Reduced brain volume may represent a genetically-conferred predispositional risk factor for heavier alcohol consumption


For years, researchers have observed that alcohol consumption is associated with reduced brain volume and concluded that drinking can literally shrink the brain.

But new research turns that theory on its head, suggesting that reduced brain volume may represent a genetically-conferred predispositional risk factor for heavier alcohol consumption.

“Our results suggest that associations between alcohol consumption and reduced brain volume are attributable to shared genetic factors,” said senior author Ryan Bogdan, associate professor of psychological and brain sciences in Arts & Sciences and director of the Brain Lab at Washington University in St. Louis, where the research is based. “Lower brain volume in specific regions may predispose a person to greater alcohol consumption.

“The study is impressive because it uses a variety of approaches and data analysis techniques to reach findings that all converge on the same conclusion,” he said.

The study, recently published online in the journal Biological Psychiatry, is based on longitudinal and family data from three independent brain imaging studies – including the comparison of drinking behaviors in twin and non-twin siblings; longitudinal research within children who were never exposed to alcohol at baseline; and gene expression analyses using postmortem brain tissue.

“Our study provides convergent evidence that there are genetic factors that lead to both lower gray matter volumes and increased alcohol use,” said David Baranger, the study’s lead author and a former doctoral student in in Bogdan’s lab.

“These findings don’t discount the hypothesis that alcohol abuse may further reduce gray matter volumes, but it does suggest that brain volumes started out lower to begin with,” Baranger said.

“As a result, brain volumes may also serve as useful biological markers for gene variations linked to increased vulnerability for alcohol consumption.”

Baranger, who is now a postdoctoral scholar at the University of Pittsburgh, led the research project, which included other Arts & Sciences psychology graduate students and faculty from Washington University School of Medicine in St. Louis; Duke University; and the Medical University of South Carolina.

Researchers used data from the Duke Neurogenetics Study, the Human Connectome Project and the Teen Alcohol Outcomes Study to confirm that greater alcohol consumption is associated with lower gray matter volume in two brain regions, the dorsolateral prefrontal cortex and the insula, that feature prominently in emotion, memory, reward, cognitive control and decision making.

Analyses of brain imaging and family data spanning childhood to adulthood revealed genetically-conferred reductions in gray matter volume in the frontal cortex and insula, which were, in turn, predictive of future alcohol use, including the initiation of drinking in adolescence and future drinking in young adulthood.

To further confirm genetic links between lower brain volumes and alcohol consumption, the team examined data from twin and non-twin siblings with differing histories of alcohol consumption.

When compared with siblings with a shared history of low alcohol use, siblings who drank more heavily had lower grey matter volumes.

Interestingly, the study found no differences in gray matter volume in brains of same-family siblings where one drank more heavily than the other – both looked like heavy-drinkers.

This finding provides additional evidence that lower gray matter volume is a pre-existing vulnerability factor associated with the potential for alcohol use, as opposed to a consequence of alcohol use.

Finally, the research team used data of gene expression in the human brain to explore whether genetic risk for alcohol consumption is enriched for genes expressed in these regions and could be associated with the expression of specific genes.

“Our study provides convergent evidence that there are genetic factors that lead to both lower gray matter volumes and increased alcohol use,” said David Baranger, the study’s lead author and a former doctoral student in in Bogdan’s lab.

Baranger and colleagues found that genomic risk for alcohol consumption is enriched for genes that are preferentially expressed in the dorsolateral prefrontal cortex relative to other tissues and brain regions.

Further, they found that the expression of specific genes in this region are replicably associated with genomic risk for alcohol consumption.

These data provide additional convergent evidence that it is biologically plausible that lower grey matter volume in the frontal cortex may be driven by genetic risk for alcohol consumption.

“Our analyses in three independent samples provides unique convergent evidence that associations between middle/superior frontal gray matter volume and alcohol use are genetically-conferred and predict future use and initiation,” the study concludes.

