Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
30197049
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 NlmCategory: 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 NlmCategory: METHODS
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. 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 NlmCategory: RESULTS
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. 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). We found significantly lower FA in the superior longitudinal fasciculus (β = -.035, p  = .029) and significantly higher MD in a global measure of thalamic radiations (β = .029, p  = .021), as well as higher MD in the superior (β = .034, p  = .039) and inferior (β = .029, p  = .043) longitudinal fasciculus and in the anterior (β = .025, p  = .046) and superior (β = .027, p  = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts.
CONCLUSIONS NlmCategory: CONCLUSIONS
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. 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). We found significantly lower FA in the superior longitudinal fasciculus (β = -.035, p  = .029) and significantly higher MD in a global measure of thalamic radiations (β = .029, p  = .021), as well as higher MD in the superior (β = .034, p  = .039) and inferior (β = .029, p  = .043) longitudinal fasciculus and in the anterior (β = .025, p  = .046) and superior (β = .027, p  = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. 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.
Copyright 2018 Society of Biological Psychiatry. All rights reserved.
DATE PUBLISHED
2018 Jul 31
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2018/06/06
revised 2018/07/12
accepted 2018/07/12
entrez 2018/09/11 06:00
pubmed 2018/09/11 06:00
medline 2018/09/11 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Barbu MC Barbu Miruna C MC Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland. Electronic address: s1571976@sms.ed.ac.uk.
Zeng Y Zeng Yanni Y Medical Research Council, Human Genetics Unit, University of Edinburgh, Edinburgh, Scotland.
Shen X Shen Xueyi X Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
Cox SR Cox Simon R SR Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, Scotland.
Clarke TK Clarke Toni-Kim TK Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
Gibson J Gibson Jude J Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
Adams MJ Adams Mark J MJ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
Johnstone M Johnstone Mandy M Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
Haley CS Haley Chris S CS Medical Research Council, Human Genetics Unit, University of Edinburgh, Edinburgh, Scotland.
Lawrie SM Lawrie Stephen M SM Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
Deary IJ Deary Ian J IJ Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, Scotland.
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium Major Depression Disorder Working Group of the Psychiatric Genomics Consortium.
23andMe Research Team 23andMe, Inc., Mountain View, California.
McIntosh AM McIntosh Andrew M AM Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, Scotland.
Whalley HC Whalley Heather C HC Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Wray Naomi R NR
Ripke Stephan S
Mattheisen Manuel M
Trzaskowski Maciej M
Byrne Enda M EM
Abdellaoui Abdel A
Adams Mark J MJ
Agerbo Esben E
Air Tracy M TM
Andlauer Till F M TFM
Bacanu Silviu-Alin SA
Bækvad-Hansen Marie M
Beekman Aartjan T F ATF
Bigdeli Tim B TB
Binder Elisabeth B EB
Blackwood Douglas H R DHR
Bryois Julien J
Buttenschøn Henriette N HN
Bybjerg-Grauholm Jonas J
Cai Na N
Castelao Enrique E
Christensen Jane Hvarregaard JH
Clarke Toni-Kim TK
Coleman Jonathan R I JRI
Colodro-Conde Lucía L
Couvy-Duchesne Baptiste B
Craddock Nick N
Crawford Gregory E GE
Davies Gail G
Deary Ian J IJ
Degenhardt Franziska F
Derks Eske M EM
Direk Nese N
Dolan Conor V CV
Dunn Erin C EC
Eley Thalia C TC
Escott-Price Valentina V
Hassan Kiadeh Farnush Farhadi FF
Finucane Hilary K HK
Forstner Andreas J AJ
Frank Josef J
Gaspar Héléna A HA
