Common genetic contributions to alcohol and cannabis use and dependence symptomatology.

paper Cited Public

Authors: Sartor, Carolyn E; Grant, Julia D; Bucholz, Kathleen K; Madden, Pamela A F; Heath, Andrew C; Agrawal, Arpana; Whitfield, John B; Statham, Dixie J; Martin, Nicholas G; Lynskey, Michael T
Year: 2010
Journal: Alcoholism, clinical and experimental research
PMID: 20028363
DOI: 10.1111/j.1530-0277.2009.01120.x
PMCID: PMC3089946

BACKGROUND: Despite mounting evidence that use of and dependence on alcohol and cannabis are influenced by heritable factors, the extent to which heritable influences on these phenotypes overlap across the 2 substances has only rarely been explored. In the current study, we quantified cross-substance overlap in sources of variance and estimated the degree to which within-substance associations between use and dependence measures are attributable to common genetic and environmental factors for alcohol and cannabis. METHODS: The sample was comprised of 6,257 individuals (2,761 complete twin pairs and 735 singletons) from the Australian Twin Registry, aged 24 to 36 years. Alcohol and cannabis use histories were collected via telephone diagnostic interviews and used to derive an alcohol consumption factor, a frequency measure for cannabis use, and DSM-IV alcohol and cannabis dependence symptom counts. Standard genetic analyses were conducted to produce a quadrivariate model that provided estimates of overlap in genetic and environmental influences across the 4 phenotypes. RESULTS: Over 60% of variance in alcohol consumption, cannabis use, and cannabis dependence symptoms, and just under 50% of variance in alcohol dependence (AD) symptoms were attributable to genetic sources. Shared environmental factors did not contribute significantly to the 4 phenotypes. Nearly complete overlap in heritable influences was observed for within-substance measures of use and dependence symptoms. Genetic correlations across substances were 0.68 and 0.62 for use and dependence symptoms, respectively. CONCLUSIONS: Common heritable influences were evident for alcohol and cannabis use and for AD and cannabis dependence symptomatology, but findings indicate that substance-specific influences account for the majority of the genetic variance in the cannabis use and dependence phenotypes. By contrast, the substantial correlations between alcohol use and AD symptoms and between cannabis use and cannabis dependence symptoms suggest that measures of heaviness of use capture much of the same genetic liability to alcohol- and cannabis-related problems as dependence symptomatology.

Figure 1

Rates (%) of Alcohol Dependence Across Varying Levels of Alcohol Consumption By Sex

LLM interpretation

This line graph shows the percentage of alcohol dependence across five quintiles of alcohol consumption, categorized by sex (represented by a solid black line and a dashed grey line). For both groups, the rate of alcohol dependence increases as alcohol consumption increases. The solid black line shows a sharper increase in the fifth quintile, reaching approximately 60%, while the dashed grey line reaches approximately 40%.

Figure 2

Rates (%) of Cannabis Dependence Across Varying Levels of Cannabis Use By Sex

LLM interpretation

This line graph shows the percentage of cannabis dependence across five levels of cannabis use frequency, categorized by sex. Both groups show a positive correlation between frequency of use and dependence rates, with the steepest increases occurring between levels 3 and 5. The group represented by the dashed line consistently exhibits higher rates of dependence than the group represented by the solid line from level 3 onward.

Figure 3

Unstandardized Additive Genetic Path Estimates For the Four PhenotypesRaw path estimates are shown in Figure 3.Calculation of genetic variance from common and specific sources is illustrated below for cannabis dependence symptoms:Total genetic variance = (.6182)2 + (.1928)2 + (.5021)2 = 0.6715Variance explained by A1 (genetic influences common to all four phenotypes) = (.5021)2/.6715 = .3754*Variance explained by A2 (genetic influences shared by alcohol consumption, cannabis dependence symptoms, and cannabis use) = (.1928)2/.6715 = .0554**Variance explained by A3 (genetic influences common to cannabis dependence symptoms and cannabis use) = (.6182)2/.6715 = .5691*From Table 6, the genetic correlation between alcohol dependence symptoms and cannabis dependence symptoms is 0.6128, which is computed as √.3754**From Table 6, the genetic correlation between alcohol consumption and cannabis dependence symptoms is 0.6558. This is NOT equal to √.0554. To calculate this correlation, we compute the total genetic covariance across the two measures, including variance shared with alcohol dependence symptoms, and divide it by the product of the square root of the total genetic variance in alcohol consumption and cannabis dependence symptoms.Therefore, 0.6558 = (.2362 × .1928) + (.7445 × .5021) / [(√0.6715) × (√0.6100)] where .6100 = (.2362)2 + (.7445)2 = the total genetic variance in alcohol consumption explained by A1 and A2.

