A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma

Spear, M. L.; Hu, D.; Pino-Yanes, M.; Huntsman, S.; Eng, C.; Levin, A. M.; White, M. J.; McGarry, M. E.; Thakur, N.; Galanter, J. M.; Mak, A. C. Y.; Oh, S. S.; Davis, A.; Kumar, R.; Farber, H. J.; Meade, K.; Avila, P. C.; Serebrisky, D.; Lenoir, M. A.; Brigino-Buenaventura, E. A.; Rodriquez Cintron, W.; Thyne, S. M.; Rodriguez-Santana, J. R.; Ford, J. G.; Chapela, R.; Moreno Estrada, A.; Sandoval, K.; Seibold, M. A.; Williams, L. K.; Winkler, C. A.; Torgerson, D. G.; Hernandez, R. D.; Burchard, E. G.

doi:10.1101/157198

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bioRxiv · 10.1101/157198

A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma

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Abstract

BackgroundShort-acting B2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S 1, 2. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma3\n\nObjectiveTo identify genetic variants that may contribute to differences in BDR in African Americans with asthma.\n\nMethodsWe performed a genome-wide association study of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase 3 genotypes. We used linear regression models adjusting for age, sex, body mass index and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. Two additional populations of 416 Latinos and 1,325 African Americans were used to replicate significant associations.\n\nResultsWe identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69 x 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p[≤]5 x 10-8).\n\nConclusionsOur findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.\n\nKey messagesO_LIA GWAS for BDR in African American children with asthma identified an intergenic population specific variant at 9q21 to be associated with increased bronchodilator drug response (BDR).\nC_LIO_LIA meta-analysis of GWAS across African Americans and Latinos identified shared genetic variants at 10q21 in the intron of PRKG1 to be associated with differences in BDR.\nC_LIO_LIFurther genetic studies need to be performed in diverse populations to identify the full set of genetic variants that contribute to BDR.\nC_LI

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Spear, M. L., Hu, D., Pino-Yanes, M., Huntsman, S., Eng, C., Levin, A. M., White, M. J., McGarry, M. E., Thakur, N., Galanter, J. M., Mak, A. C. Y., Oh, S. S., Davis, A., Kumar, R., Farber, H. J., Meade, K., Avila, P. C., Serebrisky, D., Lenoir, M. A., Brigino-Buenaventura, E. A., Rodriquez Cintron, W., Thyne, S. M., Rodriguez-Santana, J. R., Ford, J. G., Chapela, R., Moreno Estrada, A., Sandoval, K., Seibold, M. A., Williams, L. K., Winkler, C. A., Torgerson, D. G., Hernandez, R. D., Burchard, E. G.. 2017-06-28. A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma. https://doi.org/10.1101/157198

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