Gill Michael M
Goes Fernando S FS
Gordon Scott D SD
Grove Jakob J
Hall Lynsey S LS
Hansen Christine Søholm CS
Hansen Thomas F TF
Herms Stefan S
Hickie Ian B IB
Hoffmann Per P
Homuth Georg G
Horn Carsten C
Hottenga Jouke-Jan JJ
Hougaard David M DM
Ising Marcus M
Jansen Rick R
Jorgenson Eric E
Knowles James A JA
Kohane Isaac S IS
Kraft Julia J
Kretzschmar Warren W WW
Krogh Jesper J
Kutalik Zoltán Z
Li Yihan Y
Lind Penelope A PA
MacIntyre Donald J DJ
MacKinnon Dean F DF
Maier Robert M RM
Maier Wolfgang W
Marchini Jonathan J
Mbarek Hamdi H
McGrath Patrick P
McGuffin Peter P
Medland Sarah E SE
Mehta Divya D
Middeldorp Christel M CM
Mihailov Evelin E
Milaneschi Yuri Y
Milani Lili L
Mondimore Francis M FM
Montgomery Grant W GW
Mostafavi Sara S
Mullins Niamh N
Nauck Matthias M
Ng Bernard B
Nivard Michel G MG
Nyholt Dale R DR
O'Reilly Paul F PF
Oskarsson Hogni H
Owen Michael J MJ
Painter Jodie N JN
Pedersen Carsten Bøcker CB
Pedersen Marianne Giørtz MG
Peterson Roseann E RE
Pettersson Erik E
Peyrot Wouter J WJ
Pistis Giorgio G
Posthuma Danielle D
Quiroz Jorge A JA
Qvist Per P
Rice John P JP
Riley Brien P BP
Rivera Margarita M
Mirza Saira Saeed SS
Schoevers Robert R
Schulte Eva C EC
Shen Ling L
Shi Jianxin J
Shyn Stanley I SI
Sigurdsson Engilbert E
Sinnamon Grant C B GCB
Smit Johannes H JH
Smith Daniel J DJ
Stefansson Hreinn H
Steinberg Stacy S
Streit Fabian F
Strohmaier Jana J
Tansey Katherine E KE
Teismann Henning H
Teumer Alexander A
Thompson Wesley W
Thomson Pippa A PA
Thorgeirsson Thorgeir E TE
Traylor Matthew M
Treutlein Jens J
Trubetskoy Vassily V
Uitterlinden André G AG
Umbricht Daniel D
Van der Auwera Sandra S
van Hemert Albert M AM
Viktorin Alexander A
Visscher Peter M PM
Wang Yunpeng Y
Webb Bradley T BT
Weinsheimer Shantel Marie SM
Wellmann Jürgen J
Willemsen Gonneke G
Witt Stephanie H SH
Wu Yang Y
Xi Hualin S HS
Yang Jian J
Zhang Futao F
Arolt Volker V
Baune Bernhard T BT
Berger Klaus K
Boomsma Dorret I DI
Cichon Sven S
Dannlowski Udo U
de Geus E J C EJC
DePaulo J Raymond JR
Domenici Enrico E
Domschke Katharina K
Esko Tõnu T
Grabe Hans J HJ
Hamilton Steven P SP
Hayward Caroline C
Heath Andrew C AC
Kendler Kenneth S KS
Kloiber Stefan S
Lewis Glyn G
Li Qingqin S QS
Lucae Susanne S
Madden Pamela A F PAF
Magnusson Patrik K PK
Martin Nicholas G NG
McIntosh Andrew M AM
Metspalu Andres A
Mors Ole O
Mortensen Preben Bo PB
Müller-Myhsok Bertram B
Nordentoft Merete M
Nöthen Markus M MM
O'Donovan Michael C MC
Paciga Sara A SA
Pedersen Nancy L NL
Penninx Brenda W J H BWJH
Perlis Roy H RH
Porteous David J DJ
Potash James B JB
Preisig Martin M
Rietschel Marcella M
Schaefer Catherine C
Schulze Thomas G TG
Smoller Jordan W JW
Stefansson Kari K
Tiemeier Henning H
Uher Rudolf R
Völzke Henry H
Weissman Myrna M MM
Werge Thomas T
Lewis Cathryn M CM
Levinson Douglas F DF
Breen Gerome G
Børglum Anders D AD
Sullivan Patrick F PF
Agee Michelle M
Alipanahi Babak B
Auton Adam A
Bell Robert K RK
Bryc Katarzyna K
Elson Sarah L SL
Fontanillas Pierre P
Furlotte Nicholas A NA
Hinds David A DA
Huber Karen E KE
Kleinman Aaron A
Litterman Nadia K NK
McCreight Jennifer C JC
McIntyre Matthew H MH
Mountain Joanna L JL
Noblin Elizabeth S ES
Northover Carrie A M CAM
Pitts Steven J SJ
Sathirapongsasuti J Fah JF
Sazonova Olga V OV
Shelton Janie F JF
Shringarpure Suyash S
Tian Chao C
Tung Joyce Y JY
Vacic Vladimir V
Wilson Catherine H CH
JOURNAL
VOLUME:
ISSUE:
TITLE: Biological psychiatry. Cognitive neuroscience and neuroimaging
ISOABBREVIATION: Biol Psychiatry Cogn Neurosci Neuroimaging
YEAR: 2018
MONTH: Jul
DAY: 31
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 2451-9030
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Biol Psychiatry Cogn Neurosci Neuroimaging
COUNTRY: United States
ISSNLINKING: 2451-9022
NLMUNIQUEID: 101671285
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
100135 Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
KEYWORD
Biological pathway
Major depressive disorder
NETRIN1
Polygenic risk score
Thalamic radiations
White matter
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's