Genetic Analysis of Smoking-based Phenotypes Using Polygenic Risk Score Methodology through Identification of Risk Alleles within the Direct and Indirect Striatal Pathways
This study addresses the underlying genetic components of addiction, specifically that which relates to nicotine use, abuse, and dependence. One of the problems with genetic research on a trait as complicated as substance use is that multiple genes are likely to play a role, but each with a very small effect. Polygenic risk scores potentially help with this problem by analyzing the role of multiple genes as a set to substance abuse. Three polygenic risk scores were created to test markers within 19 genes that are differentially expressed in the Striatal direct and indirect pathways, which have been shown to play a crucial role in reward learning and addiction-related behaviors (Lobo et al., 2011). A polygenic risk score was created for 79 SNPs spanning all 19 genes that make up these two pathways together, as well as for the 39 and 40 SNPs that make up the two pathways individually. Of the three polygenic risk scores that were created, the score created for just the indirect Striatopallidal pathway was the only score variable to return significant results (p-value: 0.0289). This indicates that an individual possessing risk alleles within this pathway is at a greater risk of developing or exhibiting smoking-related behaviors such as smoking initiation or progressing to addiction, than an individual who does not possess these risk alleles. These findings both strengthen the case for use of polygenic risk score analyses as well as provide findings on novel SNPs that have not previously been shown to be associated with smoking-related phenotypes.