Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use

Abstract

Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system is involved in mechanisms underlying alcohol seeking and consumption. Accordingly, the GLP-1 receptor (GLP-1R) has begun to be studied as a potential pharmacotherapeutic target for alcohol use disorder (AUD). The aim of this study was to investigate the association between genetic variation at the GLP-1R and brain functional connectivity, according to the severity of alcohol use. Participants were 181 individuals categorized as high-risk (n = 96) and low-risk (n = 85) alcohol use, according to their AUD identification test (AUDIT) score. Two uncommon single nucleotide polymorphisms (SNPs), rs6923761 and rs1042044, were selected a priori for this study because they encode amino-acid substitutions with putative functional consequences on GLP-1R activity. Genotype groups were based on the presence of the variant allele for each of the two GLP-1R SNPs of interest [rs6923761: AA + AG (n = 65), GG (n = 116); rs1042044: AA + AC (n = 114), CC (n = 67)]. Resting-state functional MRI data were acquired for 10 min and independent component (IC) analysis was conducted. Multivariate analyses of covariance (MANCOVA) examined the interaction between GLP-1R genotype group and AUDIT group on within- and between-network connectivity. For rs6923761, three ICs showed significant genotype × AUDIT interaction effects on within-network connectivity: two were mapped onto the anterior salience network and one was mapped onto the visuospatial network. For rs1042044, four ICs showed significant interaction effects on within-network connectivity: three were mapped onto the dorsal default mode network and one was mapped onto the basal ganglia network. For both SNPs, post-hoc analyses showed that in the group carrying the variant allele, high versus low AUDIT was associated with stronger within-network connectivity. No significant effects on between-network connectivity were found. In conclusion, genetic variation at the GLP-1R was differentially associated with brain functional connectivity in individuals with low versus high severity of alcohol use. Significant findings in the salience and default mode networks are particularly relevant, given their role in the neurobiology of AUD and addictive behaviors.

The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission

“…The present set of psychopharmacological and electrophysiological data provide further support for a role of GLP-1 in alcohol drinking and other consummatory behaviors. These are translationally relevant findings and overall consistent with recent human evidence that suggest a role of the GLP-1 system in alcohol drinking and AUD, as indicated by alcohol administration studies ( 115 , 116 ), postmortem brain analyses ( 115 ), and neuroimaging-genetic investigations ( 116 , 117 ). Our behavioral experiments were performed in 2 species of both sexes, employed a range of alcohol-related phenotypes, and included a comprehensive set of control experiments to account for semaglutide’s potential nonspecific effects.…”

Testing for association between exonic glucagon‐like peptide 1 receptor mutation with physical and brain health traits in UK Biobank

“…In this study, we focused on rs103054982, as this has been examined in previous studies. SNPS rs3765467, 8,17 rs6923761 and rs1042044 17 have been identified as additional potential drivers of reduced insulin secretion; these showed no additional (multiple‐testing adjusted) significant associations in subsequent post‐hoc analyses. Future studies may investigate other mutations in GLP‐1R pathways.…”

Genetic variants of the GLP-1R gene affect the susceptibility and glucose metabolism of gestational diabetes mellitus: a two-center nested case‒control study

“…Although rs1042044 had nothing to do with insulin secretion [ 15 ], it was reported to be associated with susceptibility of T2DM in a Chinese literature [ 19 ] and the risk of papillary thyroid cancer among the Egyptian population in a recent study [ 44 ]. Moreover, rs1042044 was also differentially associated with brain functional connectivity in individuals with low versus high severity of alcohol use [ 45 ]. Yapici-Eser et al [ 46 ] suggested a possible association of rs1042044 with anhedonia but no association with depression diagnosis.…”