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

• Published in: Journal of Alzheimer's disease Vol. 45; no. 3; pp. 851 - 864
• Main Authors: Khondoker, Mizanur, Newhouse, Stephen, Westman, Eric, Muehlboeck, J-Sebastian, Mecocci, Patrizia, Vellas, Bruno, Tsolaki, Magda, Kłoszewska, Iwona, Soininen, Hilkka, Lovestone, Simon, Dobson, Richard, Simmons, Andrew
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.01.2015
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Brain - pathology; Carrier Proteins - genetics; Cell Adhesion Molecules - genetics; Cell Cycle Proteins - genetics; Cohort Studies; Female; Genetic Association Studies; Homer Scaffolding Proteins; Humans; Magnetic Resonance Imaging; Male; Nuclear Proteins - genetics; Polymorphism, Single Nucleotide - genetics; Protein-Tyrosine Kinases - genetics; Quantitative Trait Loci - genetics; Sex Factors; T-Box Domain Proteins - genetics; genome wide association study; magnetic resonance imaging; mild cognitive impairment; imaging quantitative trait loci; Alzheimer's disease
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-142214

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.