Christopher R Gignoux1, Dara G Torgerson2, Maria Pino-Yanes3, Lawrence H Uricchio4, Joshua Galanter5, Lindsey A Roth2, Celeste Eng2, Donglei Hu2, Elizabeth A Nguyen2, Scott Huntsman2, Rasika A Mathias6, Rajesh Kumar7, Jose Rodriguez-Santana8, Neeta Thakur2, Sam S Oh2, Meghan McGarry9, Andres Moreno-Estrada10, Karla Sandoval10, Cheryl A Winkler11, Max A Seibold12, Badri Padhukasahasram13, David V Conti14, Harold J Farber15, Pedro Avila16, Emerita Brigino-Buenaventura17, Michael Lenoir18, Kelley Meade19, Denise Serebrisky20, Luisa N Borrell21, William Rodriguez-Cintron22, Shannon Thyne2, Bonnie R Joubert23, Isabelle Romieu24, Albert M Levin13, Juan-Jose Sienra-Monge25, Blanca Estela Del Rio-Navarro25, Weiniu Gan26, Benjamin A Raby27, Scott T Weiss27, Eugene Bleecker28, Deborah A Meyers28, Fernando J Martinez29, W James Gauderman14, Frank Gilliland14, Stephanie J London23, Carlos D Bustamante10, Dan L Nicolae30, Carole Ober31, Saunak Sen32, Kathleen Barnes6, L Keoki Williams33, Ryan D Hernandez34, Esteban G Burchard35. 1. Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif. Electronic address: chris.gignoux@ucdenver.edu. 2. Department of Medicine, University of California, San Francisco, San Francisco, Calif. 3. Department of Medicine, University of California, San Francisco, San Francisco, Calif; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 4. Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif. 5. Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif; Department of Medicine, University of California, San Francisco, San Francisco, Calif. 6. Department of Medicine, Johns Hopkins University, Baltimore, Md. 7. Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Ill. 8. Centro de Neumologia Pediatrica, San Juan, Puerto Rico. 9. Department of Pediatrics, University of California, San Francisco, San Francisco, Calif. 10. Department of Genetics, Stanford University, Palo Alto, Calif. 11. Molecular Genetics Epidemiology Section, Frederick National Laboratory for Cancer Research, Frederick, Md. 12. Integrated Center for Genes, Environment, and Health, Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo. 13. Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Mich. 14. Department of Preventative Medicine, University of Southern California, Los Angeles, Calif. 15. Department of Pediatrics, Section of Pulmonology, Baylor College of Medicine and Texas Children's Hospital, Houston, Tex. 16. Division of Allergy-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Ill. 17. Department of Allergy & Immunology, Kaiser Permanente-Vallejo Medical Center, Vallejo, Calif. 18. Bay Area Pediatrics, Oakland, Calif. 19. Children's Hospital and Research Center Oakland, Oakland, Calif. 20. Pediatric Pulmonary Division, Jacobi Medical Center, Bronx, NY. 21. Department of Health Sciences, Graduate Program in Public Health, Lehman College, City University of New York, Bronx, NY. 22. Veterans Caribbean Health Care System, San Juan, Puerto Rico. 23. National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. 24. Nutritional Epidemiology Group, International Agency for Research on Cancer, Lyon, France. 25. Departmento de Alergia e Inmunologia, Clinica Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico. 26. Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Md. 27. Department of Medicine, Harvard Medical School, Boston, Mass. 28. Center for Genomics & Personalized Medicine Research, Wake Forest University, Winston-Salem, NC. 29. BIO5 Institute, University of Arizona, Tucson, Ariz. 30. Physical Sciences Division, Department of Statistics, University of Chicago, Chicago, Ill. 31. Department of Human Genetics, University of Chicago, Chicago, Ill. 32. Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis, Tenn. 33. Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Mich; Department of Internal Medicine, Henry Ford Health System, Detroit, Mich. 34. Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif. 35. Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif; Department of Medicine, University of California, San Francisco, San Francisco, Calif.
Abstract
BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.
BACKGROUND:Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.
