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

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 - 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 - Beekman, Aartjan T.f.

AU - Bigdeli, Tim B.

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 - Derks, Eske M.

AU - Direk, Nese

AU - Dolan, Conor V.

AU - Dunn, Erin C.

AU - Eley, Thalia C.

AU - Escott-price, Valentina

AU - Hassan Kiadeh, Farnush Farhadi

AU - Finucane, Hilary K.

AU - Forstner, Andreas J.

AU - Frank, Josef

AU - Gaspar, Héléna A.

AU - Gill, Michael

AU - Goes, Fernando S.

AU - Gordon, Scott D.

AU - Grove, Jakob

AU - Hall, Lynsey S.

AU - Hansen, Christine Søholm

AU - Hansen, Thomas F.

AU - Herms, Stefan

AU - Hickie, Ian B.

AU - Hoffmann, Per

AU - Homuth, Georg

AU - Horn, Carsten

AU - Hottenga, Jouke-jan

AU - Hougaard, David M.

AU - Ising, Marcus

AU - Jansen, Rick

AU - Jorgenson, Eric

AU - Knowles, James A.

AU - Kohane, Isaac S.

AU - Kraft, Julia

AU - Kretzschmar, Warren W.

AU - Krogh, Jesper

AU - Kutalik, Zoltán

AU - Li, Yihan

AU - Lind, Penelope A.

AU - Macintyre, Donald J.

AU - Mackinnon, Dean F.

AU - Maier, Robert M.

AU - Maier, Wolfgang

AU - Marchini, Jonathan

AU - Mbarek, Hamdi

AU - Mcgrath, Patrick

AU - Mcguffin, Peter

AU - Medland, Sarah E.

AU - Mehta, Divya

AU - Middeldorp, Christel M.

AU - Mihailov, Evelin

AU - Milaneschi, Yuri

AU - Milani, Lili

AU - Mondimore, Francis M.

AU - Montgomery, Grant W.

AU - Mostafavi, Sara

AU - Mullins, Niamh

AU - Nauck, Matthias

AU - Ng, Bernard

AU - Nivard, Michel G.

AU - Nyholt, Dale R.

AU - O'reilly, Paul F.

AU - Oskarsson, Hogni

AU - Owen, Michael J.

AU - Painter, Jodie N.

AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - Peterson, Roseann E.

AU - Pettersson, Erik

AU - Peyrot, Wouter J.

AU - Pistis, Giorgio

AU - Posthuma, Danielle

AU - Quiroz, Jorge A.

AU - Qvist, Per

AU - Rice, John P.

AU - Riley, Brien P.

AU - Rivera, Margarita

AU - Mirza, Saira Saeed

AU - Schoevers, Robert

AU - Schulte, Eva C.

AU - Shen, Ling

AU - Shi, Jianxin

AU - Shyn, Stanley I.

AU - Sigurdsson, Engilbert

AU - Sinnamon, Grant C.b.

AU - Smit, Johannes H.

AU - Smith, Daniel J.

AU - Stefansson, Hreinn

AU - Steinberg, Stacy

AU - Streit, Fabian

AU - Strohmaier, Jana

AU - Tansey, Katherine E.

AU - Teismann, Henning

AU - Teumer, Alexander

AU - Thompson, Wesley

AU - Thomson, Pippa A.

AU - Thorgeirsson, Thorgeir E.

AU - Traylor, Matthew

AU - Treutlein, Jens

AU - Trubetskoy, Vassily

AU - Uitterlinden, André G.

AU - Umbricht, Daniel

AU - Van Der Auwera, Sandra

AU - Van Hemert, Albert M.

AU - Viktorin, Alexander

AU - Visscher, Peter M.

AU - Wang, Yunpeng

AU - Webb, Bradley T.

AU - Weinsheimer, Shantel Marie

AU - Wellmann, Jürgen

AU - Willemsen, Gonneke

AU - Witt, Stephanie H.

AU - Wu, Yang

AU - Xi, Hualin S.

AU - Yang, Jian

AU - Zhang, Futao

AU - Arolt, Volker

AU - Baune, Bernhard T.

AU - Berger, Klaus

AU - Boomsma, Dorret I.

AU - Cichon, Sven

AU - Dannlowski, Udo

AU - De Geus, E.j.c.

AU - Depaulo, J. Raymond

AU - Domenici, Enrico

AU - Domschke, Katharina

AU - Esko, Tõnu

AU - Grabe, Hans J.

AU - Hamilton, Steven P.

AU - Hayward, Caroline

AU - Heath, Andrew C.

AU - Kendler, Kenneth S.

AU - Kloiber, Stefan

AU - Lewis, Glyn

AU - Li, Qingqin S.

AU - Lucae, Susanne

AU - Madden, Pamela A.f.

AU - Magnusson, Patrik K.

AU - Martin, Nicholas G.

AU - Mcintosh, Andrew M.

AU - Metspalu, Andres

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Müller-myhsok, Bertram

AU - Nordentoft, Merete

AU - Nöthen, Markus M.

AU - O'donovan, Michael C.

AU - Paciga, Sara A.

AU - Pedersen, Nancy L.

AU - Penninx, Brenda W.j.h.

AU - Perlis, Roy H.

AU - Porteous, David J.

AU - Potash, James B.

AU - Preisig, Martin

AU - Rietschel, Marcella

AU - Schaefer, Catherine

AU - Schulze, Thomas 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.

AU - Agee, Michelle

AU - Alipanahi, Babak

AU - Auton, Adam

AU - Bell, Robert K.

AU - Bryc, Katarzyna

AU - Elson, Sarah L.

AU - Fontanillas, Pierre

AU - Furlotte, Nicholas A.

AU - Hinds, David A.

AU - Huber, Karen E.

AU - Kleinman, Aaron

AU - Litterman, Nadia K.

AU - Mccreight, Jennifer C.

AU - Mcintyre, Matthew H.

AU - Mountain, Joanna L.

AU - Noblin, Elizabeth S.

AU - Northover, Carrie A.m.

AU - Pitts, Steven J.

AU - Sathirapongsasuti, J. Fah

AU - Sazonova, Olga V.

AU - Shelton, Janie F.

AU - Shringarpure, Suyash

AU - Tian, Chao

AU - Tung, Joyce Y.

AU - Vacic, Vladimir

AU - Wilson, Catherine H.

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 - Journal article

C2 - 30197049

SN - 2451-9022

VL - 4

SP - 91

EP - 100

JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

IS - 1

ER -