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© Research
Publication : Neuropharmacology

Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Neuropharmacology - 29 Jul 2020

Icick R, Forget B, Cloëz-Tayarani I, Pons S, Maskos U, Besson M

Link to Pubmed [PMID] – 32738310

Link to DOI [DOI] – 10.1016/j.neuropharm.2020.108234

Neuropharmacology. 2020;108234.

Over the last decade, robust human genetic findings have been instrumental in elucidating the heritable basis of nicotine addiction (NA). They highlight coding and synonymous polymorphisms in a cluster on chromosome 15, encompassing the CHRNA5, CHRNA3 and CHRNB4 genes, coding for three subunits of the nicotinic acetylcholine receptor (nAChR). They have inspired an important number of preclinical studies, and will hopefully lead to the definition of novel drug targets for smoking cessation. Here, we review these candidate gene and genome-wide association studies (GWAS) and their direct implication in human brain function and NA-related phenotypes. We continue with a description of preclinical work in transgenic rodents that has led to a mechanistic understanding of several of the genetic hits. We also highlight important issues with regards to CHRNA3 and CHRNB4 where we are still lacking a dissection of their role in NA, including even in preclinical models. We further emphasize the use of human induced pluripotent stem cell-derived models for the analysis of synonymous and intronic variants on a human genomic background. Finally, we indicate potential avenues to further our understanding of the role of this human genetic variation.

https://www.sciencedirect.com/science/article/abs/pii/S0028390820303026?via%3Dihub