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.
Original language | English |
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Pages (from-to) | 91-100 |
Number of pages | 10 |
Journal | Biological Psychiatry : Cognitive Neuroscience and Neuroimaging |
Volume | 4 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jan 2019 |
Funding
This study was supported by a Wellcome Trust Strategic Award “ Stratifying Resilience and Depression Longitudinally ” (STRADL) (Grant No. 104036/Z/14/Z ) and by the Sackler Foundation. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6 ) and the Scottish Funding Council (Grant No. HR03006 ). Genotyping of the Generation Scotland: Scottish Family Health Study samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, UK, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award STRADL [Grant No. 104036/Z/14/Z]). HCW is supported by a John, Margaret, Alfred and Stewart Sim fellowship from the Royal College of Physicians of Edinburgh and by an Edinburgh Scientific Academic Track College Fellowship from the University of Edinburgh. SRC is supported by a Medical Research Council grant (Grant No. MR/M013111/1). MJ is supported by a Wellcome Trust Clinical Fellowship (Grant No. WT/100135/Z/12/Z ). Part of the work was undertaken in the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and MRC is gratefully acknowledged. Age UK (The Disconnected Mind project) also provided support for the work undertaken at CCACE. This study was supported by a Wellcome Trust Strategic Award ?Stratifying Resilience and Depression Longitudinally? (STRADL) (Grant No. 104036/Z/14/Z) and by the Sackler Foundation. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6) and the Scottish Funding Council (Grant No. HR03006). Genotyping of the Generation Scotland: Scottish Family Health Study samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, UK, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award STRADL [Grant No. 104036/Z/14/Z]). HCW is supported by a John, Margaret, Alfred and Stewart Sim fellowship from the Royal College of Physicians of Edinburgh and by an Edinburgh Scientific Academic Track College Fellowship from the University of Edinburgh. SRC is supported by a Medical Research Council grant (Grant No. MR/M013111/1). MJ is supported by a Wellcome Trust Clinical Fellowship (Grant No. WT/100135/Z/12/Z). Part of the work was undertaken in the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and MRC is gratefully acknowledged. Age UK (The Disconnected Mind project) also provided support for the work undertaken at CCACE. AMM has previously received grant support from Pfizer, Lilly, and Janssen. These studies are not connected to the current investigation. In the previous three years, SML has received grant and personal fees from Janssen and personal fees from Otsuka and Sunovion, outside the submitted work. Members of the 23andMe Research Team are employees of 23andMe, Inc. All other authors report no biomedical financial interests or potential conflicts of interest.
Funders | Funder number |
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CCACE | |
University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology | |
cross council Lifelong Health and Wellbeing Initiative | |
National Institute of Mental Health | U01MH109536 |
Eli Lilly and Company | |
Pfizer | |
Janssen Biotech | |
Wellcome Trust | 104036/Z/14/Z |
Royal College of Physicians of Edinburgh | |
Raymond and Beverly Sackler Foundation | |
Chief Scientist Office, Scottish Government Health and Social Care Directorate | CZD/16/6 |
Medical Research Council | MR/K026992/1 |
Biotechnology and Biological Sciences Research Council | |
Scottish Funding Council | HR03006 |
University of Edinburgh | MR/M013111/1, WT/100135/Z/12/Z |
Cohort Studies
- Netherlands Twin Register (NTR)