Smoking, alcohol consumption, and frailty: A Mendelian randomization study

Area of Science:

• Gerontology and Public Health
• Genetic Epidemiology
• Substance Use Research

Background:

• Observational studies suggest links between tobacco smoking, alcohol consumption, and frailty.
• Causality has not been definitively established for these associations.

Purpose of the Study:

• To investigate the causal relationship between smoking initiation, alcohol consumption, and the frailty index (FI) using Mendelian randomization (MR).
• To evaluate the independent effects of smoking and alcohol on frailty and assess potential reverse causation.

Main Methods:

• Two-sample Mendelian randomization (MR) design utilizing large-scale genome-wide association study summary statistics.
• Analysis included smoking initiation (N=2,669,029), alcohol consumption (N=2,428,851), and the frailty index (N=175,226) in European ancestry populations.
• Univariable and multivariable MR, sensitivity analyses, and reverse direction MR were performed.

Main Results:

• Genetic predisposition to smoking initiation was strongly associated with an increased FI (causal effect).
• Genetically predicted alcohol consumption showed a suggestive inverse association with FI, but results were inconsistent across sensitivity analyses.
• Lifetime smoking, but not alcohol use disorder, was associated with FI in complementary analyses. No evidence of reverse causation was found.

Conclusions:

• Smoking initiation is a causal risk factor for developing frailty.
• The causal role of alcohol consumption in frailty requires further investigation due to inconsistent findings.