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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

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Mizanur Khondoker ; Stephen Newhouse ; Eric Westman ; J-Sebastian Muehlboeck ; Patrizia Mecocci ; Bruno Vellas ; Magda Tsolaki ; Iwona Kłoszewska ; Hilkka Soininen ; Simon Lovestone ; Richard Dobson ; Andrew Simmons

Original languageEnglish
Pages (from-to)851-864
Number of pages14
JournalJournal of Alzheimer's disease : JAD
Volume45
Issue number3
Early online date3 Feb 2015
DOIs
StatePublished - 2015

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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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