Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts

Barr, Peter B.; Driver, Morgan N.; Kuo, Sally I‐Chun; Stephenson, Mallory; Alıev, Fazil; Linnér, Richard Karlsson; Marks, Jesse; Anokhin, Andrey P.; Bucholz, Kathleen K.; Chan, Grace; Edenberg, Howard J.; Edwards, Alexis C.; Francis, Meredith W.; Hancock, Dana B.; Harden, K. Paige; Kamarajan, Chella; Kaprio, Jaakko; Kinreich, Sivan; Kramer, John; Kuperman, Samuel; Latvala, Antti; Meyers, Jacquelyn L.; Palmer, Abraham A.; Plawecki, Martin H.; Porjesz, Bernice; Rose, Richard J.; Schuckit, Marc A.; Salvatore, Jessica E.; Dick, Danielle M.

doi:10.1038/s41380-022-01801-6

Cited by 16 publications

(15 citation statements)

References 67 publications

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“…Problems related to behavioral disinhibition, commonly referred to as externalizing, can have far reaching health consequences. We and others have shown that risk for EXT disorders overlaps with a variety of key public health outcomes at both the genetic and phenotypic level 11,[13][14][15][16][17][18]48 . In the current analysis, we leveraged these recent, novel insights into the underlying biology of EXT, extended analyses to multiple ancestries, and evaluated their correlates and consequences in the largest integrated healthcare system in the US.…”

Section: Discussionmentioning

confidence: 95%

“…Additional work is needed to ensure that the study results generalize beyond the VA. Third, we did not examine PGS in conjunction with social and environmental factors. Both polygenic and environmental risk factors are important for understanding key outcomes in veterans' health, including substance use disorders 48 , major depressive disorder 52 , and other mental health problems 53 . Many veterans are at risk for adverse environmental experiences due to poverty, minority status, and physical and psychiatric challenges 54 .…”

Section: Discussionmentioning

confidence: 99%

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Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

Barr

Bigdeli

Meyers

et al. 2023

Preprint

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Many psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the importance of EXT for aspects of veterans health, such as suicide-related behaviors, substance use disorders, and other medical conditions. To better understand how genetic risk for EXT is related to veterans health, we conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychopathology (depression, schizophrenia, suicide attempt) in an ancestrally diverse cohort of U.S. veterans (Total N = 560,824), using diagnostic codes from electronic health records. First, to identify phenotypes associated with the EXT PGS, we conducted ancestry-specific PheWAS in the European, African, and Admixed American ancestries (separately). Second, to determine if associations were driven by risk for other comorbid psychiatric conditions, we performed a conditional PheWAS of the significant associations from the main PheWAS, covarying for PGS related to depression, schizophrenia, and suicide attempt (European ancestries only). Lastly, to adjust for unmeasured confounders we performed a within-family PheWAS of the significant associations from the main PheWAS in full-siblings identified in MVP (N = 12,127, European ancestries only). EXT PGS was associated with outcomes across all bodily systems, independent of risk for depression, schizophrenia, or suicide attempt. Within-family analyses uncovered robust associations between EXT and consequences of substance use disorders, including chronic liver disease, chronic airway obstruction, and viral hepatitis C. These results demonstrate a shared polygenic basis of EXT across populations of diverse ancestries and highlight the negative consequences of EXT for health and functioning in the US veteran population.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

Barr

Bigdeli

Meyers

et al. 2023

Preprint

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“…As our gene identification efforts continue to evolve, COGA has initiated efforts to combine genetic information with known environmental risk factors to predict risk for substance use disorders in clinical and population-based samples. 134,135 Although these are not yet ready for integration into clinical practice, we have begun to lay the groundwork for the utilization of genetic risk information by reviewing the current status of genetic feedback for psychiatric conditions, 136 studying public interest in receiving personalized genetic risk scores, 137 and examining how we can return complex risk information in ways that will promote healthy behavior. 138 It will be critical to carefully consider the benefits and potential harm that could result from the incorporation of genetic risk information into clinical care.…”

Section: Risk Prediction and Contributions To Precision Medicinementioning

confidence: 99%

The collaborative study on the genetics of alcoholism: Sample and clinical data

Dick

Balcke

Francis

et al. 2023

Genes Brain and Behavior

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The collaborative study on the genetics of alcoholism (COGA) is a multi‐site, multidisciplinary project with the goal of identifying how genes are involved in alcohol use disorder and related outcomes, and characterizing how genetic risk unfolds across development and in conjunction with the environment and brain function. COGA is a multi‐generational family‐based study in which probands were recruited through alcohol treatment centers, along with a set of community comparison families. Nearly 18,000 individuals from >2200 families have been assessed over a period of over 30 years with a rich phenotypic battery that includes semi‐structured psychiatric interviews and questionnaire measures, along with DNA collection and electrophysiological data on a large subset. Participants range in age from 7 to 97, with many having longitudinal assessments, providing a valuable opportunity to study alcohol use and problems across the lifespan. Here we provide an overview of data collection methods for the COGA sample, and details about sample characteristics and comorbidity. We also review key research findings that have emerged from analyses of the COGA data. COGA data are available broadly to researchers, and we hope this overview will encourage further collaboration and use of these data to advance the field.

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“…The identification of these multiple variants will help predict the onset and development of individual risk for dependence. PGS analysis has been used to evaluate risk for AUD both by others 16,75,76 and within COGA [77][78][79][80][81][82]…”

Section: Combined Effect Of Multiple Aud-related Genetic Variants On ...mentioning

confidence: 99%

5. Collaborative Study on the Genetics of Alcoholism: Functional genomics

Gameiro‐Ros

Popova

Prytkova

et al. 2023

Genes Brain and Behavior

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Alcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome‐wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post‐mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell‐derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.

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Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts

Abstract: doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 16 publications

References 67 publications

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

The collaborative study on the genetics of alcoholism: Sample and clinical data

5. Collaborative Study on the Genetics of Alcoholism: Functional genomics

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