Expression quantitative trait locus fine mapping of the 17q12–21 asthma locus in African American children: a genetic association and gene expression study

Carole Ober, Chris G. McKennan, Kevin M. Magnaye, Matthew C. Altman, Charles Washington, Catherine Stanhope, Katherine A. Naughton, Mario G. Rosasco, Leonard B. Bacharier, Dean Billheimer, Diane R. Gold, Lisa Gress, Tina Hartert, Suzanne Havstad, Gurjit K. Khurana Hershey, Brian Hallmark, D. Kyle Hogarth, Daniel J. Jackson, Christine C. Johnson, Meyer KattanRobert F. Lemanske, Susan V. Lynch, Eneida A. Mendonca, Rachel L. Miller, Edward T. Naureckas, George T. O'Connor, Christine M. Seroogy, Ganesa Wegienka, Steven R. White, Robert A. Wood, Anne L. Wright, Edward M. Zoratti, Fernando D. Martinez, Dennis Ownby, Dan L. Nicolae, Albert M. Levin, James E. Gern, Niek Achten, John Ainsworth, Nonna Akkerman, Elizabeth Anderson, Larry J. Anderson, Howard Andrews, Elizabeth Armagost, Mary Ann Aubuchon, Julia Bach, Leonard Bacharier, Kathrine L. Barnes, Charles Barone, Irma Bauer, Paloma Beamer, Patrice Becker, Alyssa Bednarek, Stacey Bellemore, Casper G. Bendixsen, Jocelyn M. Biagini Myers, Christine Billstrand, Geraldine Birg, Shirley Blocki, Gordon Bloomberg, Kevin Bobbitt, Yury Bochkov, Karen Bourgeois, Homer Boushey, Rebecca Brockman-Schneider, Steven M. Brunwasser, Richard Budrevich, Jeffrey W. Burkle, William Busse, Agustin Calatroni, Janice Campbell, Kirsten Carlson-Dakes, Andrea Cassidy-Bushrow, James D. Chappell, Deborah Chasman, Teresa M. Chipps, Tatiana Chirkova, Deanna Cole, Alexandra Connolly, Michelle Cootauco, Kaitlin Costello, Philip Couch, Brent Coull, Mark Craven, Gina Crisafi, William Cruikshank, Kristi Curtsinger, Adnan Custovic, Suman R. Das, Douglas DaSilva, Soma Datta, Brent Davidson, Lydia De La Ossa, Mark DeVries, Qian Di, Samara Dixon, Erin Donnerbauer, Marian Dorst, Susan Doyle, Amy Dresen, William D. Dupont, Janet Durrange, Heidi Erickson, Michael D. Evans, Jerel Ezell, Leanna Farnham, Roxanne Filardo-Collins, Salvatore Finazzo, Zachary Flege, Conner Fleurat, Heather Floerke, Dorothy Floerke, Terry Foss, Angela Freie, Wayne Frome, Samantha Fye, Lisa Gagalis, Rebecca Gammell, Ronald E. Gangnon, James E. Ge, Tebeb Gebretsadik, Peter Gergen, James E. Gern, Heike Gibson, Edlira Gjerasi, Diane R. Gold, Nicole Gonzalez, Kayla Goodman, Kristine Grindle, Taylor Groeschen, Marilyn Halonen, Jaime Hart, Tina V. Hartert, Patrick Heinritz, Sharon Hensley Alford, Julie Herbstman, Kellie Hernandez, Lori Hoepner, Daniel J. Jackson, Samadhan J. Jadhao, Katy Jaffee, Peter James, Jacqueline Jezioro, Marcia Jimenez Pescador, Christine C. Johnson, Tara Johnson, Camille Johnson, Amelia Jones, Kyra Jones, Paul Jones, Carolina Jordan, Christine LM Joseph, Kristina Keidel, Matthew C. Keifer, Rick Kelley, Gurgit K. Khurana Hershey, Haejin Kim, Itai Kloog, Tammy Kronenwetter Koepel, Clint Koerkenmeier, Laura Ladick, Carin Lamm, Emma Larkin, Howard Lederman, Aviva Lee-Parritz, Stephanie Leimenstoll, Robert F. Lemanske, Grace K. LeMasters, Albert M. Levin, Jessica Levine, Xinhua Liu, Zhouwen Liu, Silvia Lopez, Nathan Lothrop, Stephanie Lovinsky-Desir, Nicholas Lukacs, Susan Lynch, Christian Lynch, Erik Mann, Jennifer Martin, Lisa Martin, Fernando D. Martinez, Elizabeth