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

J Alzheimers Dis. 2015;45(3):851-64. 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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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


  • Carrier Proteins
  • Cell Adhesion Molecules
  • Cell Cycle Proteins
  • EOMES protein, human
  • Homer Scaffolding Proteins
  • JAM2 protein, human
  • Nuclear Proteins
  • T-Box Domain Proteins
  • Protein-Tyrosine Kinases
  • WEE1 protein, human