Chromatin architecture in addiction circuitry elucidates biological mechanisms underlying cigarette smoking and alcohol use traits

Abstract

Cigarette smoking and alcohol use are among the most prevalent substances used worldwide and account for a substantial proportion of preventable morbidity and mortality, underscoring the public health significance of understanding their etiology. Genome-wide association studies (GWAS) have successfully identified genetic variants associated with cigarette smoking and alcohol use traits. However, the vast majority of risk variants reside in non-coding regions of the genome, and their target genes and neurobiological mechanisms are unknown. Chromosomal conformation mappings can address this knowledge gap by charting the interaction profiles of risk-associated regulatory variants with target genes. To investigate the functional impact of common variants associated with cigarette smoking and alcohol use traits, we applied Hi-C coupled MAGMA (H-MAGMA) built upon cortical and midbrain dopaminergic neuronal Hi-C datasets to GWAS summary statistics of nicotine dependence, cigarettes per day, problematic alcohol use, and drinks per week. The identified risk genes mapped to key pathways associated with cigarette smoking and alcohol use traits, including drug metabolic processes and neuronal apoptosis. Risk genes were highly expressed in cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons, suggesting them as relevant cell types in understanding the mechanisms by which genetic risk factors influence cigarette smoking and alcohol use. Lastly, we identified pleiotropic genes between cigarette smoking and alcohol use traits under the assumption that they may reveal substance-agnostic, shared neurobiological mechanisms of addiction. The number of pleiotropic genes was ∼26-fold higher in dopaminergic neurons than in cortical neurons, emphasizing the critical role of ascending dopaminergic pathways in mediating general addiction phenotypes. Collectively, brain region- and neuronal subtype-specific 3D genome architecture refines neurobiological hypotheses for smoking, alcohol, and general addiction phenotypes by linking genetic risk factors to their target genes.

Sex significantly impacts the function of major depression-linked variantsin vivo

“…3D). This region is rich in human neural chromatin contacts (56)(57)(58)(59)(60)(61), implicating several target genes of the identified rSNPs. Interestingly, SxG effects in hippocampus and Vglut1 + segregated into distinct portions of this LD region (Fig.…”

“…P0-while not amenable to regionallytargeted viral assays-is in the midst of the testosterone surge, during which both acute activational effects and transcriptional-regulatory organizational effects occur; by contrast, P10 is a timepoint where sex hormones are effectively absent in normal development. 15); Ast: astrocyte (58); dlPFC: dorsolateral prefrontal cortex; DA: dopamine neurons of substantia nigra and ventral tegmental area (56); Ctx N: cortical neuron ( 61); LMN: lower motor neuron; eN: excitatory neuron ( 58); iPSC N: iPSC-derived neuron (59). *: pemp-derived FDR < 0.25; **: <0.2; ‡ < 0.15; ‡ ‡ < 0.1; & < 0.05.…”

“…39) included (C) rs67446837 and (D) rs1048243. (E) rSNPs identified in the RSRC1 locus and their regulatory significant condition, is embedded with its x-axis in human genomic (hg19) coordinates; chromatin contacts between the SNPs and distal gene promoters are illustrated below (56)(57)(58)(59)(60)(61). Curve heights correspond to -log10pemp for the plotted rSNP.…”