|
|
| PMID |
|
|
| TITLE |
|
| Identifying the Common Genetic Basis of Antidepressant Response. |
|
| ABSTRACT |
|
| Background |
NlmCategory: UNASSIGNED |
| Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. |
| Methods |
NlmCategory: UNASSIGNED |
| Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Genome-wide analysis of remission ( = 1852, = 3299) and percentage improvement ( = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. |
| Results |
NlmCategory: UNASSIGNED |
| Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Genome-wide analysis of remission ( = 1852, = 3299) and percentage improvement ( = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission ( = 0.132, SE = 0.056) but not for percentage improvement ( = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified and as significantly associated with antidepressant response. |
| Conclusions |
NlmCategory: UNASSIGNED |
| Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Genome-wide analysis of remission ( = 1852, = 3299) and percentage improvement ( = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission ( = 0.132, SE = 0.056) but not for percentage improvement ( = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified and as significantly associated with antidepressant response. This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response. |
| © 2021 The Authors. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| received |
2021/04/29 |
| revised |
2021/07/15 |
| accepted |
2021/07/19 |
| entrez |
2022/06/17 02:36 |
| pubmed |
2022/06/18 06:00 |
| medline |
2022/06/18 06:01 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Pain O |
|
Pain |
Oliver |
O |
|
Social, Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom. |
| Hodgson K |
|
Hodgson |
Karen |
K |
|
Social, Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom. |
| Trubetskoy V |
|
Trubetskoy |
Vassily |
V |
|
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Medical Psychology, Berlin, Germany. |
| Ripke S |
|
Ripke |
Stephan |
S |
|
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts. |
| Marshe VS |
|
Marshe |
Victoria S |
VS |
|
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. |
| Adams MJ |
|
Adams |
Mark J |
MJ |
|
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom. |
| Byrne EM |
|
Byrne |
Enda M |
EM |
|
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. |
| Campos AI |
|
Campos |
Adrian I |
AI |
|
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Carrillo-Roa T |
|
Carrillo-Roa |
Tania |
T |
|
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. |
| Cattaneo A |
|
Cattaneo |
Annamaria |
A |
|
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom. |
| Als TD |
|
Als |
Thomas D |
TD |
|
Center for Genomics and Personalized Medicine, Central Region Denmark and Aarhus University, Aarhus, Denmark. |
| Souery D |
|
Souery |
Daniel |
D |
|
Centre Européen de Psychologie Medicale (PsyPluriel), Brussels, Belgium. |
| Dernovsek MZ |
|
Dernovsek |
Mojca Z |
MZ |
|
University Psychiatric Clinic, University of Ljubliana, Ljubljana, Slovakia. |
| Fabbri C |
|
Fabbri |
Chiara |
C |
|
Social, Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom. |
| Hayward C |
|
Hayward |
Caroline |
C |
|
MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom. |
| Henigsberg N |
|
Henigsberg |
Neven |
N |
|
Department of Psychiatry, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, Croatia. |
| Hauser J |
|
Hauser |
Joanna |
J |
|
Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland. |
| Kennedy JL |
|
Kennedy |
James L |
JL |
|
Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. |
| Lenze EJ |
|
Lenze |
Eric J |
EJ |
|
Healthy Mind Lab, Washington University School of Medicine in St. Louis, St. Louis, Missouri. |
| Lewis G |
|
Lewis |
Glyn |
G |
|
Division of Psychiatry, University College London, London, United Kingdom. |
| Müller DJ |
|
Müller |
Daniel J |
DJ |
|
Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Mulsant BH |
|
Mulsant |
Benoit H |
BH |
|
Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. |
| Mors O |
|
Mors |
Ole |
O |
|
Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark. |
| Perroud N |
|
Perroud |
Nader |
N |
|
Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland. |
| Porteous DJ |
|
Porteous |
David J |
DJ |
|
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. |
| Rentería ME |
|
Rentería |
Miguel E |
