Susceptibility of brain atrophy to TRIB3 in Alzheimer's disease, evidence from functional prioritization in imaging genetics

Marco Lorenzi, Andre Altmann, Boris Gutman, Selina Wray, Charles Arber, Derrek P. Hibar, Neda Jahanshad, Jonathan M. Schott, Daniel C. Alexander, Paul M. Thompson, Sebastien Ourselin

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


The joint modeling of brain imaging information and genetic data is a promising research avenue to highlight the functional role of genes in determining the pathophysiological mechanisms of Alzheimer's disease (AD). However, since genome-wide association (GWA) studies are essentially limited to the exploration of statistical correlations between genetic variants and phenotype, the validation and interpretation of the findings are usually nontrivial and prone to false positives. To address this issue, in this work, we investigate the functional genetic mechanisms underlying brain atrophy in AD by studying the involvement of candidate variants in known genetic regulatory functions. This approach, here termed functional prioritization, aims at testing the sets of gene variants identified by high-dimensional multivariate statistical modeling with respect to known biological processes to introduce a biology-driven validation scheme. When applied to the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, the functional prioritization allowed for identifying a link between tribbles pseudokinase 3 (TRIB3) and the stereotypical pattern of gray matter loss in AD, which was confirmed in an independent validation sample, and that provides evidence about the relation between this gene and known mechanisms of neurodegeneration.

Original languageEnglish
Pages (from-to)3162-3167
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - 20 Mar 2018
Externally publishedYes


  • Alzheimer's disease
  • Brain atrophy
  • Imaging-genetics
  • Neuroimaging
  • TRIB3


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