The intertwined nature of psychiatric disorders and substance use behaviours presents a complex challenge in understanding their collective impact on longevity. Recent studies have leveraged genomic data to explore whether genetic predispositions for psychiatric conditions and substance use behaviours correlate with reduced lifespan. The study discussed here utilised genome-wide association studies (GWAS) and mendelian randomisation (MR) methods to dissect these relationships, particularly focusing on the genetic liability of smoking and its adverse effects on longevity.

Genetic Liabilities and Longevity

The study employed multivariable mendelian randomisation (MVMR) to evaluate the associations between the genetic predisposition for psychiatric disorders, substance use behaviours, and longevity. Analysing data from cohorts of European ancestry, the findings revealed a significant deleterious association between the genetic liability for smoking and reduced longevity. Conversely, major psychiatric disorders, such as depression, bipolar disorder, and schizophrenia, did not demonstrate independent associations with longevity once accounting for comorbid substance use.

A cohort consisting of 709,709 individuals (60.8% female) was analysed, revealing a negative association for smoking with longevity (β = -0.33, P = 4.59 × 10^-34) and an increase in epigenetic age acceleration (EAA). Genetic liabilities for other psychiatric conditions did not show direct longevity associations, suggesting that smoking plays a pivotal role in the observed reduction in lifespan and healthy ageing in these populations.

Transcriptomic and Proteomic Insights

The study also utilised transcriptomic imputation to identify genes associated with smoking and longevity. Out of 249 genes linked to smoking, 36 were novel, highlighting pathways involved in DNA repair, chromatin remodelling, and telomere maintenance. These pathways are crucial for genomic integrity and cellular ageing, underscoring the damaging effects of smoking on longevity.

Cis-instrument MR analyses identified several brain proteins associated with smoking behaviour, with LY6H and RIT2 emerging as potential therapeutic targets for smoking cessation. These proteins, linked to neuronal signalling pathways, offer promising avenues for developing interventions aimed at nicotine dependence.

Implications for Smoking Cessation

The findings underscore the importance of addressing smoking as a significant mediator of reduced longevity, particularly in psychiatric populations. By identifying specific genetic and protein targets, this research provides a foundation for developing targeted smoking cessation therapies. The study suggests leveraging genetic insights to inform public health strategies and therapeutic developments, aiming to mitigate the adverse effects of smoking on ageing-related processes.

Detailed Findings and Statistics

• Smoking and Longevity: The genetic liability for smoking significantly impacted longevity, with MR models showing robust associations across various analyses.
• Psychiatric Disorders: No independent adverse genetic associations were found for psychiatric disorders concerning longevity when accounting for smoking and alcohol use.
• Gene Pathways: Transcriptomic analyses identified key pathways, such as DNA repair and telomere maintenance, linking smoking with ageing.
• Protein Targets: Proteomic analyses highlighted brain proteins like LY6H and RIT2 as promising targets for smoking cessation, offering potential pathways for therapeutic development.

This comprehensive examination of genetic liabilities illuminates the pathways through which smoking influences longevity, providing a nuanced understanding of how substance use behaviours intersect with psychiatric disorders to affect lifespan.

Source: JAMA Psychiatry