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, 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 & 32 others Esben Agerbo, Tracy M. Air, Till F.M. Andlauer, Silviu Alin Bacanu, Marie Bækvad-Hansen, Tim B. Bigdeli, Aartjan T.F. Beekman, 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, Rick Jansen, Christel M. Middeldorp, Yuri Milaneschi, Wouter J. Peyrot, Danielle Posthuma, Johannes H. Smit, E. J.C. de Geus, Brenda W.J.H. Penninx

Research output: Contribution to journalArticleAcademicpeer-review

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.

LanguageEnglish
Pages91-100
Number of pages10
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Volume4
Issue number1
DOIs
StatePublished - 1 Jan 2019

Cite this

@article{531df7bfeab64a3fa3fdebf64d00e53c,
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.",
keywords = "Biological pathway, Major depressive disorder, NETRIN1, Polygenic risk score, Thalamic radiations, White matter",
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 Adams, {Mark J.} and Esben Agerbo and Air, {Tracy M.} and Andlauer, {Till F.M.} and Bacanu, {Silviu Alin} and Marie B{\ae}kvad-Hansen and Bigdeli, {Tim B.} and Beekman, {Aartjan T.F.} 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 Clarke, {Toni Kim} 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 Deary, {Ian J.} and Franziska Degenhardt and Rick Jansen and Middeldorp, {Christel M.} and Yuri Milaneschi and Peyrot, {Wouter J.} and Danielle Posthuma and Smit, {Johannes H.} and {de Geus}, {E. J.C.} and Penninx, {Brenda W.J.H.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.bpsc.2018.07.006",
language = "English",
volume = "4",
pages = "91--100",
journal = "Biological Psychiatry: Cognitive Neuroscience and Neuroimaging",
issn = "2451-9022",
publisher = "Elsevier Inc.",
number = "1",

}

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, 01.01.2019, p. 91-100.

Research output: Contribution to journalArticleAcademicpeer-review

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 - Adams,Mark J.

AU - Agerbo,Esben

AU - Air,Tracy M.

AU - Andlauer,Till F.M.

AU - Bacanu,Silviu Alin

AU - Bækvad-Hansen,Marie

AU - Bigdeli,Tim B.

AU - Beekman,Aartjan T.F.

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 - Clarke,Toni Kim

AU - Coleman,Jonathan R.I.

AU - Colodro-Conde,Lucía

AU - Couvy-Duchesne,Baptiste

AU - Craddock,Nick

AU - Crawford,Gregory E.

AU - Davies,Gail

AU - Deary,Ian J.

AU - Degenhardt,Franziska

AU - Jansen,Rick

AU - Middeldorp,Christel M.

AU - Milaneschi,Yuri

AU - Peyrot,Wouter J.

AU - Posthuma,Danielle

AU - Smit,Johannes H.

AU - de Geus,E. J.C.

AU - Penninx,Brenda W.J.H.

PY - 2019/1/1

Y1 - 2019/1/1

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

VL - 4

SP - 91

EP - 100

JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

T2 - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

SN - 2451-9022

IS - 1

ER -