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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

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  • Miruna C. Barbu
  • Yanni Zeng
  • Xueyi Shen
  • Simon R. Cox
  • Toni Kim Clarke
  • Jude Gibson
  • Mark J. Adams
  • Mandy Johnstone
  • Chris S. Haley
  • Stephen M. Lawrie
  • Ian J. Deary
  • Naomi R. Wray
  • Stephan Ripke
  • Manuel Mattheisen
  • Maciej Trzaskowski
  • Enda M. Byrne
  • Abdel Abdellaoui
  • Mark J. Adams
  • Esben Agerbo
  • Tracy M. Air
  • Till F.M. Andlauer
  • Silviu Alin Bacanu
  • Marie Bækvad-Hansen
  • Aartjan T.F. Beekman
  • Tim B. Bigdeli
  • Elisabeth B. Binder
  • Douglas H.R. Blackwood
  • Julien Bryois
  • Henriette N. Buttenschøn
  • Jonas Bybjerg-Grauholm
  • Na Cai
  • Enrique Castelao
  • Jane Hvarregaard Christensen
  • Toni Kim Clarke
  • Jonathan R.I. Coleman
  • Lucía Colodro-Conde
  • Baptiste Couvy-Duchesne
  • Nick Craddock
  • Gregory E. Crawford
  • Gail Davies
  • Ian J. Deary
  • Franziska Degenhardt
  • Eske M. Derks
  • Nese Direk
  • Thomas F. Hansen
  • Jesper Krogh
  • Wesley Thompson
  • Shantel Marie Weinsheimer
  • Merete Nordentoft
  • Thomas Werge
  • Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
  • 23andMe Research Team
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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.

Original languageEnglish
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Issue number1
Pages (from-to)91-100
Publication statusPublished - 2019

    Research areas

  • Biological pathway, Major depressive disorder, NETRIN1, Polygenic risk score, Thalamic radiations, White matter

ID: 55294980