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; Andrew M McIntosh; Heather C Whalley; A. Abdellaoui; C.V. Dolan; J.J. Hottenga; H. Mbarek; C.M. Middeldorp; M.G. Nivard; Danielle Posthuma; Gonneke Willemsen; D.I. Boomsma; Eco JC de Geus; Brenda W J H Penninx; Rick Jansen; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

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

Miruna C Barbu, Andrew M McIntosh, Heather C Whalley, A. Abdellaoui, C.V. Dolan, J.J. Hottenga, H. Mbarek, C.M. Middeldorp, M.G. Nivard, Danielle Posthuma, Gonneke Willemsen, D.I. Boomsma, Eco JC de Geus, Brenda W J H Penninx, Rick Jansen, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to Journal › Article › Academic › peer-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 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

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

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bpsc.2018.07.006

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374980

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Barbu, M. C., McIntosh, A. M., Whalley, H. C., Abdellaoui, A., Dolan, C. V., Hottenga, J. J., Mbarek, H., Middeldorp, C. M., Nivard, M. G., Posthuma, D., Willemsen, G., Boomsma, D. I., de Geus, E. JC., W J H Penninx, B., Jansen, R., & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (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

@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 = "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 and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium}",

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",

issn = "2451-9022",

publisher = "Elsevier Inc.",

number = "1",

}

Barbu, MC, McIntosh, AM, Whalley, HC, Abdellaoui, A, Dolan, CV , Hottenga, JJ, Mbarek, H, Middeldorp, CM, Nivard, MG , Posthuma, D, Willemsen, G, Boomsma, DI , de Geus, EJC, W J H Penninx, B, Jansen, R & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium 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; McIntosh, Andrew M; Whalley, Heather C et al.
In: Biological Psychiatry : Cognitive Neuroscience and Neuroimaging, Vol. 4, No. 1, 01.2019, p. 91-100.

Research output: Contribution to Journal › Article › Academic › peer-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 - 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

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

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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U2 - 10.1016/j.bpsc.2018.07.006

DO - 10.1016/j.bpsc.2018.07.006

M3 - Article

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SN - 2451-9022

VL - 4

SP - 91

EP - 100

JO - Biological Psychiatry : Cognitive Neuroscience and Neuroimaging

JF - Biological Psychiatry : Cognitive Neuroscience and Neuroimaging

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ER -

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

Funding

Cohort Studies

UN SDGs

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