Genome-wide association study of opioid-induced vomiting in the 23andMe cohort. J. L. Mountain1, N. Eriksson1, J. Y. Tung1, A. S. Shmygelska1, H. L. McLoed2, U. Francke1,3, A. K. Kiefer1, D. A. Hinds1 1) 23andMe, Inc, Mountain View, CA; 2) Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC; 3) Department of Genetics, Stanford University, Stanford, CA.

   To date the vast majority of pharmacogenetic studies have been conducted in vitro or within a relatively small cohort. Here we present results of a large genome-wide association study of side effects of codeine. Codeine is an opiate medication used to control mild to moderate pain. In the body, codeine is activated to morphine which is then thought to bind to receptors in the brain and spinal cord that play a role in transmitting the sensation of pain throughout the body. Opioids also bind to receptors in the gastrointestinal tract. Among the more common side effects of codeine are vomiting, itching, euphoria, and constipation. Participants in this study were unrelated customers of 23andMe, a personal genetics company, with European ancestry. They consented to take part in research and reported their experiences with commonly used medications via a web-based survey. 2,479 cases reported vomiting in response to codeine use; 10,789 controls reported none of the four side effects named above. Participants were genotyped at up to 1 million positions; genotypes for 20 million positions were imputed. We performed logistic regression assuming an additive model for allelic effects, controlling for age, sex, and genetically-derived ancestry. We identified two genome-wide significant regions. The top hit, rs9620007 (p=1.4e-09; OR=0.79), is located within the WBP2NL gene on chromosome 22. Located about 0.1 Mb from the WBP2NL gene is the CYP2D6 gene. Previous studies have yielded strong evidence for a link between CYP2D6 genotype and codeine metabolism. However, these studies have focused primarily on drug metabolism (e.g. excretion of morphine after codeine use) rather than on specific side effects. The second hit, rs10732842 (p=2.9e-08;OR=1.29), is located near the LRRIQ3 gene on chromosome 1. We identified a third association, nearly significant at the genome-wide level (p=2.9e-07; OR=0.77), between vomiting in response to codeine and a variant (rs1799971, g.A118G) in the opioid receptor gene OPRM1. Previously this SNP was found to be linked to susceptibility to opioid dependence. This study is novel in demonstrating associations between the side effect of vomiting in response to codeine and two genes linked to opioid pathways. The significance likely reflects several factors including the relatively high frequency of use of codeine, the relatively high frequency of this particular side effect, and the participants ability to recall a more dramatic side effect.