| 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 |
| Journal: | Biological Psychiatry Cognitive Neuroscience and Neuroimaging |
| Published: | 31 Jul 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/30197049/ |
| DOI: | https://doi.org/10.1016/j.bpsc.2018.07.006 |
Publication 4244
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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.</p>
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).</p>
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.</p>
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.</p>
17 Keywords
- Aged
- Biological Specimen Banks
- Brain
- Depressive Disorder, Major
- Diffusion Tensor Imaging
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Multifactorial Inheritance
- Netrin-1
- Polymorphism, Single Nucleotide
- Signal Transduction
- United Kingdom
- White Matter
238 Authors
- 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
- Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
- 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
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- Thorgeir E. Thorgeirsson
- Matthew Traylor
- Jens Treutlein
- Vassily Trubetskoy
- André G. Uitterlinden
- Daniel Umbricht
- Sandra Van der Auwera
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- 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
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- 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
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- 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
- 23andMe Research Team
- Michelle Agee
- Babak Alipanahi
- Adam Auton
- Robert K. Bell
- Katarzyna Bryc
- Sarah L. Elson
- Pierre Fontanillas
- Nicholas A. Furlotte
- David A. Hinds
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- Aaron Kleinman
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- Steven J. Pitts
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- Olga V. Sazonova
- Janie F. Shelton
- Suyash Shringarpure
- Chao Tian
- Joyce Y. Tung
- Vladimir Vacic
- Catherine H. Wilson
- Andrew M. McIntosh
- Heather C. Whalley
Enabling scientific discoveries that improve human health