“Taken alongside evidence that heavy alcohol consumption induces gray matter volume reductions, our data raise the intriguing possibility that genetically-conferred reductions in regional gray matter volumes may promote alcohol use from adolescence to young adulthood, which may, in turn, lead to accelerated atrophy within these and other regions,” the authors wrote

The results might be generalized to other substances, the group concluded, because different substances can all be affected by the same genetic factors.

Cigarette smoking has been associated with higher risk of cognitive decline and dementia in older adults14.

Although the mechanisms are not fully understood, these associations are predominantly thought to arise from accumulated smoking-related damage to cardiovascular and respiratory processes in the brain1,2,5,6.

Parallel to its established impact on vascular and respiratory functions, tobacco dependence is the most prevalent substance-dependence disorder and frequently co-occurs with psychiatric conditions such as mood and substance use disorders79.

For instance, among persons with alcohol abuse disorder, smoking prevalence has been estimated to be as high as 90%10,11.

In line with its documented effects on cardiovascular health, some imaging studies have reported that smoking is related to compromised vascular and circulation processes in the brain, including changes in perfusion and white matter (WM) lesions4,1214.

One consistent finding from imaging studies is that smokers have smaller total brain volume4,12,15, and smaller gray matter (GM) volume in particular, compared to never-smokers6,16. Interestingly, several results show that this association may be differentially localized16,17, suggesting that more direct links between smoking and specific brain structures could be underlying the associations of smoking to functional outcomes such as addiction and cognitive functioning.

However, findings on which brain structures may preferentially be affected by smoking are heterogeneous.

The discrepancy could be explained by methodological limitations. One limitation of published studies is that they were mostly conducted in small (often fewer than 100 subjects)15,16 and selective samples (based on participants with several morbidities)18,19.

Further, studies in community-dwelling individuals have focused mainly on older populations and thus may have had limited ability to disentangle the primary brain changes associated with smoking from those resulting from general accumulated damage such as advanced forms of cardiovascular disease4,5,20.

Another main limitation is that prior studies included limited adjustment for important contributing factors, such as cardiovascular, respiratory, and substance use/psychological factors17. Given their high co-occurrence and complex relationships with smoking and GM, the role of these factors warrants careful investigation1,2,5,11,21.

In this study, we used a community-based sample of middle-aged adults to assess the associations of smoking with total brain GM volume and with volumes of candidate brain regions linked to cognitive impairment and addictive behaviors, while assessing the role of vascular, respiratory, and substance use/psychological factors. We first adjusted for these factors and then tested whether they modified the smoking-GM relationship. We hypothesized that GM volumes would be smaller in smokers, particularly in smokers with additional vascular risk factors and addiction-related behaviors.


Compared to never and former smokers, current smokers were younger and had the highest proportion of black participants, the lowest educational attainment, and the highest prevalence of hypertension (Table ​(Table1).1).

Other cardiovascular risk factors were not different across smoking groups (Table ​(Table1).1).

Current smokers had the highest frequency of respiratory illnesses and the lowest FEV1. All substance use/psychological measures were more frequent in smokers (Table ​(Table1):1): compared to never-smokers, current and former-smokers had higher prevalence of high-risk alcohol drinking and illicit drug use; current smokers had more depressive symptoms.

Smoking and GM volume

Brain volumes are presented in Supplementary Table S2. Compared to never-smokers, current smokers had significantly smaller total GM volume (−8.86 cm3 (95% CI = −13.44, −4.29); Table ​Table2).2). There were no differences in total white matter volume across smoking groups; the trend of smaller total brain volume in smokers reflected the association between smoking and smaller GM (Table ​(Table22).

Adjustment for vascular and respiratory factors

Adjusting for vascular or respiratory factors slightly attenuated the associations of smoking and total GM volume (with a 6 to 13% change in the smoking-GM volume estimated association; Table ​Table2).2). There was no indication of interaction between smoking and vascular or respiratory factors in the smoking-GM relationship.

