Convergent Evidence for Predispositional Effects of Brain Gray Matter Volume on Alcohol Consumption

Abstract

Background: Alcohol use has been reliably associated with smaller subcortical and cortical regional gray matter volumes (GMVs). Whether these associations reflect shared predisposing risk factors and/or causal consequences of alcohol use remains poorly understood.Methods: Data came from 3 neuroimaging samples (total n=2,423), spanning childhood/adolescence to middle age, with prospective or family-based data. First, we identified replicable GMV correlates of alcohol use. Next, we used family-based and longitudinal data to test whether these associations may plausibly reflect a predispositional liability for alcohol use, and/or a causal consequence of alcohol use. Finally, we evaluated whether GWAS-defined genomic risk for alcohol consumption is enriched for genes preferentially expressed in regions identified in our neuroimaging analyses, using heritability and gene-set enrichment, and transcriptome-wide association study (TWAS) approaches.Results: Smaller right dorsolateral prefrontal cortex (DLPFC; i.e., middle and superior frontal gyri) and insula GMVs were associated with increased alcohol use across samples. Family-based and prospective longitudinal data suggest these associations are genetically conferred and that DLPFC GMV prospectively predicts future use and initiation. Genomic risk for alcohol use was enriched in gene-sets preferentially expressed in the DLPFC and associated with differential expression of C16orf93, CWF19L1, and C18orf8 in the DLPFC.Conclusions: These data suggest that smaller DLPFC and insula GMV plausibly represent predispositional risk factors for, as opposed to consequences of, alcohol use. Alcohol use, particularly when heavy, may potentiate these predispositional risk factors. DLPFC and insula .

Multi-omics integration analysis identifies novel genes for alcoholism with potential link to neurodegenerative diseases

“…For example, our LDSC based enrichment analysis shows that GWAS variants for both AUD and DPW are enriched in the genes expressed during early brain development. Drinking in later years might interact with this genetic predisposition making individuals more susceptible not only to AUD but also to other neuropsychiatric disorders 32 . Identification of SPI1 and MAPT as genes for AUD are good examples of pleiotropy and/ or causal links between the alcohol intake and susceptibility to AUD, other psychiatric disorders (e.g., depression) and even Alzheimer's disease 15,33 and other neurodegenerative diseases.…”

Brain anatomical covariation patterns linked to binge drinking and age at first full drink

“…Human neuroimaging studies indicate that early onset of alcohol use and BD in adolescents or emerging adults are linked to aberrations in brain structure relative to healthy controls (HCs) ( Lees et al, 2020 , Squeglia and Cservenka, 2017 ). The identified deviations in brain structure include, for example, reduced cortical thickness ( Brumback et al, 2016 ), decreased surface area ( Infante et al, 2018 ), and increased grey matter (GM) densities ( Sousa et al, 2017 ) in frontal regions, and a GM volume reduction in multiple regions ( Baranger et al, 2020 , Squeglia et al, 2014 , Yang et al, 2016 ) with exceptions including greater striatal volume ( Howell et al, 2013 ). Gender-related effects have also been observed, with cortical thickness in selected frontal regions thinner in males, and thicker in females ( Squeglia et al, 2012 ); and putamenal volumes smaller in males, and larger in females who report early onset of alcohol use or BD, relative to controls ( Fein et al, 2013 ).…”

Alcohol Induced Brain and Liver Damage: Advantages of a Porcine Alcohol Use Disorder Model

“…Subjects from both groups had no or limited access to alcohol, eliminating the effects of alcohol as a confounder. A large neuroimaging study with 2,423 individuals also found a smaller right dorsolateral prefrontal cortex and insula GM volumes were associated with increased alcohol use, thus providing further support that a reduction in cortical thickness may be an AUD risk factor ( Baranger et al, 2019 ). Family based and prospective longitudinal data suggested this association is of genetic origin and that smaller GM volumes could serve as a prognostic biomarker for AUD.…”

“…These inconsistencies in anatomical boundaries generate confusion as unique structural specific activities and responses identified in rodents are then ascribed to the incorrect human brain region ( Laubach et al, 2018 ). Rodents lack the homologous structures to the dorsolateral prefrontal regions, which exhibit pronounced vulnerability to alcohol ( Preuss, 1995 ; Miguel-Hidalgo et al, 2002 ; Chanraud et al, 2007 ; Makris et al, 2008 ; Baranger et al, 2019 ). Consequently, rodents provide less information pertaining to alcohol induced pathophysiology and overall effect on the dorsolateral prefrontal region ( Preuss, 1995 ).…”

“…There was a negative correlation between prefrontal cortex GM volumes and alcohol consumption frequency, average number of drinks, maximum number of drinks per episode, age of onset, and lifetime duration for AUD ( Fein et al, 2002 ; De Bellis et al, 2005 ). More specifically, the prefrontal dorsolateral cortex volume was highly associated with alcohol dependence and the amount of consumption as well as a decrease in both density and size of glia ( Miguel-Hidalgo et al, 2002 ; Chanraud et al, 2007 ; Makris et al, 2008 ; Baranger et al, 2019 ). Negative correlations in the volume of both global and regional GM in the bilateral frontal gyri is associated with lifetime alcohol intake in social drinkers as well ( Taki et al, 2006 ).…”