Authors: Katarzyna Bryc; Christopher Velez; Tatiana Karafet; Andres Moreno-Estrada; Andy Reynolds; Adam Auton; Michael Hammer; Carlos D Bustamante; Harry Ostrer Journal: Proc Natl Acad Sci U S A Date: 2010-05-05 Impact factor: 11.205
Authors: Shweta Choudhry; Natasha E Coyle; Hua Tang; Keyan Salari; Denise Lind; Suzanne L Clark; Hui-Ju Tsai; Mariam Naqvi; Angie Phong; Ngim Ung; Henry Matallana; Pedro C Avila; Jesus Casal; Alfonso Torres; Sylvette Nazario; Richard Castro; Natalie C Battle; Eliseo J Perez-Stable; Pui-Yan Kwok; Dean Sheppard; Mark D Shriver; William Rodriguez-Cintron; Neil Risch; Elad Ziv; Esteban Gonzàlez Burchard Journal: Hum Genet Date: 2005-11-08 Impact factor: 4.132
Authors: Neeta Thakur; Sam S Oh; Elizabeth A Nguyen; Melissa Martin; Lindsey A Roth; Joshua Galanter; Christopher R Gignoux; Celeste Eng; Adam Davis; Kelley Meade; Michael A LeNoir; Pedro C Avila; Harold J Farber; Denise Serebrisky; Emerita Brigino-Buenaventura; William Rodriguez-Cintron; Rajesh Kumar; L Keoki Williams; Kirsten Bibbins-Domingo; Shannon Thyne; Saunak Sen; Jose R Rodriguez-Santana; Luisa N Borrell; Esteban G Burchard Journal: Am J Respir Crit Care Med Date: 2013-11-15 Impact factor: 21.405
Authors: Joshua M Galanter; Christopher R Gignoux; Dara G Torgerson; Lindsey A Roth; Celeste Eng; Sam S Oh; Elizabeth A Nguyen; Katherine A Drake; Scott Huntsman; Donglei Hu; Saunak Sen; Adam Davis; Harold J Farber; Pedro C Avila; Emerita Brigino-Buenaventura; Michael A LeNoir; Kelley Meade; Denise Serebrisky; Luisa N Borrell; William Rodríguez-Cintrón; Andres Moreno Estrada; Karla Sandoval Mendoza; Cheryl A Winkler; William Klitz; Isabelle Romieu; Stephanie J London; Frank Gilliland; Fernando Martinez; Carlos Bustamante; L Keoki Williams; Rajesh Kumar; José R Rodríguez-Santana; Esteban G Burchard Journal: J Allergy Clin Immunol Date: 2014-01-07 Impact factor: 10.793
Authors: Dara G Torgerson; Christopher R Gignoux; Joshua M Galanter; Katherine A Drake; Lindsey A Roth; Celeste Eng; Scott Huntsman; Raul Torres; Pedro C Avila; Rocio Chapela; Jean G Ford; José R Rodríguez-Santana; William Rodríguez-Cintrón; Ryan D Hernandez; Esteban G Burchard Journal: J Allergy Clin Immunol Date: 2012-04-13 Impact factor: 10.793
Authors: Joshua M Galanter; Dara Torgerson; Christopher R Gignoux; Saunak Sen; Lindsey A Roth; Marc Via; Melinda C Aldrich; Celeste Eng; Scott Huntsman; Jose Rodriguez-Santana; William Rodriguez-Cintrón; Rocio Chapela; Jean G Ford; Esteban G Burchard Journal: J Allergy Clin Immunol Date: 2011-05-28 Impact factor: 10.793
Authors: Maria Pino-Yanes; Christopher R Gignoux; Joshua M Galanter; Albert M Levin; Catarina D Campbell; Celeste Eng; Scott Huntsman; Katherine K Nishimura; Pierre-Antoine Gourraud; Kiana Mohajeri; Brian J O'Roak; Donglei Hu; Rasika A Mathias; Elizabeth A Nguyen; Lindsey A Roth; Badri Padhukasahasram; Andres Moreno-Estrada; Karla Sandoval; Cheryl A Winkler; Fred Lurmann; Adam Davis; Harold J Farber; Kelley Meade; Pedro C Avila; Denise Serebrisky; Rocio Chapela; Jean G Ford; Michael A Lenoir; Shannon M Thyne; Emerita Brigino-Buenaventura; Luisa N Borrell; William Rodriguez-Cintron; Saunak Sen; Rajesh Kumar; Jose R Rodriguez-Santana; Carlos D Bustamante; Fernando D Martinez; Benjamin A Raby; Scott T Weiss; Dan L Nicolae; Carole Ober; Deborah A Meyers; Eugene R Bleecker; Steven J Mack; Ryan D Hernandez; Evan E Eichler; Kathleen C Barnes; L Keoki Williams; Dara G Torgerson; Esteban G Burchard Journal: J Allergy Clin Immunol Date: 2014-12-06 Impact factor: 10.793
