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

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; 23andMe Research Team

doi:10.1016/j.bpsc.2018.07.006

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

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team

Vagelos College of Physicians and Surgeons

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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, p_corrected =.029) and significantly higher MD in a global measure of thalamic radiations (β =.029, p_corrected =.021), as well as higher MD in the superior (β =.034, p_corrected =.039) and inferior (β =.029, p_corrected =.043) longitudinal fasciculus and in the anterior (β =.025, p_corrected =.046) and superior (β =.027, p_corrected =.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
Pages (from-to)	91-100
Number of pages	10
Journal	Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Volume	4
Issue number	1
DOIs	https://doi.org/10.1016/j.bpsc.2018.07.006
Publication status	Published - Jan 2019

Bibliographical note

Publisher Copyright:
© 2018 Society of Biological Psychiatry

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
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

ASJC Scopus Subject Areas

Radiology Nuclear Medicine and imaging
Cognitive Neuroscience
Clinical Neurology
Biological Psychiatry

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10.1016/j.bpsc.2018.07.006

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Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, & 23andMe Research Team (2019). Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 4(1), 91-100. https://doi.org/10.1016/j.bpsc.2018.07.006

Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank. / Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; 23andMe Research Team.
In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Vol. 4, No. 1, 01.2019, p. 91-100.

Research output: Contribution to journal › Article › peer-review

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium & 23andMe Research Team 2019, 'Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank', Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, vol. 4, no. 1, pp. 91-100. https://doi.org/10.1016/j.bpsc.2018.07.006

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team. Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2019 Jan;4(1):91-100. doi: 10.1016/j.bpsc.2018.07.006

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium ; 23andMe Research Team. / Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank. In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2019 ; Vol. 4, No. 1. pp. 91-100.

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

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.",

author = "{Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and {23andMe Research Team} and Barbu, {Miruna C.} and Yanni Zeng and Xueyi Shen and Cox, {Simon R.} and Clarke, {Toni Kim} and Jude Gibson and Adams, {Mark J.} and Mandy Johnstone and Haley, {Chris S.} and Lawrie, {Stephen M.} and Deary, {Ian J.} and Wray, {Naomi R.} and Stephan Ripke and Manuel Mattheisen and Maciej Trzaskowski and Byrne, {Enda M.} and Abdel Abdellaoui and Esben Agerbo and Air, {Tracy M.} and Andlauer, {Till F.M.} and Bacanu, {Silviu Alin} and Marie B{\ae}kvad-Hansen and Beekman, {Aartjan T.F.} and Bigdeli, {Tim B.} and Binder, {Elisabeth B.} and Blackwood, {Douglas H.R.} and Julien Bryois and Buttensch{\o}n, {Henriette N.} and Jonas Bybjerg-Grauholm and Na Cai and Enrique Castelao and Christensen, {Jane Hvarregaard} and Coleman, {Jonathan R.I.} and Luc{\'i}a Colodro-Conde and Baptiste Couvy-Duchesne and Nick Craddock and Crawford, {Gregory E.} and Gail Davies and Franziska Degenhardt and Derks, {Eske M.} and Nese Direk and Dolan, {Conor V.} and Dunn, {Erin C.} and Eley, {Thalia C.} and Valentina Escott-Price and {Hassan Kiadeh}, {Farnush Farhadi} and Finucane, {Hilary K.} and Forstner, {Andreas J.} and Josef Frank and Weissman, {Myrna M.}",

note = "Publisher Copyright: {\textcopyright} 2018 Society of Biological Psychiatry",

year = "2019",

month = jan,

doi = "10.1016/j.bpsc.2018.07.006",

language = "English",

volume = "4",

pages = "91--100",

journal = "Biological Psychiatry: Cognitive Neuroscience and Neuroimaging",

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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 - Forstner, Andreas J.

AU - Frank, Josef

AU - Weissman, Myrna M.

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.

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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

Abstract

Bibliographical note

Funding

ASJC Scopus Subject Areas

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