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

Article type: Research Article

Authors: Khondoker, Mizanura; b; * | Newhouse, Stephena; b | Westman, Erica; d | Muehlboeck, J-Sebastiana; d | Mecocci, Patriziae | Vellas, Brunof | Tsolaki, Magdaf | Kłoszewska, Iwonah | Soininen, Hilkkai | Lovestone, Simonj | Dobson, Richarda; c; 1 | Simmons, Andrewa; c; 1 | for the AddNeuroMed consortium and for the Alzheimer's Disease Neuroimaging Initiative2

Affiliations: [a] King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom | [b] King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Biostatistics, London, United Kingdom | [c] NIHR Biomedical Research Unit Dementia, London, United Kingdom | [d] Departments of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden | [e] Institute of gerontology and Geriatrics, University of Perugia, Perugia, Italy | [f] INSERM U 558, University of Toulouse, Toulouse, France | [g] Aristotle University of Thessaloniki, Thessaloniki, Greece | [h] Medical University of Lodz, Lodz, Poland | [i] Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland | [j] Department of Psychiatry, University of Oxford, United Kingdom

Correspondence: [*] Correspondence to: Mizanur Khondoker, Department of Biostatistics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom. Tel.: +44 207 848 0305; Fax: +44 207 848 0281; E-mail: mizanur.khondoker@kcl.ac.uk.

Note: [1] Joint last authors.

Note: [2] The ADNI data used in preparation of this article were obtained from the Alzheimer’s disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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

DOI: 10.3233/JAD-142214

Journal: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 851-864, 2015

Accepted 5 January 2015
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Published: 24 March 2015
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Supplementary Materials:

Supplementary Material.

Supplementary Material.

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.

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