Protein Associations With Alcohol Consumption and Genetic Risk for Alcohol-Related Sociomedical Conditions

Abstract

Studies investigating proteomic associations with alcohol consumption and the genetic links of these proteins to alcohol-related traits are scarce. The aims of our study were (1) to identify proteins associated with alcohol consumption and (2) to investigate the molecular pathways and genetics linking the identified proteins to alcohol consumption and related sociomedical conditions. We generated proteomic and genotypic data from blood samples of 387 Finnish twins (age range: 56-70) and calculated polygenic risk scores (PRSs) of eight alcohol-related traits: obesity, alcohol dependence, number of drinks per week, number of cigarettes per day, major depressive disorders (MDDs), schizophrenia, externalising behaviour and educational attainment. We identified 20 (out of 2321) proteins associated with alcohol consumption, expressed as log ethanol grams per month, after Bonferroni correction and adjustment for BMI, sex and age. Within-pair analyses in monozygotic twin pairs showed that some of the identified associations persisted after accounting for genetic confounding. While only the PRS representing genetic risk for the number of alcoholic drinks per week was associated with alcohol consumption, several proteins were associated with PRSs, in particular the PRS of MDD. All identified proteins were significantly replicated in the UK Biobank, and pathway analysis suggested their collective connection to alcohol consumption might be explained by oxidative stress and cell damage. In conclusion, we identified several alcohol-associated plasma proteins whose levels are also linked to genetic risk for mental illness and substance use. Our study suggests the potential of proteins as biomarkers for early detection of alcohol-related disorders.

Keywords: alcohol consumption; genetics; major depressive disorder; polygenic risk scores; proteomics; substance use; twins.

FIGURE 1

Associations between identified proteins and polygenic risk scores in the EH‐Epi sample. (a) Radar plot showing the number of associations with nominal (green zone) or Bonferroni‐corrected (yellow zone) p values below 0.05. Summary statistics are available in the supporting information (Table S1). (b) Scatterplot of coefficients between proteins with alcohol consumption (y‐axis) and a polygenic risk score (PRS) (x‐axis) for PRS–protein associations with nominal p values below 0.05. Associations that do not pass Bonferroni correction are represented with triangle shapes. Summary statistics are available in the supporting information (Table S1).