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

Mizanur Khondoker, Stephen Newhouse, Eric Westman, J-Sebastian Muehlboeck, Patrizia Mecocci, Bruno Vellas, Magda Tsolaki, Iwona Kloszewska, Hilkka Soininen, Simon Lovestone, Richard Dobson, Andrew Simmons, AddNeuroMed Consortium, Alzheimer's Disease Neuroimaging Initiative

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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 = 8.7x10(-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.

Original languageEnglish
Pages (from-to)851-864
Number of pages14
JournalJournal of Alzheimer's Disease
Volume45
Issue number3
DOIs
Publication statusPublished - 2015

Keywords

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

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