Investigating causal relationship between smoking behavior and global brain volume

Abstract

Background Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate whether smoking causes lowered brain volume or whether a lower brain volume is a risk factor for smoking. We address this debate through multiple methods that evaluate causality: Bradford Hill's Criteria to understand a causal relationship in epidemiological studies, mediation analysis, and Mendelian Randomization. Methods In 28,404 participants of European descent from the UK Biobank dataset, we examined relationships between a history of daily smoking and brain imaging phenotypes as well as associations of genetic predisposition to smoking initiation with brain volume. Results A history of daily smoking is strongly associated with decreased brain volume, and a history of heavier smoking is associated with a greater decrease in brain volume. The strongest association was between total grey matter volume and a history of daily smoking (p-value = 8.28 ×10-33), and there was a dose-response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score (PRS) for smoking initiation was strongly associated with a history of daily smoking (p-value = 4.09×10-72 ), yet only modestly associated with total grey matter volume (p-value = 0.02). Mediation analysis indicated that a history of daily smoking is a mediator between smoking initiation PRS and total grey matter volume. Mendelian Randomization showed a causal effect of daily smoking on total grey matter volume (p-value = 0.022). Conclusions These converging findings strongly support the hypothesis that smoking causes decreased brain volume.

Competing Interest Statement

Dr. Laura J. Bierut is listed as an inventor on Issued U.S. Patent 8,080,371, Markers for Addiction, covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. The other authors report no biomedical financial interests or potential conflicts of interest

Funding Statement

This work was supported by National Institute on Alcohol Abuse and Alcoholism grants U10AA008401 (APA, LJB, YC) and R01AA027049 (LJB, DBH, EOJ, VT), National Institute on Drug Abuse grants K12DA041449 (LJB) and R01DA044014 (LJB, VT), and National Institute on Aging grant R56AG058726 (LJB, PI: Galama). JB is funded by the NIH (R34NS118618 and R01MH128286) and the McDonnell Center for Systems Neuroscience. APA is funded by the NIH (R01AA025646, R01DA89801). VT is additionally funded by Washington University Institute of Clinical and Translational Sciences (TL1TR002344). RB is funded by NIH (R21AA027827, R01DA054750, R01AG061162, U01DA055367). AC is funded by NIH (R01AA029308 (PI: Hartz)).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

UK Biobank dataset: Our sample included the 2019 UK Biobank released data of participants with imaging data. The UK Biobank study was approved by the National Health Service National Research Ethics Service (11/NW/0382). All the participants provided informed consent to participate in the UK Biobank study (Study ID: 47267, 48123). GSCAN dataset: We used GSCAN summary statistics with the UK Biobank sample excluded for the initiation of daily smoking (Smoking Initiation) to create a polyenic risk score (PRS). https://conservancy.umn.edu/handle/11299/201564

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Data Availability

All data produced in the present work are contained in the manuscript.

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