|
|
| PMID |
|
|
| 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 |
|
| 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 |
|
| 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, 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 |
|
| 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, 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. 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 |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| received |
2018/06/06 |
| revised |
2018/07/12 |
| accepted |
2018/07/12 |
| pubmed |
2018/09/11 06:00 |
| medline |
2020/01/07 06:00 |
| entrez |
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 |
|
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. |
| 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: 4 |
| ISSUE: 1 |
| TITLE: Biological psychiatry. Cognitive neuroscience and neuroimaging |
| ISOABBREVIATION: Biol Psychiatry Cogn Neurosci Neuroimaging |
| YEAR: 2019 |
| MONTH: 01 |
| DAY: |
| 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 |
| Research Support, Non-U.S. Gov't |
|
| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| MC_UU_00007/10 |
Medical Research Council |
United Kingdom |
| MR/N015746/1 |
Medical Research Council |
United Kingdom |
| MC_QA137853 |
Medical Research Council |
United Kingdom |
| CZD/16/6 |
Chief Scientist Office |
United Kingdom |
|
Biotechnology and Biological Sciences Research Council |
United Kingdom |
| MR/M013111/1 |
Medical Research Council |
United Kingdom |
| MR/R024065/1 |
Medical Research Council |
United Kingdom |
| MR/K026992/1 |
Medical Research Council |
United Kingdom |
| G0200243 |
Medical Research Council |
United Kingdom |
| MC_PC_U127592696 |
Medical Research Council |
United Kingdom |
| U01 MH109536 |
NIMH NIH HHS |
United States |
| 100135 |
Wellcome Trust |
United Kingdom |
|
Wellcome Trust |
United Kingdom |
| MC_PC_17228 |
Medical Research Council |
United Kingdom |
| K01 MH113848 |
NIMH NIH HHS |
United States |
| 104036/Z/14/Z |
Wellcome Trust |
United Kingdom |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
| KEYWORD |
| Biological pathway |
| Major depressive disorder |
| NETRIN1 |
| Polygenic risk score |
| Thalamic radiations |
| White matter |
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Aged |
|
| Biological Specimen Banks |
|
| Brain |
pathology |
| Depressive Disorder, Major |
pathology |
| Diffusion Tensor Imaging |
pathology |
| Female |
pathology |
| Genetic Predisposition to Disease |
pathology |
| Genome-Wide Association Study |
pathology |
| Humans |
pathology |
| Male |
pathology |
| Middle Aged |
pathology |
| Multifactorial Inheritance |
pathology |
| Netrin-1 |
genetics |
| Polymorphism, Single Nucleotide |
genetics |
| Signal Transduction |
genetics |
| United Kingdom |
genetics |
| White Matter |
pathology |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
NTN1 protein, human |
| 158651-98-0 |
Netrin-1 |
|
| OTHER ID's |
|
|
|
