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Ann Neurol. 2016 May;79(5):739-747. doi: 10.1002/ana.24621. Epub 2016 Feb 23.

Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.

Author information

1
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
2
Department of Medical & Molecular Genetics, King's College London, London, UK.
3
Stroke and Dementia Research Centre, St George's University of London, London, UK.
4
School of Biotechnology, Dublin City University, Dublin, Ireland.
5
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany.
6
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
7
Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
8
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.

Abstract

OBJECTIVE:

Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic Stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases.

METHODS:

Using genome wide association study (GWAS) data from METASTROKE+ (15,916 IS cases and 68,826 controls) and IGAP (17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets to identify the SNPs and molecular pathways through which disease risk may be conferred.

RESULTS:

We found evidence of a shared genetic contribution between AD and small vessel stroke (rG(SE)=0.37(0.17); p=0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall, or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE+ small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1), associated with both diseases (p=1.8x10-8 ). A pathway analysis identified four associated pathways, involving cholesterol transport and immune response.

INTERPRETATION:

Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. This article is protected by copyright. All rights reserved.

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