RESUMEN
Background: Genetics influence the vulnerability to alcohol use disorders, and among the implicated genes, three previous studies have provided evidences for the involvement of LRRK2 in alcohol dependence (AD). LRRK2 expression is broadly dysregulated in postmortem brain from AD humans, as well as in the brain of mice with alcohol dependent-like behaviors and in a zebrafish model of alcohol preference. The aim of the present study was to evaluate the association of variants in the LRRK2 gene with AD in multiethnic populations from South and North America. Methods: Alcohol-screening questionnaires [such as CAGE and Alcohol Use Disorders Identification Test (AUDIT)] were used to determine individual risk of AD. Multivariate logistic regression analyses were done in three independent populations (898 individuals from Bambuí, Brazil; 3,015 individuals from Pelotas, Brazil; and 1,316 from the United States). Linkage disequilibrium and conditional analyses, as well as in silico functional analyses, were also conducted. Results: Four LRRK2 variants were significantly associated with AD in our discovery cohort (Bambuí): rs4768231, rs4767971, rs7307310, and rs1465527. Two of these variants (rs4768231 and rs4767971) were replicated in both Pelotas and US cohorts. The consistent association signal (at the LRRK2 locus) found in populations with different genetic backgrounds reinforces the relevance of our findings. Conclusion: Taken together, these results support the notion that genetic variants in the LRRK2 locus are risk factors for AD in humans.
RESUMEN
Gene prioritization approaches are useful tools to explore and select candidate genes in transcriptome studies. Knowing the importance of processes such as neuronal activity, intracellular signal transduction, and synapse plasticity to the development and maintenance of compulsive ethanol drinking, the aim of the present study was to explore and identify functional candidate genes associated with these processes in an animal model of inflexible pattern of ethanol intake. To do this, we applied a guilt-by-association approach, using the GUILDify and ToppGene software, in our previously published microarray data from the prefrontal cortex (PFC) and striatum of inflexible drinker mice. We then tested some of the prioritized genes that showed a tissue-specific pattern in postmortem brain tissue (PFC and nucleus accumbens (NAc)) from humans with alcohol use disorder (AUD). In the mouse brain, we prioritized 44 genes in PFC and 26 in striatum, which showed opposite regulation patterns in PFC and striatum. The most prioritized of them (i.e., Plcb1 and Prkcb in PFC, and Dnm2 and Lrrk2 in striatum) were associated with synaptic neuroplasticity, a neuroadaptation associated with excessive ethanol drinking. The identification of transcription factors among the prioritized genes suggests a crucial role for Irf4 in the pattern of regulation observed between PFC and striatum. Lastly, the differential transcription of IRF4 and LRRK2 in PFC and nucleus accumbens in postmortem brains from AUD compared to control highlights their involvement in compulsive ethanol drinking in humans and mice.