The temporal relationship of the onsets of alcohol dependence and major depression: using a genetically informative study design

2006 ◽  
Vol 36 (8) ◽  
pp. 1153-1162 ◽  
Author(s):  
PO-HSIU KUO ◽  
CHARLES O. GARDNER ◽  
KENNETH S. KENDLER ◽  
CAROL A. PRESCOTT
Keyword(s):  
Major Depression ◽  
Alcohol Dependence ◽  
Temporal Relationship ◽  
Causal Effect ◽  
Age At Onset ◽  
Familial Risk ◽  
Population Based ◽  
Structured Interviews ◽  
Self Medication ◽  
Relationship Of

Background. Although alcohol dependence (AD) and major depression (MD) are highly co-morbid, their causal relationship is unclear. In this longitudinal study, we used a genetically informative population-based twin sample to examine the age-at-onset distributions and the temporal relationship of AD and MD.Method. Our sample included 7477 twins, whose diagnoses of AD and MD and age-at-onset information were obtained from structured interviews. Individual-level survival analyses were conducted based on 2603 monozygotic (MZ) twins, and co-twin diagnosis was included in models as an index of familiar liability to AD and MD.Results. The age-at-onset distributions of AD and MD differed substantially. Most onsets of AD were in young adulthood, whereas MD had a flatter distribution across age. Most subjects, especially women, had an onset of MD preceding AD. Prior MD significantly affected risk for developing AD, and this risk decreased over time. By contrast, preceding AD had negligible effects on the risk for future MD. Familial risk was transmitted within disorders but there was little evidence of additional familial liability shared across disorders.Conclusions. Risk for developing AD was substantially increased by a prior episode of MD. The association was only partially accounted for by familial factors, providing support for a direct causal effect such as self-medication. The etiologic path from AD to MD was insignificant.

The Clinical Characteristics of Major Depression as Indices of the Familial Risk to Illness

1994 ◽  
Vol 165 (1) ◽  
pp. 66-72 ◽  
Author(s):  
Kenneth S. Kendler ◽  
Michael C. Neale ◽  
Ronald C. Kessler ◽  
Andrew C. Heath ◽  
Lindon J. Eaves
Keyword(s):  
Major Depression ◽  
Clinical Characteristics ◽  
Age At Onset ◽  
Familial Risk ◽  
Population Based ◽  
Treatment Seeking ◽  
Generalised Anxiety Disorder ◽  
Increased Risk ◽  
Co Morbidity ◽  
Familial Vulnerability

BackgroundFrom both a clinical and an aetiological perspective, major depression (MD) is probably a heterogeneous condition. We attempt to relate these two domains.MethodWe examined which of an extensive series of clinical characteristics in 646 female twins from a population-based register with a lifetime diagnosis of MD predicts the risk for MD in co-twins. MD was defined by DSM–III–R criteria.ResultsFour variables uniquely predicted an increased risk for MD in the co-twin: number of episodes, degree of impairment and co-morbidity with panic disorder or bulimia. One variable uniquely predicted decreased risk: co-morbidity with phobia. Variables that did not uniquely predict risk of MD in the co-twin included age at onset, number and kind of depressive symptoms, treatment seeking, duration of the longest episode and co-morbidity with generalised anxiety disorder and alcohol dependence.ConclusionsOur results suggest that the clinical features of MD can be meaningfully related to the familial vulnerability to illness, particularly with respect to recurrence, impairment and patterns of co-morbidity.

scholarly journals Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

2019 ◽  
Vol 49 (07) ◽  
pp. 1218-1226 ◽  
Author(s):  
Renato Polimanti ◽  
Roseann E. Peterson ◽  
Jue-Sheng Ong ◽  
Stuart MacGregor ◽  
Alexis C. Edwards ◽  
...  
Keyword(s):  
Major Depression ◽  
Alcohol Dependence ◽  
Genetic Correlation ◽  
Causal Relationship ◽  
Causal Effect ◽  
Uk Biobank ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Genetic Mechanisms ◽  
Shared Genetic

AbstractBackgroundDespite 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.MethodsLinkage 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).ResultsPositive 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.ConclusionThis 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.

