|
|
| PMID |
|
|
| TITLE |
|
| The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study. |
|
| ABSTRACT |
|
| BACKGROUND |
|
| Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. |
| METHODS |
|
| Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r ) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). |
| RESULTS |
|
| Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r ) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). ADHD and PTSD had consistent r (r range, 0.43-0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186-0.552; p = 7.68 × 10 ). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 , p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98-3.53). |
| CONCLUSIONS |
|
| Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r ) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). ADHD and PTSD had consistent r (r range, 0.43-0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186-0.552; p = 7.68 × 10 ). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 , p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98-3.53). Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life. |
| Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| received |
2022/05/03 |
| revised |
2022/08/11 |
| accepted |
2022/08/17 |
| pubmed |
2022/11/06 06:00 |
| medline |
2023/01/21 06:00 |
| entrez |
2022/11/05 23:13 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Wendt FR |
|
Wendt |
Frank R |
FR |
|
Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Department of Anthropology, University of Toronto, Toronto, Ontario, Canada. |
| Garcia-Argibay M |
|
Garcia-Argibay |
Miguel |
M |
|
School of Medical Sciences, Örebro University, Örebro, Sweden. |
| Cabrera-Mendoza B |
|
Cabrera-Mendoza |
Brenda |
B |
|
Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut. |
| Valdimarsdóttir UA |
|
Valdimarsdóttir |
Unnur A |
UA |
|
Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. |
| Gelernter J |
|
Gelernter |
Joel |
J |
|
Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut. |
| Stein MB |
|
Stein |
Murray B |
MB |
|
Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, California; Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California. |
| Nivard MG |
|
Nivard |
Michel G |
MG |
|
Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, VU University, Amsterdam, The Netherlands. |
| Maihofer AX |
|
Maihofer |
Adam X |
AX |
|
Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California; Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, California. |
|
Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium |
|
|
|
|
|
| Nievergelt CM |
|
Nievergelt |
Caroline M |
CM |
|
Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California; Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, California. |
| Larsson H |
|
Larsson |
Henrik |
H |
|
School of Medical Sciences, Örebro University, Örebro, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. |
| Mattheisen M |
|
Mattheisen |
Manuel |
M |
|
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada; Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany; Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada. |
| Polimanti R |
|
Polimanti |
Renato |
R |
|
Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut. Electronic address: renato.polimanti@yale.edu. |
| Meier SM |
|
Meier |
Sandra M |
SM |
|
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada; Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address: sandra.meier@iwk.nshealth.ca. |
|
| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Maihofer |
Adam X |
AX |
|
| Choi |
Karmel W |
KW |
|
| Coleman |
Jonathan R I |
JRI |
|
| Daskalakis |
Nikolaos P |
NP |
|
| Denckla |
Christy A |
CA |
|
| Ketema |
Elizabeth |
E |
|
| Morey |
Rajendra A |
RA |
|
| Polimanti |
Renato |
R |
|
| Ratanatharathorn |
Andrew |
A |
|
| Torres |
Katy |
K |
|
| Wingo |
Aliza P |
AP |
|
| Zai |
Clement C |
