LRRK2 Gene Variants Associated With a Higher Risk for Alcohol Dependence in Multiethnic Populations.

Pablo Rafael Silveira Oliveira,Nora D Volkow,Mauricio Lima Barreto,Lorena Oliveira De Matos,Corinde E Wiers,Nathalia Matta Araujo,Luana Martins De Carvalho,Hanaísa P Sant Anna,Bernardo L Horta,Andresa K Andrade Damasceno,Daniel Almeida Da Silva E Silva,Ana Lúcia Brunialti Godard,Maria Fernanda Lima-Costa

doi:10.3389/fpsyt.2021.665257

Abstract

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.

Highlights

Alcohol use disorder (AUD) represents a global public health problem with profound personal, social, and economic costs [1]
Taken together, these results support the notion that genetic variants in the LRRK2 locus are risk factors for alcohol dependence (AD) in humans
We investigate the association of LRRK2 variants and alcohol dependence in three distinct multiethnic cohorts, two from Brazil and one from the United States, and consistently show that intronic single-nucleotide polymorphisms (SNPs) were associated with alcohol dependence

Summary

Introduction

Alcohol use disorder (AUD) represents a global public health problem with profound personal, social, and economic costs [1]. According to the Global Status Report on Alcohol and Health 2018 [2], from the World Health Organization (WHO), more than half of the world’s population (57% or 3.1 billion people) consumed alcohol in the previous year. The Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD), characterize AUD by the continued use of alcohol despite negative psychological, biological, behavioral, and social consequences [5]. 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). 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

Objectives

Methods

Results

Conclusion