A longitudinal study of personality and major depression in a population-based sample of male twins

2007 ◽  
Vol 37 (8) ◽  
pp. 1163-1172 ◽  
Author(s):  
AYMAN H. FANOUS ◽  
MICHAEL C. NEALE ◽  
STEVEN H. AGGEN ◽  
KENNETH S. KENDLER
Keyword(s):  
Major Depression ◽  
Environmental Factors ◽  
Structural Equation ◽  
Causal Effect ◽  
Population Based ◽  
Twin Model ◽  
Genetic Overlap ◽  
Genetic And Environmental Factors ◽  
One Year ◽  
Time To Onset

ABSTRACTBackgroundThe relationship between personality and psychiatric illness is complex. It is not clear whether one directly causes the other.MethodIn a population-based sample of male twins (n=3030), we attempted to predict major depression (MD) from neuroticism (N) and extraversion (E) and vice versa, to evaluate the causal, scar, state, and prodromal hypotheses. In a longitudinal, structural equation twin model, we decomposed the covariation between N and MD into (a) genetic and environmental factors that are common to both traits, as well as specific to each one and (b) direct causal effects of N at time 1 on subsequent MD, as well as between MD and subsequent N.ResultsE was negatively correlated with lifetime and one-year prevalence of MD. N predicted the new onset of MD, and was predicted by both current and past MD. It did not predict the time to onset of MD. All of the covariation between N and MD was due to additive genetic and individual-specific environmental factors shared by both traits and a direct causal path between MD and N assessed later. No genetic factors were unique to either trait.ConclusionsIn men, N may be a vulnerability factor for MD but does not cause it directly. However, MD may have a direct causal effect on N. The genetic overlap between N and MD in men may be greater than in women.

Co-morbidity and familial aggregation of alcoholism and anxiety disorders

1998 ◽  
Vol 28 (4) ◽  
pp. 773-788 ◽  
Author(s):  
K. R. MERIKANGAS ◽  
D. E. STEVENS ◽  
B. FENTON ◽  
M. STOLAR ◽  
S. O'MALLEY ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Alcohol Dependence ◽  
Social Phobia ◽  
Familial Aggregation ◽  
Familial Risk ◽  
Family History Information ◽  
Self Medication ◽  
Co Morbidity ◽  
History Information ◽  
Familial Risk Factors

Background. This study examined the patterns of familial aggregation and co-morbidity of alcoholism and anxiety disorders in the relatives of 165 probands selected for alcoholism and/or anxiety disorders compared to those of 61 unaffected controls.Methods. Probands were either selected from treatment settings or at random from the community. DSM-III-R diagnoses were obtained for all probands and their 1053 first-degree relatives, based on direct interview or family history information.Results. The findings indicate that: (1) alcoholism was associated with anxiety disorders in the relatives, particularly among females; (2) both alcoholism and anxiety disorders were highly familial; (3) the familial aggregation of alcoholism was attributable to alcohol dependence rather than to alcohol abuse, particularly among male relatives; and (4) the pattern of co-aggregation of alcohol dependence and anxiety disorders in families differed according to the subtype of anxiety disorder; there was evidence of a partly shared diathesis underlying panic and alcoholism, whereas social phobia and alcoholism tended to aggregate independently.Conclusions. The finding that the onset of social phobia tended to precede that of alcoholism, when taken together with the independence of familial aggregation of social phobia and alcoholism support a self-medication hypothesis as the explanation for the co-occurrence of social phobia and alcoholism. In contrast, the lack of a systematic pattern in the order of onset of panic and alcoholism among subjects with both disorders as well as evidence for shared underlying familial risk factors suggests that co-morbidity between panic disorder and alcoholism is not a consequence of self-medication of panic symptoms. The results of this study emphasize the importance of examining co-morbid disorders and subtypes thereof in identifying sources of heterogeneity in the pathogenesis of alcoholism.

Biopsychosocial correlates of lifetime major depression in a multiple sclerosis population

2000 ◽  
Vol 6 (2) ◽  
pp. 115-120 ◽  
Author(s):  
Scott B Patten ◽  
Luanne M Metz ◽  
Marlene A Reimer
Keyword(s):  
Multiple Sclerosis ◽  
Major Depression ◽  
Depressive Disorders ◽  
Causal Effect ◽  
Composite International Diagnostic Interview ◽  
Population Based ◽  
Diagnostic Interview ◽  
Cross Sectional ◽  
Multiple Sclerosis Population ◽  
Additional Data Collection

The objective of this paper was to evaluate the lifetime and point prevalence of major depression in a population-based Multiple Sclerosis (MS) clinic sample, and to describe associations between selected biopsychosocial variables and the prevalence of lifetime major depression in this sample. Subjects who had participated in an earlier study were re-contacted for additional data collection. Eighty-three per cent (n=136) of those eligible consented to participate. Each subject completed the Composite International Diagnostic Interview (CIDI) and an interviewer-administered questionnaire evaluating a series of biopsychosocial variables. The lifetime prevalence of major depression in this sample was 22.8%, somewhat lower than previous estimates in MS clinic populations. Women, those under 35, and those with a family history of major depression had a higher prevalence. Also, subject reporting high levels of stress and heavy ingestion of caffeine (>400 mg) had a higher prevalence of major depression. As this was a cross-sectional analysis, the direction of causal effect for the observed associations could not be determined. By identifying variables that are associated with lifetime major depression, these data generate hypotheses for future prospective studies. Such studies will be needed to further understand the etiology of depressive disorders in MS.

