Webcast: Common Genetic Variants Modulate Nicotinic Alpha5 Receptor mRNA Expression and Risk for Nicotine Dependence

Presenters: Ryan M. Smith and Audrey C. Papp, Ohio State University

Date: October 27, 2010

Duration: 35 Minutes

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Abstract

CHRNA5, encoding the nicotinic alpha5 subunit, is implicated in nicotine addiction, lung cancer, and chronic obstructive pulmonary disease. Expression of this gene is significantly associated with promoter polymorphisms, but the responsible sequence variants remain uncertain.

In this webcast, Ryan Smith and Audrey Papp of Ohio State University will discuss their search for cis-regulatory variants, by measuring allele-specific mRNA expression of CHRNA5 in human prefrontal cortex autopsy tissues and scanning the CHRNA5 locus for regulatory variants.

They will also review their findings, recently published in the European Journal of Human Genetics, including their observation that genetic variants within a proposed enhancer region, residing more than 13 kilobases upstream of the CHRNA5 transcription start site, fully account for a >2.5-fold allelic expression difference and a fourfold increase in overall CHRNA5 mRNA expression. The same upstream variants failed to affect CHRNA5 mRNA expression in peripheral blood lymphocytes, indicating tissue-specific gene regulation. Other promoter polymorphisms were also correlated with overall CHRNA5 mRNA expression in the brain, but were inconsistent with allelic mRNA expression ratios, and therefore unlikely to be cis-regulatory variants. The enhancer region is significantly associated with nicotine dependence, and together with nonsynonymous variant rs16969968, forms three main haplotypes predicted to have distinct biological functions.

About the Presenters

Ryan M. Smith is currently a Ph.D. candidate in his final month of the Neuroscience Graduate Studies Program at The Ohio State University. Under the direction of Wolfgang Sadee in the Department of Pharmacology, his research is focused on uncovering functional genetic variants that contribute to human behavioral phenotypes (drug abuse, response to pharmacological therapies, neuropsychiatric disorders, etc.) by studying expression genetics in human brain tissue. Ryan received his B.A. in Psychology from The Ohio State University in 2005, during which time he researched human cognition and memory. 

Audrey C. Papp is a research specialist in Pharmacology with expertise in pharmacogenomics and drug addiction at Ohio State University. As Director of the Pharmacogenomics Core Laboratory since its inception in 2002, she has been instrumental in developing new methodology for identifying regulatory polymorphisms and has recently implemented a series of next generation sequencing experiments. Prior to her current tenure, Audrey was supervisor of the Clinical Molecular Pathology Laboratory in the Department of Pathology at OSUMC. She has been a contributing author on over 60 papers.