CC |
|
| Aiello |
Allison E |
AE |
|
| Almli |
Lynn M |
LM |
|
| Amstadter |
Ananda B |
AB |
|
| Andersen |
Soren B |
SB |
|
| Andreassen |
Ole A |
OA |
|
| Arbisi |
Paul A |
PA |
|
| Ashley-Koch |
Allison E |
AE |
|
| Austin |
S Bryn |
SB |
|
| Avdibegovic |
Esmina |
E |
|
| Borglum |
Anders D |
AD |
|
| Babic |
Dragan |
D |
|
| Bækvad-Hansen |
Marie |
M |
|
| Baker |
Dewleen G |
DG |
|
| Beckham |
Jean C |
JC |
|
| Bierut |
Laura J |
LJ |
|
| Bisson |
Jonathan I |
JI |
|
| Boks |
Marco P |
MP |
|
| Bolger |
Elizabeth A |
EA |
|
| Bradley |
Bekh |
B |
|
| Brashear |
Meghan |
M |
|
| Breen |
Gerome |
G |
|
| Bryant |
Richard A |
RA |
|
| Bustamante |
Angela C |
AC |
|
| Bybjerg-Grauholm |
Jonas |
J |
|
| Calabrese |
Joseph R |
JR |
|
| Caldas-de-Almeida |
Jose Miguel |
JM |
|
| Chen |
Chia-Yen |
CY |
|
| Dale |
Anders M |
AM |
|
| Dalvie |
Shareefa |
S |
|
| Deckert |
Jürgen |
J |
|
| Delahanty |
Douglas L |
DL |
|
| Dennis |
Michelle F |
MF |
|
| Disner |
Seth G |
SG |
|
| Domschke |
Katharina |
K |
|
| Duncan |
Laramie E |
LE |
|
| Kulenovic |
Alma Dzubur |
AD |
|
| Erbes |
Christopher R |
CR |
|
| Evans |
Alexandra |
A |
|
| Farrer |
Lindsay A |
LA |
|
| Feeny |
Norah C |
NC |
|
| Flory |
Janine D |
JD |
|
| Forbes |
David |
D |
|
| Franz |
Carol E |
CE |
|
| Galea |
Sandro |
S |
|
| Garrett |
Melanie E |
ME |
|
| Gautam |
Aarti |
A |
|
| Gelaye |
Bizu |
B |
|
| Gelernter |
Joel |
J |
|
| Geuze |
Elbert |
E |
|
| Gillespie |
Charles F |
CF |
|
| Uka |
Aferdita Goci |
AG |
|
| Gordon |
Scott D |
SD |
|
| Guffanti |
Guia |
G |
|
| Hammamieh |
Rasha |
R |
|
| Hauser |
Michael A |
MA |
|
| Heath |
Andrew C |
AC |
|
| Hemmings |
Sian M J |
SMJ |
|
| Hougaard |
David Michael |
DM |
|
| Jakovljevic |
Miro |
M |
|
| Jett |
Marti |
M |
|
| Johnson |
Eric Otto |
EO |
|
| Jones |
Ian |
I |
|
| Jovanovic |
Tanja |
T |
|
| Qin |
Xue-Jun |
XJ |
|
| Karstoft |
Karen-Inge |
KI |
|
| Kaufman |
Milissa L |
ML |
|
| Kessler |
Ronald C |
RC |
|
| Khan |
Alaptagin |
A |
|
| Kimbrel |
Nathan A |
NA |
|
| King |
Anthony P |
AP |
|
| Koen |
Nastassja |
N |
|
| Kranzler |
Henry R |
HR |
|
| Kremen |
William S |
WS |
|
| Lawford |
Bruce R |
BR |
|
| Lebois |
Lauren A M |
LAM |
|
| Lewis |
Catrin |
C |
|
| Liberzon |
Israel |
I |
|
| Linnstaedt |
Sarah D |
SD |
|
| Logue |
Mark W |
MW |
|
| Lori |
Adriana |
A |
|
| Lugonja |
Bozo |
B |
|
| Luykx |
Jurjen J |
JJ |
|
| Lyons |
Michael J |
MJ |
|
| Maples-Keller |
Jessica L |
JL |
|
| Marmar |
Charles |
C |
|
| Martin |
Nicholas G |
NG |
|
| Maurer |
Douglas |
D |
|
| Mavissakalian |
Matig R |
MR |
|
| McFarlane |
Alexander |
A |
|
| McGlinchey |
Regina E |
RE |
|
| McLaughlin |
Katie A |
KA |
|
| McLean |
Samuel A |
SA |
|
| Mehta |
Divya |
D |
|
| Mellor |
Rebecca |
R |
|
| Michopoulos |
Vasiliki |
V |
|
| Milberg |
William |
W |
|
| Miller |
Mark W |
MW |
|
| Morris |
Charles Phillip |
CP |
|
| Mors |
Ole |
O |
|
| Mortensen |
Preben Bo |
PB |
|
| Nelson |
Elliot C |
EC |
|
| Nordentoft |
Merete |
M |
|
| Norman |
Sonya B |
SB |
|
| O'Donnell |
Meaghan |
M |
|
| Orcutt |
Holly K |
HK |
|
| Panizzon |
Matthew S |
MS |
|
| Peters |
Edward S |
ES |
|
| Peterson |
Alan L |
AL |
|
| Peverill |
Matthew |
M |
|
| Pietrzak |
Robert H |
RH |
|
| Polusny |
Melissa A |
MA |
|
| Rice |
John P |
JP |
|
| Risbrough |
Victoria B |
VB |
|
| Roberts |
Andrea L |
AL |
|
| Rothbaum |
Alex O |
AO |
|
| Rothbaum |
Barbara O |
BO |
|
| Roy-Byrne |
Peter |
P |
|
| Ruggiero |
Kenneth J |
KJ |
|
| Rung |
Ariane |
A |
|
| Rutten |
Bart P F |
BPF |
|
| Saccone |
Nancy L |
NL |
|
| Sanchez |
Sixto E |
SE |
|
| Schijven |
Dick |
D |
|
| Seedat |
Soraya |
S |
|
| Seligowski |
Antonia V |
AV |
|
| Seng |
Julia S |
JS |
|
| Sheerin |
Christina M |
CM |
|
| Silove |
Derrick |
D |
|
| Smith |
Alicia K |
AK |
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Jordan W |
JW |
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Scott R |