LLM interpretation

This is a path diagram illustrating unstandardized additive genetic path estimates for four phenotypes: Alcohol Dependence Symptoms, Alcohol Consumption, Cannabis Dependence Symptoms, and Cannabis Use. The diagram shows genetic influences represented by latent variables ($A_1$ through $A_4$), with arrows indicating the paths to each phenotype and their corresponding numerical coefficients (e.g., $a_{11} = .6836$). Solid lines represent direct paths, while dashed lines indicate other genetic contributions to the phenotypes.

#	Section	Preview
20	MATERIALS AND METHODS — Data Analysis — Quadrivariate Model	A quadrivariate triangular decomposition (also known as a Cholesky decomposition) was fitted to…
21	MATERIALS AND METHODS — Data Analysis — Quadrivariate Model	A series of sub-models examining the statistical significance of A, C, and E were compared to the…
22	RESULTS — Level of Use and Risk for Dependence	As seen in Figure 1, a linear relationship between alcohol consumption and AD was observed in males,…
23	RESULTS — Co-occurrence of Alcohol Dependence and Cannabis Dependence	Rates of cannabis dependence were substantially higher in individuals who met criteria for alcohol…
24	RESULTS — Quadrivariate Model	The sub-models tested and their corresponding model fit statistics are reported in Table 3. Models 1…
25	RESULTS — Quadrivariate Model	the parameter estimates can be equated across sex; Model 3 was therefore selected as the…
26	RESULTS — Quadrivariate Model	Under the best-fitting model (shown in Table 4), heritable influences accounted for over 60% of the…
27	RESULTS — Quadrivariate Model	Phenotypic correlations among alcohol consumption, cannabis use, AD symptoms, and cannabis…
28	RESULTS — Quadrivariate Model	The proportion of genetic variance attributable to various sources was calculated using…
29	RESULTS — Quadrivariate Model	Analyses revealed both within- and cross-substance overlap in non-shared environmental factors as…
30	DISCUSSION	Our investigation of genetic and environmental contributions to use and dependence symptomatology…
31	DISCUSSION	The correspondence between heaviness of alcohol consumption and level of risk for dependence in the…
32	DISCUSSION	have measured heaviness of cannabis use in terms of number of days used per week or month, whereas…
33	DISCUSSION	Genetic modeling revealed that just under half of the variance in AD symptoms and over 60% of…
34	DISCUSSION	for cannabis use and dependence symptoms closely match those from prior studies, which have…
35	DISCUSSION	We found a high degree of within-substance overlap in heritable influences on use and dependence. In…
36	DISCUSSION	highly informative for investigations focusing on the other phenotype; it may even be possible to…
37	DISCUSSION	With respect to individual-specific environmental influences, the degree of overlap across use and…
38	DISCUSSION	In addition to the high within-substance correlations, we found a moderate degree of overlap in…
39	DISCUSSION	symptoms. Our estimates of overlap in heritable influences on dependence symptoms are highly…