Childhood parental loss and risk for first-onset of major depression and alcohol dependence: the time-decay of risk and sex differences

2002 ◽  
Vol 32 (7) ◽  
pp. 1187-1194 ◽  
Author(s):  
K. S. KENDLER ◽  
K. SHETH ◽  
C. O. GARDNER ◽  
C. A. PRESCOTT
Keyword(s):  
Sex Differences ◽  
Major Depression ◽  
Alcohol Dependence ◽  
Time Course ◽  
Conditional Logistic Regression ◽  
Population Based ◽  
Parental Loss ◽  
Proportional Hazard ◽  
Increased Risk ◽  
The Impact

Background. Whereas a number of studies have suggested that parental loss is associated with increased risk for major depression (MD), much less is known about possible gender differences, diagnostic specificity and the time course of the impact of loss.Method. First-onsets for MD and alcohol dependence (AD) were assessed at personal interviews in 5070 twins from same-sex (SS) and 2118 from opposite-sex (OS) twin pairs ascertained from a population-based registry. Cox Proportional Hazard (PH) and Non-Proportional Hazard (NPH) models, examining first onsets of MD and AD, were used with twins from SS pairs and conditional logistic regression for OS pairs. Parent–child separations prior to age 17 were divided into death and separation from other causes.Results. The PH assumptions of constant increased risk were rejected for the impact of loss on risk for MD but not for AD. NPH models found significantly increased risk for MD after both death and separation with the risk lasting much longer for separations. For AD, the PH model found significantly increased risk after parental separation but not death. In both SS and OS twin pairs, no sex differences were seen in the impact of parental loss on risk for MD whereas the association between separation and risk for AD was significantly stronger in females than in males.Conclusion. Consistent sex differences in the association with parental loss were seen for AD but not MD. The analysis of the time-course of increased risk after loss suggests three different patterns which may reflect different relationships: parental death and MD (return to baseline within ∼12 years), separation and MD (return to baseline within ∼30 years) and separation and AD (no change in risk over time).

Are there sex differences in the reliability of a lifetime history of major depression and its predictors?

2001 ◽  
Vol 31 (4) ◽  
pp. 617-625 ◽  
Author(s):  
K. S. KENDLER ◽  
C. O. GARDNER ◽  
C. A. PRESCOTT
Keyword(s):  
Sex Differences ◽  
Major Depression ◽  
Age At Onset ◽  
High Sensitivity ◽  
High Specificity ◽  
Population Based ◽  
History Of ◽  
The Stability ◽  
Depressive Episodes

Background. Although lifetime major depression (LTMD) is assessed with only moderate reliability in community samples, some predictors have emerged for ‘reliable’ LTMD. Given the large impact of sex on risk for LTMD, it is of interest to know if there are sex differences in the reliability of LTMD and its predictors.Methods. A total of 5603 members of male–male and male–female twin pairs from a population-based registry were interviewed twice with a mean inter-interview interval of 19 months. LTMD was assessed on each occasion using DSM-III-R criteria. Univariate and multivariate logistic regression analyses were used, combining forward and back-prediction.Results. The long-term test–retest reliability of LTMD was moderate (κ = +0·48) and did not differ significantly between males and females. In a multivariate model, the significant predictors of a stable diagnosis of LTMD, none of which differed across sex, were younger age at onset, older current age, history of treatment, increasing number of symptoms, level of impairment or level of distress, longer duration of episodes, higher current level of depression and the presence during the depressive episode of sad mood, weight loss, hypersomnia or fatigue. Using these variables, it was not possible to predict ‘stably diagnosed’ LTMD with both high sensitivity and high specificity.Conclusion. In community samples, LTMD is diagnosed with moderate reliability. Although diagnostic stability can be predicted by variables related to severity, distress and treatment-seeking (probably acting to make depressive episodes more ‘memorable’), highly accurate prediction of stably diagnosed cases is not possible. Long-term recall is also significantly influenced by current symptoms. Neither the stability of LTMD nor its predictors differ in men and women.

scholarly journals Evidence of causal effect of major depression on alcohol dependence: Findings from the Psychiatric Genomics Consortium

2018 ◽  
Author(s):  
Renato Polimanti ◽  
Roseann E. Peterson ◽  
Jue-Sheng Ong ◽  
Stuart MacGregor ◽  
Alexis C. Edwards ◽  
...  
Keyword(s):  
Major Depression ◽  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Causal Relationships ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Genetic Mechanisms ◽  
Shared Genetic

