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BackgroundMajor 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.MethodsWe 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).ResultsWe 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.ConclusionsOur 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.

Original publication




Journal article


Biological psychiatry. Cognitive neuroscience and neuroimaging

Publication Date





91 - 100


Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland. Electronic address:


Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team, Brain, Humans, Genetic Predisposition to Disease, Depressive Disorder, Major, Signal Transduction, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Aged, Middle Aged, Biological Specimen Banks, Female, Male, Genome-Wide Association Study, Diffusion Tensor Imaging, White Matter, United Kingdom, Netrin-1