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

Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Jan;4(1):91-100. doi: 10.1016/j.bpsc.2018.07.006. Epub 2018 Jul 31.


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.

Keywords: Biological pathway; Major depressive disorder; NETRIN1; Polygenic risk score; Thalamic radiations; White matter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biological Specimen Banks
  • Brain / pathology*
  • Depressive Disorder, Major / genetics*
  • Depressive Disorder, Major / metabolism
  • Depressive Disorder, Major / pathology*
  • Diffusion Tensor Imaging
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Netrin-1 / genetics*
  • Polymorphism, Single Nucleotide
  • Signal Transduction
  • United Kingdom
  • White Matter / pathology*


  • NTN1 protein, human
  • Netrin-1