ABSTRACTBackgroundDespite 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.MethodsThis study was conducted using genome-wide data from the Psychiatric Genomics Consortium (MD: 135,458 cases and 344,901 controls; AD: 10,206 cases and 28,480 controls) and UK Biobank (AC-Frequency: from “daily or almost daily” to “never”, 438,308 individuals; AC-Quantity: total units of alcohol per week, 307,098 individuals). Linkage disequilibrium score regression and Mendelian Randomization (MR) analyses were applied to investigate shared genetic mechanisms (horizontal pleiotropy) and causal relationships (mediated pleiotropy) among these traits.OutcomesPositive 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 traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e., causal relationship) with a causal role of MD on AD (beta=0.28, P=1.29×10-6) that does not appear to be biased by confounding such as horizontal pleiotropy. No evidence of reverse causation was observed as the AD genetic instrument did not show a causal effect on MD.InterpretationResults support a causal role for MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity not only addresses important public health concerns but also has the potential to facilitate prevention and intervention efforts.FundingNational Institute of Mental Health and National Institute on Drug Abuse.Putting data into contextEvidence before this studyWe searched PubMed up to August 24, 2018, for research studies that investigated causality among alcohol-and depression related phenotypes using Mendelian randomization approaches. We used the search terms “alcohol” AND “depression” AND “Mendelian Randomization”. No restrictions were applied to language, date, or article type. Ten articles were retrieved, but only two were focused on alcohol consumption and depression-related traits. The studies were based on genetic variants in alcohol dehydrogenase (ADH) genes only, did not find evidence for a causal effect of alcohol consumption on depression phenotypes, with one study finding a causal effect of alcohol consumption on alcoholism. Both studies noted that future studies are needed with increased sample sizes and clinically derived phenotypes. To our knowledge, no previous study has applied two-sample Mendelian randomization to investigate causal relationships between alcohol dependence and major depression.Twin studies show genetic factors influence susceptibility to MD, AD, and alcohol consumption. Differently from observational approaches where several studies have investigated the relationship between alcohol-and depression-related phenotypes, very limited use of molecular genetic data has been applied to investigate this issue. Additionally, the use of genetic information has been shown to be less biased by confounders and reverse causation than observation data. However, genetic approaches, like Mendelian randomization, require large sample sizes to be informative.Added value of this studyIn this study, we used genome-wide data from the Psychiatric Genomic Consortium and UK Biobank, which include information regarding hundred thousands of individuals, to test the presence of shared genetic mechanisms and causal relationships among major depression, alcohol dependence, and alcohol consumption. The results support a causal influence of MD on AD, while alcohol consumption showed shared genetic mechanisms with respect to both major depression and alcohol dependence.Implications of all the available evidenceGiven the significant morbidity and mortality associated with MD, AD, and the comorbid condition, understanding mechanisms underlying these associations not only address important public health concerns but also has the potential to facilitate prevention and intervention efforts.

Neuroticism, major depression and gender: a population-based twin study

2002 ◽  
Vol 32 (4) ◽  
pp. 719-728 ◽  
Author(s):  
A. FANOUS ◽  
C. O. GARDNER ◽  
C. A. PRESCOTT ◽  
R. CANCRO ◽  
K. S. KENDLER
Keyword(s):  
Major Depression ◽  
Genetic Correlation ◽  
Short Form ◽  
Molecular Genetic ◽  
Genetic Correlations ◽  
Population Based ◽  
Eysenck Personality Questionnaire ◽  
Structured Interviews ◽  
Best Fitting ◽  
Fitting Model

Background. A portion of the genetic risk factors for the personality trait neuroticism (N) may also increase risk for major depression (MD). Females have both higher levels of N and higher rates of MD than males, suggesting that these traits may be more genetically correlated in females.Methods. Structured interviews, including a lifetime assessment for MD by DSM-III-R criteria, were administered to 863 male–male MZ (monozygotic), 649 male–male DZ (dizygotic), 506 female–female MZ, 345 female–female DZ, and 1408 opposite-sex twin pairs. N was assessed using the short-form of the Eysenck Personality Questionnaire. A sex-limited Cholesky model was fitted which allowed us to decompose into additive genetic, common environmental, and individual-specific environmental components two main classes of correlations: within-sex between-variable and between-sex within-variable.Results. Our best-fitting model contained only additive genetic and individual-specific environmental factors for both N and MD. The within-sex genetic correlations between N and MD were estimated at +0·68 in men and +0·49 in women. This model fitted only slightly better than one in which the N–MD within-sex genetic correlation was constrained to be equal across the sexes, and estimated at +0·55. There may be sex-specific genes influencing both N and MD.Conclusion. Our best-fitting model failed to establish a significant sex difference in the genetic correlation between N and MD. These results, as well as evidence for sex-specific genetic factors for both traits, have implications for the diagnosis, classification, and treatment of the affective disorders, and molecular genetic approaches to the study of these traits.

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