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

doi:10.1016/j.bpsc.2018.07.006

. 2019 Jan;4(1):91-100.

doi: 10.1016/j.bpsc.2018.07.006. Epub 2018 Jul 31.

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 Barbu¹, Yanni Zeng², Xueyi Shen³, Simon R Cox⁴, Toni-Kim Clarke³, Jude Gibson³, Mark J Adams³, Mandy Johnstone⁵, Chris S Haley², Stephen M Lawrie³, Ian J Deary⁴; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium⁶; 23andMe Research Team⁷; Andrew M McIntosh⁸, Heather C Whalley³

Collaborators, Affiliations

Collaborators

Naomi R Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M Byrne, Abdel Abdellaoui, Mark J Adams, Esben Agerbo, Tracy M Air, Till F M Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T F Beekman, Tim B Bigdeli, 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, Eske M Derks, Nese Direk, Conor V Dolan, Erin C Dunn, Thalia C Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K Finucane, Andreas J Forstner, Josef Frank, Héléna A Gaspar, Michael Gill, Fernando S Goes, Scott D Gordon, Jakob Grove, Lynsey S Hall, Christine Søholm Hansen, Thomas F Hansen, Stefan Herms, Ian B Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M Hougaard, Marcus Ising, Rick Jansen, Eric Jorgenson, James A Knowles, Isaac S Kohane, Julia Kraft, Warren W Kretzschmar, Jesper Krogh, Zoltán Kutalik, Yihan Li, Penelope A Lind, Donald J MacIntyre, Dean F MacKinnon, Robert M Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E Medland, Divya Mehta, Christel M Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M Mondimore, Grant W Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G Nivard, Dale R Nyholt, Paul F O'Reilly, Hogni Oskarsson, Michael J Owen, Jodie N Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E Peterson, Erik Pettersson, Wouter J Peyrot, Giorgio Pistis, Danielle Posthuma, Jorge A Quiroz, Per Qvist, John P Rice, Brien P Riley, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C Schulte, Ling Shen, Jianxin Shi, Stanley I Shyn, Engilbert Sigurdsson, Grant C B Sinnamon, Johannes H Smit, Daniel J Smith, Hreinn Stefansson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A Thomson, Thorgeir E Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M van Hemert, Alexander Viktorin, Peter M Visscher, Yunpeng Wang, Bradley T Webb, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H Witt, Yang Wu, Hualin S Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T Baune, Klaus Berger, Dorret I Boomsma, Sven Cichon, Udo Dannlowski, E J C de Geus, J Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J Grabe, Steven P Hamilton, Caroline Hayward, Andrew C Heath, Kenneth S Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S Li, Susanne Lucae, Pamela A F Madden, Patrik K Magnusson, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M Nöthen, Michael C O'Donovan, Sara A Paciga, Nancy L Pedersen, Brenda W J H Penninx, Roy H Perlis, David J Porteous, James B Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas 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, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, David A Hinds, Karen E Huber, Aaron Kleinman, Nadia K Litterman, Jennifer C McCreight, Matthew H McIntyre, Joanna L Mountain, Elizabeth S Noblin, Carrie A M Northover, Steven J Pitts, J Fah Sathirapongsasuti, Olga V Sazonova, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Vladimir Vacic, Catherine H Wilson

Affiliations

¹ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland. Electronic address: s1571976@sms.ed.ac.uk.
² Medical Research Council, Human Genetics Unit, University of Edinburgh, Edinburgh, Scotland.
³ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, Scotland.
⁵ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
⁶ Major Depression Disorder Working Group of the Psychiatric Genomics Consortium.
⁷ 23andMe, Inc., Mountain View, California.
⁸ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland; Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, Scotland.

PMID: 30197049
PMCID: PMC6374980
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 et al. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Jan.

. 2019 Jan;4(1):91-100.

doi: 10.1016/j.bpsc.2018.07.006. Epub 2018 Jul 31.

Authors

Collaborators

Naomi R Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M Byrne, Abdel Abdellaoui, Mark J Adams, Esben Agerbo, Tracy M Air, Till F M Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T F Beekman, Tim B Bigdeli, 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, Eske M Derks, Nese Direk, Conor V Dolan, Erin C Dunn, Thalia C Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K Finucane, Andreas J Forstner, Josef Frank, Héléna A Gaspar, Michael Gill, Fernando S Goes, Scott D Gordon, Jakob Grove, Lynsey S Hall, Christine Søholm Hansen, Thomas F Hansen, Stefan Herms, Ian B Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M Hougaard, Marcus Ising, Rick Jansen, Eric Jorgenson, James A Knowles, Isaac S Kohane, Julia Kraft, Warren W Kretzschmar, Jesper Krogh, Zoltán Kutalik, Yihan Li, Penelope A Lind, Donald J MacIntyre, Dean F MacKinnon, Robert M Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E Medland, Divya Mehta, Christel M Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M Mondimore, Grant W Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G Nivard, Dale R Nyholt, Paul F O'Reilly, Hogni Oskarsson, Michael J Owen, Jodie N Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E Peterson, Erik Pettersson, Wouter J Peyrot, Giorgio Pistis, Danielle Posthuma, Jorge A Quiroz, Per Qvist, John P Rice, Brien P Riley, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C Schulte, Ling Shen, Jianxin Shi, Stanley I Shyn, Engilbert Sigurdsson, Grant C B Sinnamon, Johannes H Smit, Daniel J Smith, Hreinn Stefansson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A Thomson, Thorgeir E Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M van Hemert, Alexander Viktorin, Peter M Visscher, Yunpeng Wang, Bradley T Webb, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H Witt, Yang Wu, Hualin S Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T Baune, Klaus Berger, Dorret I Boomsma, Sven Cichon, Udo Dannlowski, E J C de Geus, J Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J Grabe, Steven P Hamilton, Caroline Hayward, Andrew C Heath, Kenneth S Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S Li, Susanne Lucae, Pamela A F Madden, Patrik K Magnusson, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M Nöthen, Michael C O'Donovan, Sara A Paciga, Nancy L Pedersen, Brenda W J H Penninx, Roy H Perlis, David J Porteous, James B Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas 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, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, David A Hinds, Karen E Huber, Aaron Kleinman, Nadia K Litterman, Jennifer C McCreight, Matthew H McIntyre, Joanna L Mountain, Elizabeth S Noblin, Carrie A M Northover, Steven J Pitts, J Fah Sathirapongsasuti, Olga V Sazonova, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Vladimir Vacic, Catherine H Wilson

