., Wightman, D. P., Uffelmann, E., Posthuma, D., Selbæk, G., Dale, A. M., Djurovic, S., Frei, O., & Andreassen, O. A. (2023). Shared genetic loci between Alzheimer's disease and multiple sclerosis: Crossroads between neurodegeneration and immune system. Neurobiology of Disease, 183, 1-12. Article 106174. https://doi.org/10.1016/j.nbd.2023.106174

@article{b82e85de06c7439bb38dfedcb0a1286a,

title = "Shared genetic loci between Alzheimer's disease and multiple sclerosis: Crossroads between neurodegeneration and immune system",

abstract = "Background: Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system. Methods: We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets. Results: MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons. Conclusions: Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.",

keywords = "Alzheimer's disease, Dementia, Genetic overlap, Multiple sclerosis, Neurodegeneration, Neuroinflammation, Pleiotropy",

author = "Vera Fominykh and Shadrin, {Alexey A.} and Jaholkowski, {Piotr P.} and Shahram Bahrami and Lavinia Athanasiu and Wightman, {Douglas P.} and Emil Uffelmann and Danielle Posthuma and Geir Selb{\ae}k and Dale, {Anders M.} and Srdjan Djurovic and Oleksandr Frei and Andreassen, {Ole A.}",

note = "Funding Information: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874 , and EEA grants ( EEA-RO-NO-2018-0535 , EEA-RO-NO-2018-0573 ). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo and operated and developed by the TSD service group at the University of Oslo, IT Department (USIT). Computations were also performed on resources provided by the National Infrastructure for High-Performance Computing and Data Storage in Norway. DP received funding from NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 , to D.P. and D.P.W.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057 , to D.P.). Funding Information: All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. The authors thank the researchers of the IMSGC, PGC and ADGC consortia for access to data, and for all participants who provided samples. We gratefully acknowledge support from the American National Institutes of Health ( NS057198 , EB00790 ), the Research Council of Norway (# 229129 , 213837 , 324252 , 326813 , 300309 , 273291 , 223273 , 248980 , 296030 ), the South-East Norway Regional Health Authority ( 2022-073 ), KG Jebsen Stiftelsen ( SKGJ-MED-021 ), Norwegian Health Association ({"}Nasjonalforeningen for folkehelsen{"}, # 22731 ). Funding Information: All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. The authors thank the researchers of the IMSGC, PGC and ADGC consortia for access to data, and for all participants who provided samples. We gratefully acknowledge support from the American National Institutes of Health (NS057198, EB00790), the Research Council of Norway (#229129, 213837, 324252, 326813, 300309, 273291, 223273, 248980, 296030), the South-East Norway Regional Health Authority (2022-073), KG Jebsen Stiftelsen (SKGJ-MED-021), Norwegian Health Association ({"}Nasjonalforeningen for folkehelsen{"}, #22731). This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874, and EEA grants (EEA-RO-NO-2018-0535, EEA-RO-NO-2018-0573). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo and operated and developed by the TSD service group at the University of Oslo, IT Department (USIT). Computations were also performed on resources provided by the National Infrastructure for High-Performance Computing and Data Storage in Norway. DP received funding from NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012, to D.P. and D.P.W.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057, to D.P.). Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = jul,

doi = "10.1016/j.nbd.2023.106174",

language = "English",

volume = "183",

pages = "1--12",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Academic Press Inc.",

}

Fominykh, V, Shadrin, AA, Jaholkowski, PP, Bahrami, S, Athanasiu, L, Wightman, DP , Uffelmann, E , Posthuma, D, Selbæk, G, Dale, AM, Djurovic, S, Frei, O & Andreassen, OA 2023, 'Shared genetic loci between Alzheimer's disease and multiple sclerosis: Crossroads between neurodegeneration and immune system', Neurobiology of Disease, vol. 183, 106174, pp. 1-12. https://doi.org/10.1016/j.nbd.2023.106174

TY - JOUR

T1 - Shared genetic loci between Alzheimer's disease and multiple sclerosis

T2 - Crossroads between neurodegeneration and immune system

AU - Fominykh, Vera

AU - Shadrin, Alexey A.

AU - Jaholkowski, Piotr P.

AU - Bahrami, Shahram

AU - Athanasiu, Lavinia

AU - Wightman, Douglas P.

AU - Uffelmann, Emil

AU - Posthuma, Danielle

AU - Selbæk, Geir

AU - Dale, Anders M.

AU - Djurovic, Srdjan

AU - Frei, Oleksandr

AU - Andreassen, Ole A.

N1 - Funding Information: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874 , and EEA grants ( EEA-RO-NO-2018-0535 , EEA-RO-NO-2018-0573 ). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo and operated and developed by the TSD service group at the University of Oslo, IT Department (USIT). Computations were also performed on resources provided by the National Infrastructure for High-Performance Computing and Data Storage in Norway. DP received funding from NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 , to D.P. and D.P.W.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057 , to D.P.). Funding Information: All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. The authors thank the researchers of the IMSGC, PGC and ADGC consortia for access to data, and for all participants who provided samples. We gratefully acknowledge support from the American National Institutes of Health ( NS057198 , EB00790 ), the Research Council of Norway (# 229129 , 213837 , 324252 , 326813 , 300309 , 273291 , 223273 , 248980 , 296030 ), the South-East Norway Regional Health Authority ( 2022-073 ), KG Jebsen Stiftelsen ( SKGJ-MED-021 ), Norwegian Health Association ("Nasjonalforeningen for folkehelsen", # 22731 ). Funding Information: All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. The authors thank the researchers of the IMSGC, PGC and ADGC consortia for access to data, and for all participants who provided samples. We gratefully acknowledge support from the American National Institutes of Health (NS057198, EB00790), the Research Council of Norway (#229129, 213837, 324252, 326813, 300309, 273291, 223273, 248980, 296030), the South-East Norway Regional Health Authority (2022-073), KG Jebsen Stiftelsen (SKGJ-MED-021), Norwegian Health Association ("Nasjonalforeningen for folkehelsen", #22731). This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776 and 964874, and EEA grants (EEA-RO-NO-2018-0535, EEA-RO-NO-2018-0573). This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo and operated and developed by the TSD service group at the University of Oslo, IT Department (USIT). Computations were also performed on resources provided by the National Infrastructure for High-Performance Computing and Data Storage in Norway. DP received funding from NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012, to D.P. and D.P.W.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057, to D.P.). Publisher Copyright: © 2023 The Authors

PY - 2023/7

Y1 - 2023/7

N2 - Background: Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system. Methods: We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets. Results: MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons. Conclusions: Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.

AB - Background: Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system. Methods: We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets. Results: MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons. Conclusions: Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.

KW - Alzheimer's disease

KW - Dementia

KW - Genetic overlap

KW - Multiple sclerosis

KW - Neurodegeneration

KW - Neuroinflammation

KW - Pleiotropy

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U2 - 10.1016/j.nbd.2023.106174

DO - 10.1016/j.nbd.2023.106174

M3 - Article

C2 - 37286172

AN - SCOPUS:85162917412

SN - 0969-9961

VL - 183

SP - 1

EP - 12

JO - Neurobiology of Disease

JF - Neurobiology of Disease

M1 - 106174

ER -

Shared genetic loci between Alzheimer's disease and multiple sclerosis: Crossroads between neurodegeneration and immune system

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