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Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci

bioRxiv (Cold Spring Harbor Laboratory)2017

Michelle Daya, Nicholas Rafaels, Sameer Chavan, H. Richard Johnston, Aniket Shetty, Christopher R. Gignoux, Meher Preethi Boorgula, Monica Campbell, Pissamai Maul, Trevor Maul, Candelaria Vergara, Albert M. Levin, Genevieve L. Wojcik, Dara G. Torgerson, Victor E. Ortega, Ayo P. Doumatey, Maria Ilma Araújo, Pedro C. Avila, Eugene R. Bleecker, Carlos D. Bustamante, Luis Caraballo, Georgia M. Dunston, Mezbah U. Faruque, Trevor S. Ferguson, Camila Alexandrina Figueiredo, Jean G. Ford, Pierre‐Antoine Gourraud, Nadia N. Hansel, Ryan D. Hernandez, Edwin Francisco Herrera-Paz, Eimear E. Kenny, Jennifer Knight‐Madden, Rajesh Kumar, Lesli A. Lange, Ethan M. Lange, Antoine Lizée, Alvaro Mayorga, Deborah A. Meyers, Dan L. Nicolae, Timothy D. O’Connor, Ricardo Riccio Oliveira, Christopher O. Olopade, Olufunmilayo I. Olopade, Zhaohui Qin, Charles N. Rotimi, Harold Watson, Rainford Wilks, L. Keoki Williams, James G. Wilson, Carole Ober, Esteban G. Burchard, Terri H. Beaty, Margaret A. Taub, Ingo Ruczinski, Rasika A. Mathias, Kathleen C. Barnes, Ayôla Akim Adégnika, Ganiyu Olatunbosun Arinola, Ulysse Ateba-Ngoa, Gerardo Ayestas, Adolfo Correa, Francisco M. De La Vega, Celeste Eng, Said Omar Leiva Erazo, Marilyn G. Foreman, Cassandra Foster, Li Gao, Jingjing Gao, Kimberly Gietzen, Leslie C. Grammer, Linda S. Gutierrez, Thomas Folkmann Hansen, Tina V. Hartert, Yi‐Juan Hu, Kwang‐Youn A. Kim, Pamela Landaverde-Torres, Javier Marrugo, B. Martínez, Rosella Martinez, L Mayorga, Delmy-Aracely Mejia-Mejia, Catherine Meza, Solomon K. Musani, Shaila Musharoff, Oluwafemi Oluwole, Maria Pino‐Yanes, Hector Ramos, Allan Saenz, Steven L. Salzberg, Maureen Samms‐Vaughan, R.P. Schleimer, Alan F. Scott, Suyash Shringarpure, Wei Song, Zachary A. Szpiech, Raúl Torres, Gloria Varela, Olga Marina Vasquez, Lorraine B. Ware, Maria Yazdanbakhsh

Abstract

Abstract BACKGROUND Asthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent. METHODS We performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry. RESULTS SNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 × 10 −9 and 2.97 × 10 −8 , respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 ( ARHGAP15 ) and Glycosyltransferase Like Domain Containing 1 ( GTDC1 ) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the “atopic march” and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 ×10 −6 ≤ p ≤ 3.06 ×10 −6 ). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 ( TCF21 ) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics. CONCLUSIONS We have identified a number of novel asthma association signals warranting further investigation.

Abstract

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