Matsui, Katherine McCauley, Megan Mccollum, Judith McCullough, Chris G. McKennon, Jennifer Meece, Eneida Mendonca, Lance Mikus, Rachel L. Miller, Patricia Minton, Herman Mitchell, Vicki Moon, Paul E. Moore, Wayne Morgan, Valerie Morgan, David Morgan, Liza Murrison, Charlotte Nicholas, Daniel Nicolae, Adam Nunez, George O'Connor, Sharon O'Toole, Brent F. Olson, Irene Ong, Sarah Osmundson, Tressa Pappas, Frederica Perera, Matthew Perzanowski, Edward Peterson, Marcela Pierce, Penny Price-Johnson, Victoria Rajamanickam, Judyth Ramirez, Kimberly Ray, Megan Renneberg, Weeberb Requia, Kylie Riley, Janelle Rivera, Neisha Rivers, Kathy Roberg, Theresa Rogers, Christian Rosas-Salazar, Pat Russell, Patrick H. Ryan, Yoel Sadovsky, Lisa Salazar, Hugh Sampson, Megan Sandel, Nathan Schoettler, Joel Schwartz, Dena Scott, Christine M. Seroogy, Renee Sharp, Meghan H. Shilts, Steve Sigelman, Anne Marie Singh, Alexandra Sitarik, Ernestine Smartt, Ronald Sorkness, Christine Sorkness, Amber Spangenberg, Rhoda Sperling, David Spies, Debra A. Stern, Brandy Stoffel, R. Stokes Peebles, Gina Stouffer, Cathey Strauchman Boyer, Caitlin Suddeuth, Umberto Tachinardi, Deliang Tang, Zhengzheng Tang, Jena Tate, William Taylor, Krista Tensing, Elizabeth Tesson, Kathy Thompson, Emma Thompson, Christopher Tisler, Alkis Togias, Kedir Turi, Victoria Turner, Marina Tuzova, Jeffrey J. VanWormer, Cynthia M. Visness, Rose Vrtis, Anthony Wahlman, Lena Wang, Karen Wells, William Wentworth-Sheilds, Lisa Wheatley, Nitsa Whitney, L. Keoki Williams, Frank Witter, Christopher Wolfe, Robert A. Wood, Kimberley Woodcroft, Kim B. Woodward, Anne L. Wright, Rosalind Wright, Pingsheng Wu, Melissa Yaeger, Perri Yaniv, Antonella Zanobetti, Shirley Zhang, Patricia Zook, Edward M. Zoratti

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Abstract

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12–1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13–1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [β] 1·35 [95% CI 1·25–1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (β 1·15 [1·08–1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLβ 1·24 [1·15–1·32], p<0·0001; and for ORMDL3 (β 1·19 [1·12–1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (β 1·29 [1·15–1·44], p<0·0001). Interpretation: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12–21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus. Funding: National Institutes of Health, Office of the Director.

Original languageEnglish (US)
Pages (from-to)482-492
Number of pages11
JournalThe Lancet Respiratory Medicine
Volume8
Issue number5
DOIs
StatePublished - May 2020

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Ober, C., McKennan, C. G., Magnaye, K. M., Altman, M. C., Washington, C., Stanhope, C., Naughton, K. A., Rosasco, M. G., Bacharier, L. B., Billheimer, D., Gold, D. R., Gress, L., Hartert, T., Havstad, S., Khurana Hershey, G. K., Hallmark, B., Hogarth, D. K., Jackson, D. J., Johnson, C. C., ... Zoratti, E. M. (2020). Expression quantitative trait locus fine mapping of the 17q12–21 asthma locus in African American children: a genetic association and gene expression study. The Lancet Respiratory Medicine, 8(5), 482-492. https://doi.org/10.1016/S2213-2600(20)30011-4