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J Alzheimers Dis. 2015;45(3):851-64. doi: 10.3233/JAD-142214.

Linking Genetics of Brain Changes to Alzheimer's Disease: Sparse Whole Genome Association Scan of Regional MRI Volumes in the ADNI and AddNeuroMed Cohorts.

Author information

1
King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Biostatistics, London, United Kingdom.
2
King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom Departments of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
3
Institute of gerontology and Geriatrics, University of Perugia, Perugia, Italy.
4
INSERM U 558, University of Toulouse, Toulouse, France.
5
Medical University of Lodz, Lodz, Poland.
6
Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
7
Department of Psychiatry, University of Oxford, United Kingdom.
8
King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom NIHR Biomedical Research Unit Dementia, London, United Kingdom.

Abstract

BACKGROUND:

Alzheimer's disease (AD) is a highly heritable disease, but until recently few replicated genetic markers have been identified. Markers identified so far are likely to account for only a tiny fraction of the heritability of AD and many more genetic risk alleles are thought to be undiscovered.

OBJECTIVE:

Identifying genetic markers for AD using combined analysis of genetics and brain imaging data.

METHODS:

Imaging quantitative trait loci (iQTLs) has recently emerged as an interesting research area for linking genetics of brain changes to AD. We consider a genome-wide association scan of 109 brain-wide regional imaging phenotypes to identify genetic susceptibility loci for AD from a combined set of 1,045 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the AddNeuroMed studies. We use one-SNP-at-a-time as well as multi-SNP Hyperlasso based iQTL methods for the analysis.

RESULTS:

We identified several novel markers associated with AD, namely HOMER2 (rs1256429; intronic, p = 8.7 × 10⁻¹⁰), EOMES (rs2724509; flanking), JAM2 (rs2829841; intronic), and WEE1 (rs10770042; coding). The SNP rs1256429 (HOMER2) was one of the top hits in Hyperlasso as well as in the single-SNP analysis showing an association with the volume of the right thalamus and AD, a brain region reported to be linked with AD in several studies.

CONCLUSION:

We believe that the markers identified in this study are novel additions to the existing list of genetic variants associated with AD which can be validated in future replicated studies.

KEYWORDS:

Alzheimer's disease; genome wide association study; imaging quantitative trait loci; magnetic resonance imaging; mild cognitive impairment

PMID:
25649652
DOI:
10.3233/JAD-142214
[Indexed for MEDLINE]
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