Adjustment for substance use/psychological factors

The smoking-total GM association was substantially attenuated (from −8.86 to −5.54 cm3; 37% change in estimate) when the model included substance use/psychological factors (Table ​(Table22).

Similar patterns were found in the lobar (Supplementary Table S3) and candidate region analyses (Supplementary Table S4): Current smokers had significantly smaller GM volume in the temporal, occipital, and frontal lobes, and in the amygdala, entorhinal cortex, cingulate, and insula, compared to never-smokers; these associations were largely attenuated when substance use/psychological factors were taken into account. Former-smokers had a trend for smaller GM volume but they were not significantly different than never-smokers.

Other candidate regions (hippocampus, parahippocampal gyrus, cuneus, precuneus, thalamus, caudate, putamen, and the nucleus accumbens) were not related to smoking status (Supplementary Table S4).

Interactions between substance use/psychological factors, smoking, and brain volumes

In the substance use/psychological factors model, all factors showed associations with GM volume: high-risk alcohol drinking (coefficient = −5.58 cm3 (95% CI = −10.57, −1.14)) and higher CES-D scores (−0.24 cm3 (95% CI = −0.46, −0.02) per unit increase in CES-D score) were associated with significantly smaller total GM; illicit drug use was associated with smaller GM (coefficient = −3.69; p = 0.07).

Illicit drug use and depressive symptoms did not modify the association between smoking and GM volumes (p > 0.3 for interaction terms). There was a significant interaction between alcohol use and smoking indicating that the association is differentially observed in alcohol users (p for interaction of current smoking with high-risk alcohol use = 0.03 and p = 0.07 for interaction with low-risk alcohol use). Details regarding the distribution of sample’s characteristics across alcohol use sub-groups are presented in Supplementary Table S5.

Alcohol use, smoking, and brain volumes

Results of GM volumes across smoking and alcohol use groups (Table ​(Table3)3) show that subjects who don’t use alcohol (irrespective of smoking status) and never-smokers (whether alcohol users or not) do not have different GM volumes (with adjusted mean GM volumes ranging from 516 to 520 cm3).

However, the combination of current alcohol (both low- and high-risk use) and smoking use was negatively associated with GM volume (Table ​(Table3);3); therefore, we grouped participants into alcohol non-users vs. subjects reporting any alcohol use (low-risk and high-risk). Among participants who do not use alcohol, smoking was not associated with total or regional GM volumes (Table ​(Table4).4).

In contrast, among alcohol users (light and heavy-risk combined), those who currently smoked had −12 cm3 smaller total GM volume, and specifically smaller frontal, temporal, amygdala, cingulate, and insula GM volumes, even after accounting for other substance use /psychological, vascular, and respiratory factors (Table ​(Table4).4). There was a trend toward an association of smoking to smaller occipital GM volume (p = 0.11). Similar to analyses in the total sample, volumes of other candidate structures of interest were not related to smoking in the stratified analyses (p > 0.17; data not shown).

In additional analyses (Supplementary Table S6) investigating the associations of GM volumes to smoking characteristics (cumulative pack-years, age at start of smoking, and years since smoking cessation), the interaction between alcohol use and smoking characteristics were weaker than for smoking status (p-values for interaction terms > 0.09); however, in general, associations between smoking characteristics and GM outcomes were more pronounced in alcohol users. Higher cumulative pack-years and younger age at smoking initiation were associated with smaller total GM (p = 0.11 and p = 0.07, respectively); associations with age at smoking initiation were more pronounced for amygdala and temporal GM volumes (p = 0.06 and 0.02, respectively).

Media Contacts:
Brandie Jefferson – WUSTL
Image Source:
The image is in the public domain.

Original Research: Closed access
“Convergent evidence for predispositional effects of brain gray matter volume on alcohol consumption”. Ryan Bogdan et al.
Biological Psychiatry doi:10.1016/j.biopsych.2019.08.029.


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