Name	Type
12th graders	cohort
Additive genetic local	phenotype
adolescent cannabis use	phenotype
Adolescents and adults local	cohort
AD risk	phenotype
AD symptoms	phenotype
alcohol	phenotype
Alcohol consumption heaviness local	phenotype
alcohol dependence	phenotype
Alcohol Dependence Symptoms	phenotype
alcohol-related phenotypes	phenotype
alcohol-related problems	phenotype
Alcohol Use	phenotype
Alcohol Use Disorder	phenotype
all-male adult twin sample local	cohort
anxiety	phenotype
Australian Twin Registry	cohort
Australian young adults local	cohort
Average alcohol intake local	phenotype
caffeine	drug
caffeine dependence	phenotype
cannabis dependence	phenotype
Cannabis phenotypes local	phenotype
Cannabis-related phenotype local	phenotype
Cannabis-related phenotypes local	phenotype
cannabis-related problems	phenotype
cannabis use	phenotype
Cannabis use frequency local	phenotype
cigarettes	phenotype
cocaine	phenotype
conduct disorder	phenotype
Consumption/use local	phenotype
current study	cohort
dependence	phenotype
dependence symptomatology local	phenotype
Dependence symptomatology local	phenotype
Dependence symptoms	phenotype
deviant peers	phenotype
DSM-IV cannabis dependence criteria local	phenotype
externalizing disorders	phenotype
family history of alcoholism	phenotype
Female cannabis users	phenotype
genes	gene
genetic factors	cohort
Heavier use	phenotype
Heaviness of alcohol use factor local	phenotype
Heaviness of use local	phenotype
Heaviness of Use local	phenotype
heavy cannabis use	phenotype
heavy drinking	phenotype
illicit drugs	phenotype
initiation	phenotype
King et al. 2005 longitudinal study local	cohort
Licit substances local	phenotype
Male cannabis users	phenotype
men	cohort
mood disorders	phenotype
nicotine	drug
nicotine dependence	phenotype
Non-additive genetic local	phenotype
Non-shared environmental local	phenotype
other drug use	phenotype
Parental substance-related problems local	phenotype
problematic alcohol use	phenotype
problem cannabis use	phenotype
problem use	phenotype
problem use of alcohol local	phenotype
problem use of cannabis local	phenotype
quantity consumed local	phenotype
sex	phenotype
Shared environmental local	phenotype
substance use	phenotype
Twin cohort	cohort
United States	cohort
U.S. 12th graders local	cohort
Use symptoms local	phenotype
women	cohort
Xian et al., 2008 local	cohort

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In this knowledge base

Title	Year	PMID
Comparison of Parent, Peer, Psychiatric, and Cannabis Use Influences Across Stages of Offspring Alcohol Involvement: Evidence from the COGA Prospective Study.	2017	28073157
Examining the role of common genetic variants on alcohol, tobacco, cannabis and illicit drug dependence: genetics of vulnerability to drug dependence.	2015	25424661
Genetic etiology of the common liability to drug dependence: evidence of common and specific mechanisms for DSM-IV dependence symptoms.	2012	22243758
Stable genetic effects on symptoms of alcohol abuse and dependence from adolescence into early adulthood.	2012	21818662

External

Title	Authors	Journal	Year	Link
Generalized genetic liability to substance use disorders.	Miller AP et al.	—	2024	→
Methods and Challenges for Assessing Heterogeneity.	Feczko E et al.	—	2020	→
Structural alterations within cerebellar circuitry are associated with general liability for common mental disorders.	Romer AL et al.	—	2018	→
The gene-environmental architecture of the development of adolescent substance use.	Vitaro F et al.	—	2018	→
Age of initiation and substance use progression: A multivariate latent growth analysis.	Richmond-Rakerd LS et al.	—	2017	→
Comparison of Parent, Peer, Psychiatric, and Cannabis Use Influences Across Stages of Offspring Alcohol Involvement: Evidence from the COGA Prospective Study.	Bucholz KK et al.	—	2017	→
Dimensionality and Genetic Correlates of Problem Behavior in Low-Income African American Adolescents.	Latendresse SJ et al.	—	2017	→
Comorbid trajectories of substance use as predictors of Antisocial Personality Disorder, Major Depressive Episode, and Generalized Anxiety Disorder.	Brook JS et al.	—	2016	→
Examining the role of common genetic variants on alcohol, tobacco, cannabis and illicit drug dependence: genetics of vulnerability to drug dependence.	Palmer RH et al.	—	2015	→
Genetic and Environmental Interplay in Adolescent Substance Use Disorders.	Hines LA et al.	—	2015	→
The role of conduct disorder in the relationship between alcohol, nicotine and cannabis use disorders.	Grant JD et al.	—	2015	→
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CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity.	Onaivi ES et al.	—	2012	→
Genetic etiology of the common liability to drug dependence: evidence of common and specific mechanisms for DSM-IV dependence symptoms.	Palmer RH et al.	—	2012	→
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Stable genetic effects on symptoms of alcohol abuse and dependence from adolescence into early adulthood.	van Beek JH et al.	—	2012	→
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