ME |
|
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Reynolds CF 3rd |
|
Reynolds |
Charles F |
CF |
|
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. |
| Rietschel M |
|
Rietschel |
Marcella |
M |
|
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Heidelberg University Faculty of Medicine in Mannheim, Mannheim, Germany. |
| Uher R |
|
Uher |
Rudolf |
R |
|
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. |
| Wigmore EM |
|
Wigmore |
Eleanor M |
EM |
|
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom. |
| Maier W |
|
Maier |
Wolfgang |
W |
|
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany. |
| Wray NR |
|
Wray |
Naomi R |
NR |
|
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. |
| Aitchison KJ |
|
Aitchison |
Katherine J |
KJ |
|
Department of Medical Genetics, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada. |
| Arolt V |
|
Arolt |
Volker |
V |
|
Department of Psychiatry, University of Münster, Münster, Germany. |
| Baune BT |
|
Baune |
Bernhard T |
BT |
|
Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia. |
| Biernacka JM |
|
Biernacka |
Joanna M |
JM |
|
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. |
| Bondolfi G |
|
Bondolfi |
Guido |
G |
|
Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland. |
| Domschke K |
|
Domschke |
Katharina |
K |
|
Department of Psychiatry and Psychotherapy, Medical Center, University of Freiburg, Freiburg, Germany. |
| Kato M |
|
Kato |
Masaki |
M |
|
Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan. |
| Li QS |
|
Li |
Qingqin S |
QS |
|
Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, New Jersey. |
| Liu YL |
|
Liu |
Yu-Li |
YL |
|
Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taipei, Taiwan. |
| Serretti A |
|
Serretti |
Alessandro |
A |
|
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. |
| Tsai SJ |
|
Tsai |
Shih-Jen |
SJ |
|
Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan. |
| Turecki G |
|
Turecki |
Gustavo |
G |
|
Department of Psychiatry, Douglas Institute, McGill University, Montreal, Quebec, Canada. |
| Weinshilboum R |
|
Weinshilboum |
Richard |
R |
|
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota. |
|
GSRD Consortium |
|
|
|
|
|
|
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium |
|
|
|
|
|
| McIntosh AM |
|
McIntosh |
Andrew M |
AM |
|
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom. |
| Lewis CM |
|
Lewis |
Cathryn M |
CM |
|
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom. |
|
| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Kasper |
Siegfried |
S |
|
| Zohar |
Joseph |
J |
|
| Souery |
Daniel |
D |
|
| Montgomery |
Stuart |
S |
|
| Albani |
Diego |
D |
|
| Forloni |
Gianluigi |
G |
|
| Ferentinos |
Panagiotis |
P |
|
| Rujescu |
Dan |
D |
|
| Mendlewicz |
Julien |
J |
|
| 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 Fm |
TF |
|
| Bacanu |
Silviu-Alin |
SA |
|
| Bækvad-Hansen |
Marie |
M |
|
| Beekman |
Aartjan Tf |
AT |
|
| Bigdeli |
Tim B |
TB |
|
| Binder |
Elisabeth B |
EB |
|
| 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 Ri |
JR |
|
| 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 |
|
| Foo |
Jerome C |
JC |
|
| 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 |
|
| Howard |
David M |
DM |
|
| Ising |
Marcus |
M |
|
| Jansen |
Rick |
R |
|
| Jones |
Ian |
I |
|
| Jones |
Lisa A |
LA |
|
| Jorgenson |
Eric |
E |
|
| Knowles |
James A |
JA |
|
| Kohane |
Isaac S |
IS |
|
| Kraft |
Julia |
J |
|
| Kretzschmar |
Warren W |
WW |
|
| 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 |
|
| 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 Cb |
GC |
|
| 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 Af |
PA |
|
| 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 Wjh |
BW |
|
| 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 |
|
|
| JOURNAL |
|
| VOLUME: 2 |
| ISSUE: 2 |
| TITLE: Biological psychiatry global open science |
| ISOABBREVIATION: Biol Psychiatry Glob Open Sci |
| YEAR: 2022 |
| MONTH: Apr |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 2667-1743 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
|
| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
| KEYWORD |
| Antidepressant response |
| Depression |
| GWAS |
| Genetics |
| MDD |
| Polygenic score |
|
| MESH HEADINGS |
|
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
|
| OTHER ID's |
|
|
|