Affiliations

¹ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland. Electronic address: s1571976@sms.ed.ac.uk.
² Medical Research Council, Human Genetics Unit, University of Edinburgh, Edinburgh, Scotland.
³ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, Scotland.
⁵ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
⁶ Major Depression Disorder Working Group of the Psychiatric Genomics Consortium.
⁷ 23andMe, Inc., Mountain View, California.
⁸ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland; Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, Scotland.

PMID: 30197049
PMCID: PMC6374980
DOI: 10.1016/j.bpsc.2018.07.006

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.

Keywords: Biological pathway; Major depressive disorder; NETRIN1; Polygenic risk score; Thalamic radiations; White matter.

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Figures

**Figure 1**
The effects of (left panel) major depressive disorder polygenic risk score (PRS) derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and (right panel) major depressive disorder PRS derived from the whole genome, excluding NETRIN1 pathway genes (genomic-PRS), on fractional anisotropy (FA) values of white matter tracts. The x-axis indicates the standardized effect size of each pathway's PRSs, and the y-axis indicates the white matter tracts. The legend indicates the tract category belonging to each white matter tract. The error bar represents the SD of the mean.

**Figure 2**
The effects of (left panel) major depressive disorder polygenic risk score (PRS) derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and (right panel) major depressive disorder PRS derived from the whole genome, excluding NETRIN1 pathway genes (genomic-PRS), on fractional anisotropy (FA) values of tract categories and global FA (gFA). The x-axis indicates the standardized effect size of each pathway's PRS, and the y-axis indicates the tract categories. The error bar represents the SD of the mean.

**Figure 3**
The effects of (left panel) major depressive disorder polygenic risk score (PRS) derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and (right panel) major depressive disorder (PRS) derived from the whole genome, excluding NETRIN1 pathway genes (genomic-PRS), on mean diffusivity (MD) values of white matter tracts. The x-axis indicates the standardized effect size of each pathway's PRS, and the y-axis indicates the white matter tracts. The legend indicates the tract category belonging to each white matter tract. The error bar represents the SD of the mean.

**Figure 4**
The effects of (left panel) major depressive disorder PRS derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and (right panel) major depressive disorder PRS derived from the whole genome, excluding NETRIN1 pathway genes (genomic-PRS), on mean diffusivity (MD) values of tract categories and global MD (gMD). The x-axis indicates the standardized effect size of each pathway's PRS, and the y-axis indicates the tract categories. The error bar represents the SD of the mean.

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References

1. Otte C., Gold S.M., Penninx B.W., Pariante C.M., Etkin A., Fava M. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065. - PubMed
1. Bromet E., Andrade L.H., Hwang I., Sampson N.A., Alonso J., De Girolamo G. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90. - PMC - PubMed
1. Zeng Y., Navarro P., Xia C., Amador C., Fernandez-Pujals A.M., Thomson P.A. Shared genetics and couple-associated environment are major contributors to the risk of both clinical and self-declared depression. EBioMedicine. 2016;14:161–167. - PMC - PubMed
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[1] Otte C., Gold S.M., Penninx B.W., Pariante C.M., Etkin A., Fava M. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065. - PubMed

[2] Otte C., Gold S.M., Penninx B.W., Pariante C.M., Etkin A., Fava M. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065. - PubMed

[3] Bromet E., Andrade L.H., Hwang I., Sampson N.A., Alonso J., De Girolamo G. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90. - PMC - PubMed

[4] Bromet E., Andrade L.H., Hwang I., Sampson N.A., Alonso J., De Girolamo G. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90. - PMC - PubMed

[5] Zeng Y., Navarro P., Xia C., Amador C., Fernandez-Pujals A.M., Thomson P.A. Shared genetics and couple-associated environment are major contributors to the risk of both clinical and self-declared depression. EBioMedicine. 2016;14:161–167. - PMC - PubMed

[6] Zeng Y., Navarro P., Xia C., Amador C., Fernandez-Pujals A.M., Thomson P.A. Shared genetics and couple-associated environment are major contributors to the risk of both clinical and self-declared depression. EBioMedicine. 2016;14:161–167. - PMC - PubMed

[7] Sullivan P.F. Genetic epidemiology of major depression: Review and meta-analysis. Am J Psychiatry. 2000;157:1552–1562. - PubMed

[8] Sullivan P.F. Genetic epidemiology of major depression: Review and meta-analysis. Am J Psychiatry. 2000;157:1552–1562. - PubMed

[9] Belmaker R.H., Agam G. Major depressive disorder. N Engl J Med. 2008;358:55–68. - PubMed

[10] Belmaker R.H., Agam G. Major depressive disorder. N Engl J Med. 2008;358:55–68. - PubMed

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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

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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

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