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

Neurobiology of Disease (Jul 2023)

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

Affiliations

Vera Fominykh: NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Corresponding author.
Alexey A. Shadrin: NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Piotr P. Jaholkowski: NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Shahram Bahrami: NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Lavinia Athanasiu: NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
Douglas P. Wightman: Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Emil Uffelmann: Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Danielle Posthuma: Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Department of Child and Adolescent Psychiatry and Pediatric Psychology, Section Complex Trait Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Geir Selbæk: Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway; Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tonsberg, Vestfold, Norway
Anders M. Dale: Department of Radiology, University of California San Diego, La Jolla, California, USA; Multimodal Imaging Laboratory, University of California San Diego, La Jolla, California, USA; Department of Psychiatry, University of California San Diego, La Jolla, California, USA; Department of Neurosciences, University of California San Diego, La Jolla, California, USA
Srdjan Djurovic: NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Centre for Neurodevelopmental disorders, University of Oslo and Oslo University Hospital, Oslo, Norway
Oleksandr Frei: NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Informatics, Centre for Bioinformatics, University of Oslo, Norway
Ole A. Andreassen: NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Centre for Neurodevelopmental disorders, University of Oslo and Oslo University Hospital, Oslo, Norway

Journal volume & issue: Vol. 183
p. 106174

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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