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Genetics of Tobacco Use Disorder (TUD) & Nicotine Addiction (2024 Study)

Tobacco use is a complex behavior influenced by both environmental factors and genetic predispositions.

A recent study leveraging the UCLA ATLAS biobank explored the genetic underpinnings of Tobacco Use Disorder (TUD) and its systemic health effects using a Polygenic Score (PGS).


  • Genetic Underpinnings of Tobacco Use: The study used a European ancestry-derived PGS to evaluate genetic predispositions to TUD in a diverse population.
  • Predictive Performance Across Ancestries: The PGS showed varying predictive accuracies across different genetically inferred ancestry groups (GIAs), highlighting the complexity of genetic influences on tobacco use.
  • Systemic Health Impacts: TUD-related genetic predispositions were linked with several health conditions, including cardiometabolic and respiratory diseases, even in non-smokers.
  • Implications for Precision Medicine: The study underscores the importance of including diverse populations in genetic research for equitable clinical applications and comprehensive tobacco use prevention strategies.

Source: Translational Psychiatry (2024)

Tobacco Use Disorder (TUD) & Nicotine Addiction (Overview)

Tobacco Use Disorder is a medical condition characterized by an uncontrolled dependency on tobacco products.

This dependency often leads to significant health, social, and economic consequences. The disorder encompasses a range of behaviors from occasional use to severe addiction.

Causes of Tobacco Use Disorder

  • Nicotine Dependency: Central to TUD is the addictive nature of nicotine, a key chemical in tobacco that stimulates the brain’s reward system.
  • Environmental Factors: Exposure to tobacco use in family settings, peer influence, and societal norms can contribute to the initiation and continuation of tobacco use.
  • Psychological Factors: Stress, anxiety, and other mental health conditions can increase susceptibility to TUD, often as a coping mechanism.
  • Socioeconomic Influences: Lower socioeconomic status and limited access to education are correlated with higher rates of tobacco use.

Signs & Symptoms of Tobacco Use Disorder

  • Cravings: A strong desire or urge to use tobacco.
  • Withdrawal Symptoms: Experiencing symptoms such as irritability, anxiety, or difficulty concentrating when attempting to quit or reduce tobacco use.
  • Tolerance: Needing more tobacco to feel the same effects, indicative of physical dependence.
  • Failed Attempts to Quit: Repeated unsuccessful efforts to stop or reduce tobacco use.
  • Continued Use Despite Harm: Persisting in tobacco use despite being aware of the adverse health and social consequences.
  • Social and Recreational Sacrifices: Giving up social, occupational, or recreational activities due to tobacco use.

Genetics & Tobacco Use Disorder: Development & Treatment

Research indicates that genetics play a significant role in an individual’s susceptibility to Tobacco Use Disorder.

The genetic contribution to TUD can be understood through several key aspects:

  • Genetic Predisposition: Certain genetic variants have been identified that increase the likelihood of tobacco use initiation and the progression to addiction. These variants can affect how the body processes nicotine and how rewarding nicotine is perceived to be by the brain.
  • Inherited Traits: Traits such as impulsivity and risk-taking behaviors, which are partially heritable, can predispose individuals to substance use disorders, including TUD.
  • Psychiatric Comorbidities: Genetic factors contributing to mental health disorders like depression and anxiety can overlap with those predisposing to TUD, creating a complex interplay that increases the risk of developing the disorder.

The role of genetics extends beyond the risk of developing TUD to the challenges in its treatment:

  • Variation in Treatment Response: Genetic differences can influence how individuals respond to TUD treatments, such as nicotine replacement therapy or medications like bupropion and varenicline.
  • Relapse Susceptibility: Genetic factors can also impact the likelihood of relapse after quitting. For example, genetic variations in the brain’s reward pathways may make some individuals more prone to relapse due to a heightened sense of reward from nicotine use.
  • Personalized Treatment Approaches: Understanding an individual’s genetic makeup can aid in tailoring specific treatment strategies that are more likely to be effective, ushering in an era of personalized medicine in the management of TUD.

(Read: Epigenetics & Nicotine Addiction)

Polygenic scores for tobacco use in diverse L.A. biobank sample (2024 study)

Vidhya Venkateswaran et al. analyzed the genetic underpinnings of Tobacco Use Disorder (TUD) and its systemic health effects.

Specifically, they focused on evaluating the predictive performance and risk stratification capabilities of a European ancestry-derived polygenic score (PGS) for TUD in a diverse cohort from the UCLA ATLAS biobank.


