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Smoking's Toll: Genetics, Aging, and Psychiatric Disorders

Discover how genetic predispositions for smoking and psychiatric disorders impact longevity. A recent study reveals critical insights into the relationship between these factors and highlights potential therapeutic targets for smoking cessation. Dive into the findings and their implications for healthy aging — and learn something new every day!

Major Psychiatric Disorders, Substance Use Behaviors, and Longevity: Insights from a Recent Study

A recent investigation published in JAMA Psychiatry in June has shed light on the complex relationships between psychiatric disorders, substance use behaviors, and longevity. Conducted by Daniel B. Rosoff and colleagues, the investigation used advanced genetic techniques to disentangle the associations between these factors and their impact on aging-related outcomes.

At a Glance

  • Study Focus: Genetic liabilities of psychiatric disorders and substance use behaviors in relation to longevity.

  • Key Findings:

    • Genetic liability for smoking is significantly associated with reduced longevity.

    • Major psychiatric disorders do not show an independent association with longevity when accounting for comorbid substance use behaviors.

    • Identified 249 smoking-associated genes, with potential targets for therapeutic development to aid smoking cessation.


Psychiatric disorders, such as major depression, bipolar disorder, and schizophrenia, have been linked to decreased life expectancy, with reductions estimated between 13.5 to 32.2 years. Substance use behaviors, particularly smoking and alcohol consumption, also contribute to reduced lifespans. The high comorbidity between these disorders and substance use behaviors necessitates a comprehensive analysis to identify key factors affecting longevity.

Study Design and Methods

The researchers employed a two-sample Mendelian randomization (MR) approach using genome-wide association study (GWAS) data from European populations. This method allowed the team to assess the genetic predispositions for psychiatric disorders, smoking, and alcohol consumption, and their relationships with longevity outcomes. Multiomics analyses, including transcriptomic imputation, were performed to identify underlying genetic mechanisms and potential therapeutic targets.

Key Findings

Genetic Liability and Longevity

The study found that the genetic liability for smoking had a significant negative association with longevity. Specifically, multivariable MR models indicated that smoking behavior was a critical factor in reduced healthy aging and chronic illness observed in psychiatric populations. In contrast, genetic liabilities for major psychiatric disorders did not independently impact longevity when accounting for smoking and alcohol consumption.

Smoking-Associated Genes

Transcriptomic imputation identified 249 genes associated with smoking, including several novel genes. These genes were enriched in pathways related to DNA repair, chromatin remodeling, and telomere maintenance—processes critical for aging and cellular health. Notably, the study highlighted that:

the transcriptome-wide signature of smoking was inversely associated with longevity
Rosoff DB, Hamandi AM, Bell AS, et al. Major Psychiatric Disorders, Substance Use Behaviors, and Longevity. JAMA Psychiatry. Published online June 18, 2024. doi:10.1001/jamapsychiatry.2024.1429

This emphasizes the detrimental impact of smoking on aging.

Proteomic Targets for Smoking Cessation

Cis-instrument MR prioritized several brain proteins linked to smoking behavior, including LY6H and RIT2, which may serve as potential targets for therapeutic drug development. These findings could inform future interventions aimed at reducing smoking and its associated health risks.


The study provides robust evidence that smoking is a significant mediator of reduced longevity in individuals with psychiatric disorders. While the genetic liabilities for psychiatric disorders themselves did not show independent associations with longevity, smoking emerged as a critical factor. This underscores the importance of addressing smoking behavior in psychiatric populations to promote healthy aging.


The study's findings are primarily based on data from European populations, which may limit the generalizability to other ethnic groups. Additionally, the complex, multifactorial nature of psychiatric disorders and substance use behaviors means that further research is needed to fully understand their interactions and impacts on longevity.


The findings suggest that smoking cessation should be a priority in efforts to improve longevity and healthy aging, particularly in individuals with psychiatric disorders. The identification of specific genetic targets offers promising avenues for developing effective smoking cessation therapies.

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