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Ann Clin Transl Neurol. 2016 Nov 4;3(12):924-933. doi: 10.1002/acn3.369. eCollection 2016 Dec.

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases.

Author information

1
Department of Medical & Molecular Genetics Guy's Hospital King's College London 8th Floor Tower Wing London SE1 9RT United Kingdom; Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health 250 College Street Toronto Ontario M5T 1R8 Canada; Institute of Medical Science University of Toronto 1 King's College Circle Room 2374 Toronto Ontario M5S 1A8 Canada.
2
Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health 250 College Street Toronto Ontario M5T 1R8 Canada; Institute of Medical Science University of Toronto 1 King's College Circle Room 2374 Toronto Ontario M5S 1A8 Canada; Department of Psychiatry University of Toronto 250 College Street 8th Floor Toronto Ontario M5T 1R8 Canada.
3
Institute of Neurology University College London Queen Square London WC1N 3BG United Kingdom.
4
Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health 250 College Street Toronto Ontario M5T 1R8 Canada; Institute of Medical Science University of Toronto 1 King's College Circle Room 2374 Toronto Ontario M5S 1A8 Canada; Department of Psychiatry University of Toronto 250 College Street 8th Floor Toronto Ontario M5T 1R8 Canada; Data Science Institute and Faculty of Health and Medicine Furness College Lancaster University Lancaster LA1 4YG United Kingdom.
5
William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London Charterhouse Square London EC1M 6BQ United Kingdom.
6
Department of Medical & Molecular Genetics Guy's Hospital King's College London 8th Floor Tower Wing London SE1 9RT United Kingdom.

Abstract

OBJECTIVES:

We assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases.

METHODS:

We obtained large-scale genome-wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control. We applied stratified LD score regression to determine if functional marks for cell type and tissue activity, and gene-set lists were enriched for genetic heritability. We compared our results to those from two gene-set enrichment methods (Ingenuity Pathway Analysis and enrichr).

RESULTS:

There were no significant heritability enrichments for annotations marking genes active within brain regions, but there were significant heritability enrichments for annotations marking genes active within cell types that form part of both the innate and adaptive immune systems. We found this for MS (as expected) and also for AD and PD. The strongest signals were from the adaptive immune system (e.g., T cells) for PD, and from both the adaptive (e.g., T cells) and innate (e.g., CD14: a marker for monocytes, and CD15: a marker for neutrophils) immune systems for AD. Annotations from the liver were also significant for AD. Pathway analysis provided complementary results.

INTERPRETATION:

For AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells.

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