Unlocking the Genetic Secrets of Problematic Alcohol Use

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Excessive alcohol use and alcohol use disorder (AUD) pose a significant global public health challenge, contributing to a substantial burden of disease and mortality. According to statistics, alcohol use accounts for 2.2% of female deaths and 6.8% of male deaths worldwide. AUD, a chronic relapsing disease, brings forth an array of detrimental medical, psychiatric, and social consequences.

The 2021 National Survey on Drug Use and Health in the United States revealed that approximately 29.5 million individuals aged 12 and older had been diagnosed with AUD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria in the past year. Shockingly, fewer than 8.7% of these diagnosed individuals had received any form of treatment for their condition.

In the realm of treatment, only three medications—disulfiram, naltrexone, and acamprosate—bear approval from the United States Food and Drug Administration for addressing AUD, with two others, topiramate and gabapentin, being recommended for off-label use.

The complexity of AUD stems from a combination of genetic and environmental factors. Observational studies have indicated a heritability (h2) of approximately 50%, suggesting that genetics play a substantial role in influencing AUD risk. Recognizing genetic factors associated with AUD could significantly advance the development of prevention strategies, diagnostic tools, and treatment approaches for the medical, psychiatric, and social ramifications of alcohol misuse. The field of genetics has seen significant progress through genome-wide association studies (GWAS) focused on AUD and related traits.

One noteworthy GWAS examined problematic alcohol use (PAU) in a large cohort of 435,563 individuals. PAU is a composite phenotype encompassing traits highly correlated with AUD, alcohol dependence (AD), and alcohol-related problems. This study identified 29 distinct risk variants, primarily among individuals of European ancestry. It unveiled a crucial revelation that both AUD and PAU differ genetically and phenotypically from typical alcohol consumption. They tap into aspects of excessive alcohol intake and elevated risk that are intricately intertwined with genetic predispositions to psychiatric and psychosocial factors such as major depressive disorder and lower educational attainment.

The study also revealed a two-factor genetic structure within the AUDIT questionnaire, emphasizing the unique genetic influences on alcohol consumption and alcohol-related problems. Additionally, it pointed out the confounding impact of socioeconomic status on the genetics of drinking frequency.

This genetic divergence between substance use disorder (SUD) and nondependent substance use has also been observed in the context of cannabis use disorder, highlighting a broader pattern in addictive behaviors. When considering multiple SUDs, it becomes apparent that problematic and disordered substance use has a distinct genetic architecture, shared to some extent across various SUDs, but not fully overlapping with nondependent substance use.

Despite significant findings in GWAS studies of PAU, substantial gaps persist in our comprehension of its genetic underpinnings. Firstly, the SNP-based heritability (h2) estimates for both AUD and PAU fall within the range of 5.6% to 10.0%, indicating a substantial “missing heritability” component that remains to be identified. Secondly, the majority of genetic samples utilized in these studies, including those for AUD, originate from individuals of European genetic ancestry.

This lack of diversity poses a critical limitation for understanding the genetic foundations of these traits and their applicability to diverse global populations. A previous study within the Million Veteran Program (MVP) made strides in addressing this issue by analyzing AUD across multiple ancestral groups. However, the non-European samples in this study were significantly smaller in number compared to their European counterparts, leading to a lack of statistical power and an imbalance in gene discovery across different ancestral backgrounds.

In this groundbreaking article, we present a substantial advancement in our understanding of the genetic basis of PAU across diverse populations. Our study involved an extensive GWAS of PAU in specific ancestral groups, followed by a comprehensive cross-ancestry meta-analysis, which encompassed a staggering total of 1,079,947 individuals from multiple cohorts. Our findings are transformative and promising:

  • Identification of 85 independent risk variants among individuals of European ancestry and 110 in the within-ancestry and cross-ancestry meta-analyses.
  • Exploration of the shared genetic architectures of PAU across various ancestral backgrounds.
  • Fine mapping for causal variants, providing crucial insights into the genetic mechanisms underpinning PAU.
  • Identification of numerous genes associated with the brain, offering a new perspective on the neurological aspects of PAU.
  • Drug repurposing analysis, revealing potential medications that warrant further investigation for their efficacy in treating PAU.

These findings represent a significant leap forward in our understanding of the genetic determinants of problematic alcohol use. The increased number of identified loci enhances our ability to investigate the causal relationships between PAU and other diseases, shedding light on the shared genetic architecture across diverse ancestral groups.

Furthermore, the identification of potential druggable targets opens up new avenues for pharmacological research and treatment development. This research promises to have far-reaching implications in the fields of addiction medicine, public health, and personalized treatment strategies for individuals struggling with problematic alcohol use.

Discussion

In this discussion, we delve deeper into the remarkable findings and implications of the largest multi-ancestry Genome-Wide Association Study (GWAS) for Problematic Alcohol Use (PAU) to date. With over a million individuals and more than 165,000 cases of Alcohol Use Disorder (AUD) and Alcohol Dependence (AD) included, this study has provided unprecedented insights into the genetic underpinnings of PAU and its implications for diverse populations.