Authors: Rachel A Myers; Blanca E Himes; Christopher R Gignoux; James J Yang; W James Gauderman; Cristina Rebordosa; Jianming Xie; Dara G Torgerson; Albert M Levin; James Baurley; Penelope E Graves; Rasika A Mathias; Isabelle Romieu; Lindsey A Roth; David Conti; Lydiana Avila; Celeste Eng; Hita Vora; Michael A LeNoir; Manuel Soto-Quiros; Jinghua Liu; Juan C Celedón; Joshua M Galanter; Harold J Farber; Rajesh Kumar; Pedro C Avila; Kelley Meade; Denise Serebrisky; Shannon Thyne; William Rodriguez-Cintron; Jose R Rodriguez-Santana; Luisa N Borrell; Robert F Lemanske; Eugene R Bleecker; Deborah A Meyers; Stephanie J London; Kathleen C Barnes; Benjamin A Raby; Fernando D Martinez; Frank D Gilliland; L Keoki Williams; Esteban G Burchard; Scott T Weiss; Dan L Nicolae; Carole Ober Journal: J Allergy Clin Immunol Date: 2012-10-04 Impact factor: 10.793
Authors: Stephanie A Bien; Genevieve L Wojcik; Chani J Hodonsky; Christopher R Gignoux; Iona Cheng; Tara C Matise; Ulrike Peters; Eimear E Kenny; Kari E North Journal: Annu Rev Genomics Hum Genet Date: 2019-04-12 Impact factor: 8.929
Authors: Eunice Y Lee; Angel C Y Mak; Donglei Hu; Satria Sajuthi; Marquitta J White; Kevin L Keys; Walter Eckalbar; Luke Bonser; Scott Huntsman; Cydney Urbanek; Celeste Eng; Deepti Jain; Gonçalo Abecasis; Hyun M Kang; Soren Germer; Michael C Zody; Deborah A Nickerson; David Erle; Elad Ziv; Jose Rodriguez-Santana; Max A Seibold; Esteban G Burchard Journal: Am J Respir Crit Care Med Date: 2020-10-01 Impact factor: 21.405
Authors: Kelsey E Grinde; Lisa A Brown; Alexander P Reiner; Timothy A Thornton; Sharon R Browning Journal: Am J Hum Genet Date: 2019-02-14 Impact factor: 11.025
Authors: Erick Forno; Diego D Brandenburg; Jose A Castro-Rodriguez; Carlos A Celis-Preciado; Fernando Holguin; Christopher Licskai; Stephanie Lovinsky-Desir; Marcia Pizzichini; Alejandro Teper; Connie Yang; Juan C Celedón Journal: Ann Am Thorac Soc Date: 2022-04
Authors: Briseida E Feliciano-Astacio; Katrina Celis; Jairo Ramos; Farid Rajabli; Larry Deon Adams; Alejandra Rodriguez; Vanessa Rodriguez; Parker L Bussies; Carolina Sierra; Patricia Manrique; Pedro R Mena; Antonella Grana; Michael Prough; Kara L Hamilton-Nelson; Nereida Feliciano; Angel Chinea; Heriberto Acosta; Jacob L McCauley; Jeffery M Vance; Gary W Beecham; Margaret A Pericak-Vance; Michael L Cuccaro Journal: Front Genet Date: 2019-06-19 Impact factor: 4.599
Authors: Douglas P Loesch; Andrea R V R Horimoto; Karl Heilbron; Elif I Sarihan; Miguel Inca-Martinez; Emily Mason; Mario Cornejo-Olivas; Luis Torres; Pilar Mazzetti; Carlos Cosentino; Elison Sarapura-Castro; Andrea Rivera-Valdivia; Angel C Medina; Elena Dieguez; Victor Raggio; Andres Lescano; Vitor Tumas; Vanderci Borges; Henrique B Ferraz; Carlos R Rieder; Artur Schumacher-Schuh; Bruno L Santos-Lobato; Carlos Velez-Pardo; Marlene Jimenez-Del-Rio; Francisco Lopera; Sonia Moreno; Pedro Chana-Cuevas; William Fernandez; Gonzalo Arboleda; Humberto Arboleda; Carlos E Arboleda-Bustos; Dora Yearout; Cyrus P Zabetian; Paul Cannon; Timothy A Thornton; Timothy D O'Connor; Ignacio F Mata Journal: Ann Neurol Date: 2021-07-22 Impact factor: 11.274