Association of whole-genome and NETRIN1 signaling pathway–derived polygenic risk scores for Major Depressive Disorder and white matter microstructure in the UK Biobank

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 & 51 others 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, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research team, Roy H. Perlis, David J. Porteous, James B. Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, T.G. Schulze, Jordan W. Smoller, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M. Weissman, Thomas Werge, Cathryn M. Lewis, Douglas F. Levinson, Gerome Breen, Anders D. Børglum, Patrick F. Sullivan

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.

Original languageEnglish
Pages (from-to)91-100
Number of pages10
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Volume4
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

Barbu, Miruna C. ; Zeng, Yanni ; Shen, Xueyi ; Cox, Simon R. ; Clarke, Toni Kim ; Gibson, Jude ; Adams, Mark J. ; Johnstone, Mandy ; Haley, Chris S. ; Lawrie, Stephen M. ; Deary, Ian J. ; Wray, Naomi R. ; Ripke, Stephan ; Mattheisen, Manuel ; Trzaskowski, Maciej ; Byrne, Enda M. ; Abdellaoui, Abdel ; Adams, Mark J. ; Agerbo, Esben ; Air, Tracy M. ; Andlauer, Till F.M. ; Bacanu, Silviu Alin ; Bækvad-Hansen, Marie ; Bigdeli, Tim B. ; Beekman, Aartjan T.F. ; Binder, Elisabeth B. ; Blackwood, Douglas H.R. ; Bryois, Julien ; Buttenschøn, Henriette N. ; Bybjerg-Grauholm, Jonas ; Cai, Na ; Castelao, Enrique ; Christensen, Jane Hvarregaard ; Clarke, Toni Kim ; Coleman, Jonathan R.I. ; Colodro-Conde, Lucía ; Couvy-Duchesne, Baptiste ; Craddock, Nick ; Crawford, Gregory E. ; Davies, Gail ; Deary, Ian J. ; Degenhardt, Franziska ; Jansen, Rick ; Middeldorp, Christel M. ; Milaneschi, Yuri ; Peyrot, Wouter J. ; Posthuma, Danielle ; Smit, Johannes H. ; de Geus, E. J.C. ; Penninx, Brenda W.J.H. ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium ; 23andMe Research team ; Perlis, Roy H. ; Porteous, David J. ; Potash, James B. ; Preisig, Martin ; Rietschel, Marcella ; Schaefer, Catherine ; Schulze, T.G. ; Smoller, Jordan W. ; Stefansson, Kari ; Tiemeier, Henning ; Uher, Rudolf ; Völzke, Henry ; Weissman, Myrna M. ; Werge, Thomas ; Lewis, Cathryn M. ; Levinson, Douglas F. ; Breen, Gerome ; Børglum, Anders D. ; Sullivan, Patrick F. / 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.",
keywords = "Biological pathway, Major depressive disorder, NETRIN1, Polygenic risk score, Thalamic radiations, White matter",
author = "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.} and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and {23andMe Research team} and Perlis, {Roy H.} and Porteous, {David J.} and Potash, {James B.} and Martin Preisig and Marcella Rietschel and Catherine Schaefer and T.G. Schulze and Smoller, {Jordan W.} and Kari Stefansson and Henning Tiemeier and Rudolf Uher and Henry V{\"o}lzke and Weissman, {Myrna M.} and Thomas Werge and Lewis, {Cathryn M.} and Levinson, {Douglas F.} and Gerome Breen and B{\o}rglum, {Anders D.} and Sullivan, {Patrick F.}",
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",

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Barbu, MC, Zeng, Y, Shen, X, Cox, SR, Clarke, TK, Gibson, J, Adams, MJ, Johnstone, M, Haley, CS, Lawrie, SM, Deary, IJ, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, SA, Bækvad-Hansen, M, Bigdeli, TB, Beekman, ATF, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, TK, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Jansen, R, Middeldorp, CM, Milaneschi, Y, Peyrot, WJ, Posthuma, D, Smit, JH, de Geus, EJC, Penninx, BWJH, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research team, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Völzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Børglum, AD & Sullivan, PF 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

Association of whole-genome and NETRIN1 signaling pathway–derived polygenic risk scores for Major Depressive Disorder and white matter microstructure in the UK Biobank. / Barbu, Miruna C.; Zeng, Yanni; Shen, Xueyi; Cox, Simon R.; Clarke, Toni Kim; Gibson, Jude; Adams, Mark J.; Johnstone, Mandy; Haley, Chris S.; Lawrie, Stephen M.; Deary, Ian J.; Wray, Naomi R.; Ripke, Stephan; Mattheisen, Manuel; Trzaskowski, Maciej; Byrne, Enda M.; Abdellaoui, Abdel; Adams, Mark J.; Agerbo, Esben; Air, Tracy M.; Andlauer, Till F.M.; Bacanu, Silviu Alin; Bækvad-Hansen, Marie; Bigdeli, Tim B.; Beekman, Aartjan T.F.; Binder, Elisabeth B.; Blackwood, Douglas H.R.; Bryois, Julien; Buttenschøn, Henriette N.; Bybjerg-Grauholm, Jonas; Cai, Na; Castelao, Enrique; Christensen, Jane Hvarregaard; Clarke, Toni Kim; Coleman, Jonathan R.I.; Colodro-Conde, Lucía; Couvy-Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E.; Davies, Gail; Deary, Ian J.; Degenhardt, Franziska; Jansen, Rick; Middeldorp, Christel M.; Milaneschi, Yuri; Peyrot, Wouter J.; Posthuma, Danielle; Smit, Johannes H.; de Geus, E. J.C.; Penninx, Brenda W.J.H.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; 23andMe Research team; Perlis, Roy H.; Porteous, David J.; Potash, James B.; Preisig, Martin; Rietschel, Marcella; Schaefer, Catherine; Schulze, T.G.; Smoller, Jordan W.; Stefansson, Kari; Tiemeier, Henning; Uher, Rudolf; Völzke, Henry; Weissman, Myrna M.; Werge, Thomas; Lewis, Cathryn M.; Levinson, Douglas F.; Breen, Gerome; Børglum, Anders D.; Sullivan, Patrick F.

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 - 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.

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - 23andMe Research team

AU - Perlis, Roy H.

AU - Porteous, David J.

AU - Potash, James B.

AU - Preisig, Martin

AU - Rietschel, Marcella

AU - Schaefer, Catherine

AU - Schulze, T.G.

AU - Smoller, Jordan W.

AU - Stefansson, Kari

AU - Tiemeier, Henning

AU - Uher, Rudolf

AU - Völzke, Henry

AU - Weissman, Myrna M.

AU - Werge, Thomas

AU - Lewis, Cathryn M.

AU - Levinson, Douglas F.

AU - Breen, Gerome

AU - Børglum, Anders D.

AU - Sullivan, Patrick F.

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

JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

SN - 2451-9022

IS - 1

ER -