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Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank

Barbu, MC; Zeng, Y; Shen, X; Cox, SR; Clarke, TK; Gibson, J; Adams, MJ; ... Nivard, MG; + view all (2019) Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging , 4 (1) pp. 91-100. 10.1016/j.bpsc.2018.07.006. Green open access

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Abstract

BACKGROUND: Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure. METHODS: We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390). RESULTS: We found significantly lower FA in the superior longitudinal fasciculus (β = −.035, pcorrected=.029) and significantly higher MD in a global measure of thalamic radiations (β =.029, pcorrected=.021), as well as higher MD in the superior (β =.034, pcorrected=.039) and inferior (β =.029, pcorrected=.043) longitudinal fasciculus and in the anterior (β =.025, pcorrected=.046) and superior (β =.027, pcorrected=.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. CONCLUSIONS: Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.

Type: Article
Title: Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bpsc.2018.07.006
Publisher version: http://dx.doi.org/10.1016/j.bpsc.2018.07.006
Language: English
Additional information: @ 2018 Society of Biological Psychiatry. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Biological pathway, Major depressive disorder, NETRIN1, Polygenic risk score, Thalamic radiations, White matter
UCL classification: UCL
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 > Division of Psychiatry
URI: https://discovery.ucl.ac.uk/id/eprint/10057115
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