TY - JOUR
T1 - Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank
AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
AU - 23andMe Research Team
AU - Barbu, Miruna C.
AU - Zeng, Yanni
AU - Shen, Xueyi
AU - Cox, Simon R.
AU - Clarke, Toni Kim
AU - Gibson, Jude
AU - Adams, Mark J.
AU - Johnstone, Mandy
AU - Haley, Chris S.
AU - Lawrie, Stephen M.
AU - Deary, Ian J.
AU - Wray, Naomi R.
AU - Ripke, Stephan
AU - Mattheisen, Manuel
AU - Trzaskowski, Maciej
AU - Byrne, Enda M.
AU - Abdellaoui, Abdel
AU - Agerbo, Esben
AU - Air, Tracy M.
AU - Andlauer, Till F.M.
AU - Bacanu, Silviu Alin
AU - Bækvad-Hansen, Marie
AU - Beekman, Aartjan T.F.
AU - Bigdeli, Tim B.
AU - Binder, Elisabeth B.
AU - Blackwood, Douglas H.R.
AU - Bryois, Julien
AU - Buttenschøn, Henriette N.
AU - Bybjerg-Grauholm, Jonas
AU - Cai, Na
AU - Castelao, Enrique
AU - Christensen, Jane Hvarregaard
AU - Coleman, Jonathan R.I.
AU - Colodro-Conde, Lucía
AU - Couvy-Duchesne, Baptiste
AU - Craddock, Nick
AU - Crawford, Gregory E.
AU - Davies, Gail
AU - Degenhardt, Franziska
AU - Derks, Eske M.
AU - Direk, Nese
AU - Dolan, Conor V.
AU - Dunn, Erin C.
AU - Eley, Thalia C.
AU - Escott-Price, Valentina
AU - Hassan Kiadeh, Farnush Farhadi
AU - Finucane, Hilary K.
AU - Rice, John P.
AU - Heath, Andrew C.
AU - Madden, Pamela A.F.
N1 - Funding Information:
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.
Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2018 Society of Biological Psychiatry
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - Biological pathway
KW - Major depressive disorder
KW - NETRIN1
KW - Polygenic risk score
KW - Thalamic radiations
KW - White matter
UR - http://www.scopus.com/inward/record.url?scp=85052912914&partnerID=8YFLogxK
U2 - 10.1016/j.bpsc.2018.07.006
DO - 10.1016/j.bpsc.2018.07.006
M3 - Article
C2 - 30197049
AN - SCOPUS:85052912914
SN - 2451-9022
VL - 4
SP - 91
EP - 100
JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
IS - 1
ER -