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Susceptibility of brain atrophy to TRIB3 in Alzheimer’s disease: evidence from functional prioritization in imaging-genetics

Lorenzi, M; Altmann, A; Gutman, B; Wray, S; Arber, C; Hibar, D; Jahanshad, N; ... Ourselin, S; + view all (2018) Susceptibility of brain atrophy to TRIB3 in Alzheimer’s disease: evidence from functional prioritization in imaging-genetics. Proceedings of the National Academy of Sciences of the United States of America , 115 (12) pp. 3162-3167. 10.1073/pnas.1706100115. Green open access

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Abstract

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.

Type: Article
Title: Susceptibility of brain atrophy to TRIB3 in Alzheimer’s disease: evidence from functional prioritization in imaging-genetics
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1706100115
Publisher version: https://doi.org/10.1073/pnas.1706100115
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng
URI: https://discovery.ucl.ac.uk/id/eprint/10042824
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