  • Study Population: The study involved 24,202 participants from the UCLA ATLAS biobank, encompassing diverse ancestries.
  • Polygenic Score (PGS): A PGS developed from European-ancestry individuals in the UK Biobank was used, focusing on tobacco use disorder traits.
  • Ancestry-Specific Analysis: Participants were classified into four genetically inferred ancestry groups (GIAs) – European American, Hispanic/Latin American, East Asian American, and African American.
  • Phenome-Wide Association Studies (PheWAS): PheWAS was used to examine the association of the TUD-PGS with a wide range of health conditions (phecodes).
  • Mendelian Randomization (MR): MR analysis was conducted to explore potential causal relationships between tobacco use and obesity.


  • Predictive Performance of TUD-PGS: The TUD-PGS showed significant associations with TUD in European American, Hispanic/Latin American, and East Asian American GIAs, but not in African American GIA.
  • Risk Stratification: TUD-PGS provided strong risk stratification in European American and Hispanic/Latin American GIAs, but was inconsistent in others.
  • Health Risks Beyond Tobacco Use: In individuals without a history of smoking, the TUD-PGS was still associated with obesity and alcohol-related disorders, indicating shared genetic factors.
  • Causal Associations: MR analysis suggested a causal relationship between measures of adiposity and tobacco use.


  • Ancestry Representation: Non-European ancestries had smaller sample sizes, potentially affecting the robustness of findings in these groups.
  • Phecode Limitations: Phecodes, derived from billing codes, may not fully capture the extent of an individual’s disease history and are subject to healthcare access biases.
  • Bias in Electronic Health Records: The reliance on electronic health records for phenotypic data introduces potential biases, despite attempts to adjust for these using variables like insurance class.
  • Sample Overlap in MR Analysis: Partial sample overlap in the MR analysis may lead to biased results, although subsequent analyses with different GWAS datasets supported the original findings.

Details of Results: Tobacco Use & Genetics (2024)

Ancestry-Specific Findings

  • European American (EA) GIA showed a 20% increase in the odds of TUD for each standard deviation increase in the TUD-PGS.
  • Hispanic/Latin American (HL) and East Asian American (EAA) GIAs also showed significant associations, but these were less pronounced compared to EAs.
  • African American (AA) GIA did not show a significant association with TUD-PGS, indicating potential genetic differences or a lack of representativeness in the PGS model.

Risk Stratification Across Ancestry Groups

  • Strong risk stratification was observed in EA and HL groups, with the highest TUD-PGS quintile showing considerably increased odds of TUD.
  • In EAA and AA groups, risk stratification was either weak or inconsistent, suggesting that the PGS model is less effective for these populations.

Systemic Health Effects Beyond Tobacco Use

  • PheWAS analysis revealed associations between TUD-PGS and various health conditions such as obesity, chronic bronchitis, substance addiction disorders, and ischemic heart disease.
  • These associations persisted even in individuals with no history of smoking, particularly with obesity and alcohol-related disorders, indicating shared genetic underpinnings.

Causal Relationships via Mendelian Randomization

  • The MR analysis suggested a causal relationship between adiposity measures (such as waist circumference and BMI) and tobacco use, reinforcing the link between genetic predisposition to TUD and obesity.

Potential Implications of the Findings (Tobacco Use Disorder & Genetics)

Precision Medicine in Public Health: These findings pave the way for more personalized approaches in public health, targeting individuals at high genetic risk for TUD and associated systemic health issues.

Genetic Counseling & Risk Assessment: Understanding an individual’s genetic predisposition to TUD can inform genetic counseling and risk assessment, leading to early interventions.

Broader Focus of Tobacco Cessation Programs: The study suggests the need for tobacco cessation programs to also focus on managing comorbid conditions like obesity and alcohol-related disorders.

Addressing Health Disparities: The differential effectiveness of TUD-PGS across ancestries highlights the need to address health disparities in genetic research and clinical practice.

Future Treatments of Tobacco Use Disorder (TUD) Informed by Genetics

Ancestry-Inclusive Polygenic Score (PGS) Models

  • Objective: To create PGS models that accurately predict the risk of TUD across various ancestral backgrounds.
  • Approach: This involves including diverse genetic datasets from multiple populations in PGS development to capture a broader spectrum of genetic variations.
  • Expected Outcomes: Improved risk prediction and preventive strategies tailored to individuals from underrepresented genetic backgrounds, enhancing the effectiveness of early interventions.

