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, 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, Andrew M McIntosh, Heather C Whalley, A. Abdellaoui, C.V. Dolan, J.J. Hottenga, H. Mbarek, C.M. Middeldorp, M.G. Nivard & 6 others Danielle Posthuma, Gonneke Willemsen, D.I. Boomsma, Eco JC de Geus, Brenda W J H Penninx, Rick Jansen

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
Publication statusPublished - Jan 2019

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Major Depressive Disorder
Anisotropy
Genome
Beta Particles
Diffusion Tensor Imaging
Genome-Wide Association Study
Neuroimaging
Psychiatry
White Matter
Radiation
Genes

Cite this

@article{032fab7b173a4f1c8fbb12609038998f,
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 Barbu, {Miruna C} and Yanni Zeng and Xueyi Shen and Cox, {Simon R} and Toni-Kim Clarke and Jude Gibson and Adams, {Mark J} and Mandy Johnstone and Haley, {Chris S} and Lawrie, {Stephen M} and Deary, {Ian J} and McIntosh, {Andrew M} and Whalley, {Heather C} and A. Abdellaoui and C.V. Dolan and J.J. Hottenga and H. Mbarek and C.M. Middeldorp and M.G. Nivard and Danielle Posthuma and Gonneke Willemsen and D.I. Boomsma and {de Geus}, {Eco JC} and {W J H Penninx}, Brenda and Rick Jansen",
note = "Copyright {\circledC} 2018 Society of Biological Psychiatry. All rights reserved.",
year = "2019",
month = "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",
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; Abdellaoui, A.; Dolan, C.V.; Hottenga, J.J.; Mbarek, H.; Middeldorp, C.M.; Nivard, M.G.; Posthuma, Danielle; Willemsen, Gonneke; Boomsma, D.I.; de Geus, Eco JC; W J H Penninx, Brenda; Jansen, Rick.

In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Vol. 4, No. 1, 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 - 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 - McIntosh, Andrew M

AU - Whalley, Heather C

AU - Abdellaoui, A.

AU - Dolan, C.V.

AU - Hottenga, J.J.

AU - Mbarek, H.

AU - Middeldorp, C.M.

AU - Nivard, M.G.

AU - Posthuma, Danielle

AU - Willemsen, Gonneke

AU - Boomsma, D.I.

AU - de Geus, Eco JC

AU - W J H Penninx, Brenda

AU - Jansen, Rick

N1 - Copyright © 2018 Society of Biological Psychiatry. All rights reserved.

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.

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 -