“A human CHRNA6 3′ UTR variant alters the molecular environment and microRNA engagement of the adolescent VTA without changing Chrna6 transcript abundance”
Year: 2026
Type: preprint
Abstract: A single nucleotide polymorphism (rs2304297) in the 3′ untranslated region (UTR) of CHRNA6 , encoding the α6 nicotinic acetylcholine receptor subunit, is associated with adolescent smoking behavior. Humanized rats carrying the “C” or “G” allele show sex- and genotype-dependent responses to adolescent nicotine, yet the variant does not alter the protein sequence and the mechanism has remained unknown. We examined the molecular consequences of rs2304297 in vivo in the adolescent ventral tegmental area (VTA). Chrna6 transcript abundance did not differ by genotype, nor did transcript stability or polyadenylation site selection. The variant was instead associated with a transcriptional signature spanning myelin maintenance ( Enpp6 ), lipid metabolism ( Retsat ), and genomic repair ( Polq ), and with elevated basal lipid peroxidation in α6 GG animals. Computational folding predicted greater conformational flexibility of the “G” allele, and spatial colocalization of Chrna6 with miRNA-365-5p was reduced in α6 GG animals of both sexes. Coordinated expression of the two transcripts, however, followed a sex-by-genotype pattern, absent in α6 CC females and α6 GG males. These same groups showed elevated tyrosine hydroxylase expression and dopaminergic neuron number, and expansion of the Chrna6 co-expression network following nicotine. We propose that rs2304297 acts through two distinct layers: genotype determines spatial engagement of miRNA-365-5p with the transcript, while sex determines whether that engagement produces functional regulation. These findings identify a post-transcriptional mechanism for a non-coding nicotine addiction risk variant and demonstrate that its molecular effect can be uniform while its consequences are not.
Institution: University of California, Irvine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221460499