Gene Therapy & CRISPR Gene-Editing

  • Potential Applications: Targeting specific genes implicated in nicotine dependence and addiction pathways.
  • Research Focus: Identifying key genetic targets for TUD and developing safe, targeted gene-editing tools.
  • Challenges and Considerations: Addressing ethical, safety, and regulatory concerns; ensuring long-term efficacy and monitoring unintended consequences.

Pharmacogenomics in TUD Treatment

  • Personalized Medication: Utilizing genetic information to predict individual responses to TUD pharmacotherapies, such as nicotine replacement therapies, bupropion, and varenicline.
  • Implementation: Genetic screening before medication prescription to identify the most effective and safe treatment options.
  • Research Needs: Extensive genetic studies to understand the interaction between genetic variations and medication efficacy and side effects.

Genetic Information in Clinical Decision-Making

  • Genetic Risk Assessment: Using genetic testing as a standard part of the assessment for individuals seeking treatment for TUD.
  • Tailored Interventions: Combining genetic risk information with behavioral and environmental factors to create comprehensive, personalized treatment plans.
  • Training and Resources: Educating healthcare providers on the use of genetic information in treating TUD and developing resources and tools to integrate genetic insights into clinical practice.

Tobacco Use Disorder Treatment (Current Strategies)

Tobacco Use Disorder (TUD) is a significant public health challenge, and its treatment involves a combination of behavioral interventions and pharmacotherapy.

The current guidelines focus on a holistic approach that includes patient education, counseling, and medication.

Behavioral Therapies

  • Counseling: Individual, group, and telephone counseling are effective. Support ranges from practical problem-solving advice and social support to deep psychological support.
  • Cognitive Behavioral Therapy (CBT): Helps individuals identify and change thinking and behavior patterns related to tobacco use.
  • Motivational Interviewing: A patient-centered counseling style that addresses ambivalence to change and enhances motivation towards quitting.
  • Smoking Cessation Programs: Structured programs often combine education, skills training, and social support.


  • Nicotine Replacement Therapy (NRT): Includes over-the-counter products like nicotine gum, patches, lozenges, as well as prescription nasal sprays and inhalers. NRT helps alleviate withdrawal symptoms by delivering small, steady doses of nicotine without the harmful tars and gases found in cigarettes.
  • Bupropion SR (Zyban): An antidepressant that reduces symptoms of nicotine withdrawal and cravings.
  • Varenicline (Chantix): Works by blocking nicotine receptors in the brain, reducing pleasure from smoking and easing withdrawal symptoms.

Combination Treatments: Combining behavioral therapy with pharmacotherapy is more effective than either approach alone. A combination of different forms of NRT (such as patch plus gum or lozenge) can be more effective than a single form of NRT.

Support & Follow-up: Regular follow-ups and continuous support are crucial for maintaining abstinence. Support can be in the form of healthcare provider check-ins, digital and telehealth support, or participation in support groups.

Addressing Co-occurring Conditions: Special consideration is given to individuals with co-occurring mental health disorders or substance use disorders. Treatment plans for such individuals are often more comprehensive and may involve additional psychiatric support.

Relapse Prevention: Strategies include identifying triggers, developing coping mechanisms, and creating a supportive environment to prevent relapse.

Special Populations: Treatment plans may vary for special populations like pregnant women, adolescents, older adults, or individuals with chronic diseases.

Implementing these guidelines effectively requires a personalized approach.

Healthcare providers assess the individual’s readiness to quit, degree of nicotine dependence, past quit attempts, and preferences for treatment.

It’s also essential to consider patient-specific factors like age, health status, co-morbid conditions, and personal preferences.

(Read: Optimizing Nicotine Replacement Therapy: 2023 Evidence)

Takeaway: Tobacco Use Disorder & Genetic Risk

The study’s in-depth exploration of the genetic underpinnings of Tobacco Use Disorder (TUD) reveals significant ancestry-specific variations in the predictive performance of a polygenic score (PGS).

The findings underscore the complexity of TUD as a trait influenced by both genetic and environmental factors.

Crucially, the associations between TUD predisposition and systemic health conditions like obesity and alcohol-related disorders, even among non-smokers, highlight the shared genetic architecture of these conditions.

These insights carry profound implications for public health and clinical practice, advocating for a more personalized approach in managing TUD and related health risks.

The study also emphasizes the necessity for future genetic research and treatments to be inclusive of diverse ancestries, ensuring equitable healthcare advancements.

As we advance, integrating genetics into the management of TUD promises a future where treatments are not only more effective but also more tailored to individual genetic profiles, ultimately enhancing patient outcomes and public health strategies.


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