Broadening Our Horizons: Multi-Ancestry Approach

The inclusion of multiple ancestral groups in this study has proven to be a game-changer. Not only has it expanded the scope of our findings, but it has also demonstrated that the genetic architecture of PAU is shared to a significant extent across different populations. This cross-ancestry approach has allowed for a more comprehensive understanding of the genetic factors contributing to PAU, transcending the limitations of single-ancestry studies. Furthermore, it has enabled the development of more accurate polygenic risk scores (PRS) that can predict alcohol-related traits with greater precision in independent samples, ultimately enhancing the applicability of our findings.

Unveiling Key Genetic Variants

Among the 110 variants associated with PAU identified in this study, several stand out as noteworthy candidates. One such variant is rs1799971, located in the OPRM1 gene, which encodes the μ opioid receptor—a pivotal player in regulating pain perception, reward pathways, and addictive behaviors. Intriguingly, this variant has previously been implicated in Opioid Use Disorder (OUD) through large GWAS. Notably, this study is the first to confirm the association of rs1799971 with PAU, highlighting its potential relevance in the context of alcohol addiction.

While previous research indicated a potential European-specific effect on OUD, this study found OPRM1’s association with PAU to be cross-ancestral. Further exploration in larger non-European populations is warranted to fully understand the extent of this SNP’s involvement in Substance Use Disorders (SUDs).

Another intriguing genetic variant is rs6265 in the BDNF gene (brain-derived neurotrophic factor), a protein crucial for neuronal growth and development. This variant has been extensively studied and linked to various behaviors, including smoking traits and externalizing behavior. Additionally, rs13107325 in SLC39A8, a gene associated with schizophrenia and glycemic traits, has shown associations with substance use and PAU. These findings emphasize the intricate interplay between genetic factors and complex behaviors like PAU.

Heritability and Rare Variants

The study’s estimation of the heritability of AUD, ranging from 12.4% in Latin American (LA) populations to 16.2% in African (AFR) populations, sheds light on the genetic contribution to the risk of PAU. However, it is crucial to note that accounting for a higher proportion of heritability depends on both the genetic architecture of the trait and the sample size’s power.

In comparison, whole-genome sequencing studies of more stable traits like height have provided heritability estimates closer to pedigree-based estimates, highlighting the complex nature of heritability in PAU/AUD. Further investigations using whole-genome sequencing may uncover rare variants that contribute to PAU risk, as they represent a significant source of missing heritability.

Brain-Related Traits and Functional Enrichment

Evidence from previous studies has consistently highlighted PAU as a brain-related trait, with functional and heritability enrichment in various brain regions. In this study, gene-based association, Transcriptome-Wide Association Studies (TWAS) conducted in brain tissues, and H-MAGMA analysis in brain annotations revealed 51 genes associated with PAU across multiple levels of analysis. Notably, the ADH1B gene’s expression in the putamen was linked to PAU through TWAS, indicating potential biological mechanisms beyond its known hepatic effect on alcohol metabolism.

Similarly, DRD2 gene expression in the cerebellar hemisphere and chromatin interactions across brain annotations were associated with PAU risk. This underscores the intricate interplay between alcohol metabolism, neural pathways, and genetic factors, offering new insights into the biology of PAU.

Translating Genetic Discoveries into Therapeutic Applications

While our understanding of the genetic underpinnings of PAU has grown significantly, the translation of these discoveries into effective therapeutics remains a complex challenge. Nevertheless, the identification of several genes associated with PAU that interact with drugs approved to treat AUD offers promising avenues for drug repurposing. For instance, GABRA4’s interaction with acamprosate and OPRM1’s interaction with naltrexone open up possibilities for targeted treatments.

Moreover, multivariate analysis suggests potential repurposable drugs, such as trichostatin-a, spironolactone, and clomethiazole, which have demonstrated effects on histone acetylation, neuropeptide Y expression, and alcohol withdrawal-related anxiety. This highlights the potential for novel therapeutic approaches based on genetic insights, though the journey from genetic variants to biologically significant therapeutic targets remains intricate and requires extensive further research.

Genetic Correlations and Future Directions

The study also explored the genetic relationships between PAU and various traits. Genetic correlations were identified between PAU and substance use traits, including OUD, smoking trajectory, and maximum habitual alcohol intake. These findings underscore the interconnected nature of addictive behaviors and provide a basis for future investigations into shared genetic factors.

While this study has provided invaluable insights into the genetic foundations of PAU, several limitations should be acknowledged. Phenotypic heterogeneity and differences in cohort ascertainment may introduce bias into the results. Additionally, the study’s focus on PAU, while genetically correlated with AUDIT–P, introduces heterogeneity. Differences in cohort ascertainment, such as comorbidities in certain cohorts, may have affected the findings. Furthermore, limited sample sizes in non-European ancestries remain a challenge, emphasizing the importance of collecting data from diverse genetic backgrounds.

In conclusion, this multi-ancestry GWAS for PAU has advanced our understanding of the genetic factors contributing to problematic alcohol use in multiple ways. It has highlighted the shared genetic architecture across diverse populations, identified potential candidate genes, revealed the heritability of PAU, and offered insights into brain-related traits and therapeutic possibilities.

This study marks a significant milestone in unraveling the genetic mysteries of PAU, paving the way for future research and potential breakthroughs in the prevention and treatment of alcohol-related disorders. As biobanks and large consortia continue to grow and diversify, we can anticipate a narrowing gap in genetic research between European and non-European populations, ultimately leading to more inclusive and effective interventions for individuals struggling with PAU and related conditions.


reference link : https://www.nature.com/articles/s41591-023-02653-5#Sec15

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