SR |
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Dan J |
DJ |
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Jennifer S |
JS |
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Martin H |
MH |
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Wesley K |
WK |
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Edward |
E |
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Monica |
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Robert J |
RJ |
|
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Leigh |
L |
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Miranda |
M |
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Eric |
E |
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Christiaan |
C |
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Joanne |
J |
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Yunpeng |
Y |
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Zhewu |
Z |
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Thomas |
T |
|
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Michelle A |
MA |
|
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Douglas E |
DE |
|
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Sherry |
S |
|
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Christiane |
C |
|
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Erika J |
EJ |
|
| Yehuda |
Rachel |
R |
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Keith A |
KA |
|
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Ross McD |
RM |
|
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Hongyu |
H |
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Lori A |
LA |
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Magali |
M |
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Heather |
H |
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Allison C |
AC |
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Rany M |
RM |
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Jonathan |
J |
|
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Richard |
R |
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Tianying |
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S |
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Mark J |
MJ |
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Kerry J |
KJ |
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Karestan C |
KC |
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MB |
|
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Caroline M |
CM |
|
|
| JOURNAL |
|
| VOLUME: 93 |
| ISSUE: 4 |
| TITLE: Biological psychiatry |
| ISOABBREVIATION: Biol Psychiatry |
| YEAR: 2023 |
| MONTH: Feb |
| DAY: 15 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1873-2402 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Biol Psychiatry |
| COUNTRY: United States |
| ISSNLINKING: 0006-3223 |
| NLMUNIQUEID: 0213264 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
| CommentIn |
Biol Psychiatry. 2023 Feb 15;93(4):e11-e12 |
36653108 |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| R21 DC018098 |
NIDCD NIH HHS |
United States |
| R33 DA047527 |
NIDA NIH HHS |
United States |
| F32 MH122058 |
NIMH NIH HHS |
United States |
| R01 MH106595 |
NIMH NIH HHS |
United States |
| R01 MH124847 |
NIMH NIH HHS |
United States |
| R01 MH124851 |
NIMH NIH HHS |
United States |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
| KEYWORD |
| ADHD |
| Causal inference |
| Comorbidities |
| Epidemiology |
| Genome-wide association study |
| PTSD |
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Humans |
|
| Stress Disorders, Post-Traumatic |
genetics |
| Attention Deficit Disorder with Hyperactivity |
diagnosis |
| Siblings |
diagnosis |
| Genome-Wide Association Study |
diagnosis |
| Mendelian Randomization Analysis |
diagnosis |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
|
| OTHER ID's |
|
|
|
