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.

Figure 1

Normalized within-network connectivity estimates for significant interactions between AUDIT group and rs6923761 genotype. Top panels (brain images) include the component T-map extracted during the ICA processing step; colors represent T-max values. High-AUDIT: AUDIT total score ≥ 8 (n = 96); Low-AUDIT: AUDIT total score < 8 (n = 85). A is the risk allele; A-allele carriers: AA + AG (n = 65); Non-A-allele carriers: GG (n = 116). IC35 (insula; A) and IC47 (frontal/acc/putamen; B) were mapped onto the anterior salience network; IC21 (insula/occipital/mpfc; C) was mapped onto the visuospatial network.

Figure 2

Normalized within-network connectivity estimates for significant interactions between AUDIT group and rs1042044 genotype. Top panels (brain images) include the component T-map extracted during the ICA processing step; colors represent T-max values. High-AUDIT: AUDIT total score ≥ 8 (n = 96); Low-AUDIT: AUDIT total score < 8 (n = 85). A is the risk allele; A-allele carriers: AA + AC (n = 114); Non-A-allele carriers: CC (n = 67). IC8 (hypothalamus/brainstem; A), IC45 (thalamus/3rd ventricle; B), and IC54 (pcc/tpj/occipital/mpfc; C) were mapped onto the dorsal default mode network; IC46 (thalamus/brainstem; D) was mapped onto the basal ganglia network.