title: Pathway analysis of smoking quantity in multiple GWAS identifies cholinergic and sensory pathways.
abstract: Cigarette smoking is a common addiction that increases the risk for many diseases, including lung cancer and chronic obstructive pulmonary disease. Genome-wide association studies (GWAS) have successfully identified and validated several susceptibility loci for nicotine consumption and dependence. However, the trait variance explained by these genes is only a small fraction of the estimated genetic risk. Pathway analysis complements single marker methods by including biological knowledge into the evaluation of GWAS, under the assumption that causal variants lie in functionally related genes, enabling the evaluation of a broad range of signals. Our approach to the identification of pathways enriched for multiple genes associated with smoking quantity includes the analysis of two studies and the replication of common findings in a third dataset. This study identified pathways for the cholinergic receptors, which included SNPs known to be genome-wide significant; as well as novel pathways, such as genes involved in the sensory perception of smell, that do not contain any single SNP that achieves that stringent threshold.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Oscar
authors.initials: O
authors.lastname: Harari
authors.forename: Jen-Chyong
authors.initials: JC
authors.lastname: Wang
authors.forename: Kathleen
authors.initials: K
authors.lastname: Bucholz
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Andrew
authors.initials: A
authors.lastname: Heath
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Michele L
authors.initials: ML
authors.lastname: Pergadia
authors.forename: Grant
authors.initials: G
authors.lastname: Montgomery
authors.forename: Andrew
authors.initials: A
authors.lastname: Schrage
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Pamela F
authors.initials: PF
authors.lastname: Madden
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D012176:Retinoids / Q000378:metabolism; D012677:Sensation / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D012903:Smell / Q000235:genetics; D012907:Smoking / Q000235:genetics*; D012984:Software
chemical_list: D011950:Receptors, Cholinergic; D012176:Retinoids