|
|
| PMID |
|
|
| TITLE |
|
| Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium. |
|
| ABSTRACT |
|
| BACKGROUND |
|
| Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. |
| METHODS |
|
| Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). |
| RESULTS |
|
| Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. |
| CONCLUSION |
|
| Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| pubmed |
2019/04/02 06:00 |
| medline |
2020/04/25 06:00 |
| entrez |
2019/04/02 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Polimanti R |
|
Polimanti |
Renato |
R |
|
Department of Psychiatry,Yale University School of Medicine and VA CT Healthcare Center,West Haven, Connecticut,USA. |
| Peterson RE |
|
Peterson |
Roseann E |
RE |
|
Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University, Richmond, Virginia,USA. |
| Ong JS |
|
Ong |
Jue-Sheng |
JS |
|
Statistical Genetics,QIMR Berghofer, Brisbane,Australia. |
| MacGregor S |
|
MacGregor |
Stuart |
S |
|
Statistical Genetics,QIMR Berghofer, Brisbane,Australia. |
| Edwards AC |
|
Edwards |
Alexis C |
AC |
|
Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University, Richmond, Virginia,USA. |
| Clarke TK |
|
Clarke |
Toni-Kim |
TK |
|
Division of Psychiatry,University of Edinburgh,Edinburgh,UK. |
| Frank J |
|
Frank |
Josef |
J |
|
Department of Genetic Epidemiology in Psychiatry,Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University,Mannheim, Baden-Württemberg,Germany. |
| Gerring Z |
|
Gerring |
Zachary |
Z |
|
Translational Neurogenomics, QIMR Berghofer,Brisbane,Australia. |
| Gillespie NA |
|
Gillespie |
Nathan A |
NA |
|
Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University, Richmond, Virginia,USA. |
| Lind PA |
|
Lind |
Penelope A |
PA |
|
Psychiatric Genetics, QIMR Berghofer,Brisbane,Australia. |
| Maes HH |
|
Maes |
Hermine H |
HH |
|
Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University, Richmond, Virginia,USA. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Genetic Epidemiology, QIMR Berghofer,Brisbane,Australia. |
| Mbarek H |
|
Mbarek |
Hamdi |
H |
|
Department of Biological Psychology & EMGO + Institute for Health and Care Research,Vrije Universiteit Amsterdam, Amsterdam,the Netherlands. |
| Medland SE |
|
Medland |
Sarah E |
SE |
|
Psychiatric Genetics, QIMR Berghofer,Brisbane,Australia. |
| Streit F |
|
Streit |
Fabian |
F |
|
Department of Genetic Epidemiology in Psychiatry,Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University,Mannheim, Baden-Württemberg,Germany. |
|
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium |
|
|
|
|
|
| Agrawal A |
|
Agrawal |
Arpana |
A |
|
Department of Psychiatry,Washington University School of Medicine,Saint Louis, Missouri,USA. |
| Edenberg HJ |
|
Edenberg |
Howard J |
HJ |
|
Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis, Indiana,USA. |
| Kendler KS |
|
Kendler |
Kenneth S |
KS |
|
Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University, Richmond, Virginia,USA. |
| Lewis CM |
|
Lewis |
Cathryn M |
CM |
|
Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience, King's CollegeLondon,UK. |
| Sullivan PF |
|
Sullivan |
Patrick F |
PF |
|
Department of Medical Epidemiology and Biostatistics,Karolinska Institutet,Stockholm,Sweden. |
| Wray NR |
|
Wray |
Naomi R |
NR |
|
Institute for Molecular Bioscience, The University of Queensland,Brisbane,Australia. |
| Gelernter J |
|
Gelernter |
Joel |
J |
|
Department of Psychiatry,Yale University School of Medicine and VA CT Healthcare Center,West Haven, Connecticut,USA. |
| Derks EM |
|
Derks |
Eske M |
EM |
|
Translational Neurogenomics, QIMR Berghofer,Brisbane,Australia. |
|
| INVESTIGATORS |
|
|
| JOURNAL |
|
| VOLUME: 49 |
| ISSUE: 7 |
| TITLE: Psychological medicine |
| ISOABBREVIATION: Psychol Med |
| YEAR: 2019 |
| MONTH: 05 |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1469-8978 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Psychol Med |
| COUNTRY: England |
| ISSNLINKING: 0033-2917 |
| NLMUNIQUEID: 1254142 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
|
| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| U01 MH085520 |
NIMH NIH HHS |
United States |
|
Department of Health |
United Kingdom |
| MR/K026992/1 |
Medical Research Council |
United Kingdom |
| U01 MH109536 |
NIMH NIH HHS |
United States |
| R00 DA023549 |
NIDA NIH HHS |
United States |
| G0700704 |
Medical Research Council |
United Kingdom |
| U01 MH109528 |
NIMH NIH HHS |
United States |
| K01 MH113848 |
NIMH NIH HHS |
United States |
| U01 MH109532 |
NIMH NIH HHS |
United States |
| U01 MH094421 |
NIMH NIH HHS |
United States |
| U10 AA008401 |
NIAAA NIH HHS |
United States |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
| KEYWORD |
| Alcohol consumption |
| Mendelian randomization |
| alcohol dependence |
| genetic correlation |
| genome-wide association |
| major depression |
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Adult |
|
| Aged |
|
| Alcoholism |
psychology |
| Causality |
psychology |
| Cohort Studies |
psychology |
| Comorbidity |
psychology |
| Depressive Disorder, Major |
psychology |
| Female |
psychology |
| Genetic Association Studies |
psychology |
| Genome-Wide Association Study |
psychology |
| Genomics |
psychology |
| Humans |
psychology |
| Linkage Disequilibrium |
psychology |
| Male |
psychology |
| Mendelian Randomization Analysis |
psychology |
| Middle Aged |
psychology |
| United Kingdom |
psychology |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
|
| OTHER ID's |
|
|
|
