A Barreto-Luis1, A Corrales1,2, M Acosta-Herrera1, C Gonzalez-Colino3, J Cumplido4, J Martinez-Tadeo3, A Carracedo5, J Villar2,6, T Carrillo4, M Pino-Yanes1,2, C Flores1,2. 1. Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain. 2. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 3. Allergy Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain. 4. Allergy Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain. 5. Grupo de Medicina Xenómica, CIBERER-Universidade de Santiago de Compostela-Fundación Galega de Medicina Xenómica (SERGAS), Santiago de Compostela, Spain. 6. Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.
Abstract
BACKGROUND: Genetic susceptibility to asthma is currently linked to a handful of genes which have a limited ability to predict the overall disease risk, suggesting the existence of many other genes involved in disease development. Accumulated evidence from association studies in genes related by biological pathways could reveal novel asthma genes. OBJECTIVE: To reveal novel asthma susceptibility genes by means of a pathway-based association study. METHODS: Based on summary data from a previous a genomewide association study (GWAS) of asthma, we first identified significant biological pathways using a gene-set enrichment analysis. We then mapped all tested single nucleotide polymorphisms (SNPs) on the genes contributing to significant pathways and prioritized those with a disproportionate number of nominal significant associations for further studies. For those prioritized genes, association studies were performed for selected SNPs in independent case-control samples (n = 1765) using logistic regression models, and results were meta-analysed with those from the GWAS. RESULTS: Two biological processes were significantly enriched: the cytokine-cytokine receptor interaction (P = 0.002) and the Wnt signalling (P = 0.012). From the 417 genes interacting in these two pathways, 10 showed an excess of nominal associations, including a known asthma susceptibility locus (encoding SMAD family member 3) and other novel candidate genes. From the latter, association studies of 14 selected SNPs evidenced replication in a locus near the frizzled class receptor 6 (FZD6) gene (P = 9.90 × 10-4 ), which had a consistent direction of effects with the GWAS findings (meta-analysed odds ratio = 1.49; P = 5.87 × 10-6 ) and was in high linkage disequilibrium with expression quantitative trait loci in lung tissues. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the importance of two biological pathways in asthma pathogenesis and identified a novel susceptibility locus near Wnt signalling genes.
BACKGROUND: Genetic susceptibility to asthma is currently linked to a handful of genes which have a limited ability to predict the overall disease risk, suggesting the existence of many other genes involved in disease development. Accumulated evidence from association studies in genes related by biological pathways could reveal novel asthma genes. OBJECTIVE: To reveal novel asthma susceptibility genes by means of a pathway-based association study. METHODS: Based on summary data from a previous a genomewide association study (GWAS) of asthma, we first identified significant biological pathways using a gene-set enrichment analysis. We then mapped all tested single nucleotide polymorphisms (SNPs) on the genes contributing to significant pathways and prioritized those with a disproportionate number of nominal significant associations for further studies. For those prioritized genes, association studies were performed for selected SNPs in independent case-control samples (n = 1765) using logistic regression models, and results were meta-analysed with those from the GWAS. RESULTS: Two biological processes were significantly enriched: the cytokine-cytokine receptor interaction (P = 0.002) and the Wnt signalling (P = 0.012). From the 417 genes interacting in these two pathways, 10 showed an excess of nominal associations, including a known asthma susceptibility locus (encoding SMAD family member 3) and other novel candidate genes. From the latter, association studies of 14 selected SNPs evidenced replication in a locus near the frizzled class receptor 6 (FZD6) gene (P = 9.90 × 10-4 ), which had a consistent direction of effects with the GWAS findings (meta-analysed odds ratio = 1.49; P = 5.87 × 10-6 ) and was in high linkage disequilibrium with expression quantitative trait loci in lung tissues. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the importance of two biological pathways in asthma pathogenesis and identified a novel susceptibility locus near Wnt signalling genes.
Authors: Hiam Abdala-Valencia; Mackenzie E Coden; Sergio E Chiarella; Elizabeth A Jacobsen; Bruce S Bochner; James J Lee; Sergejs Berdnikovs Journal: J Leukoc Biol Date: 2018-04-14 Impact factor: 4.962
Authors: Natalia Hernandez-Pacheco; Susanne J Vijverberg; Esther Herrera-Luis; Jiang Li; Yang Yie Sio; Raquel Granell; Almudena Corrales; Cyrielle Maroteau; Ryan Lethem; Javier Perez-Garcia; Niloufar Farzan; Katja Repnik; Mario Gorenjak; Patricia Soares; Leila Karimi; Maximilian Schieck; Lina Pérez-Méndez; Vojko Berce; Roger Tavendale; Celeste Eng; Olaia Sardon; Inger Kull; Somnath Mukhopadhyay; Munir Pirmohamed; Katia M C Verhamme; Esteban G Burchard; Michael Kabesch; Daniel B Hawcutt; Erik Melén; Uroš Potočnik; Fook Tim Chew; Kelan G Tantisira; Steve Turner; Colin N Palmer; Carlos Flores; Maria Pino-Yanes; Anke H Maitland-van der Zee Journal: Eur Respir J Date: 2021-05-13 Impact factor: 16.671
Authors: Annah B Wyss; Tamar Sofer; Mi Kyeong Lee; Natalie Terzikhan; Jennifer N Nguyen; Lies Lahousse; Jeanne C Latourelle; Albert Vernon Smith; Traci M Bartz; Mary F Feitosa; Wei Gao; Tarunveer S Ahluwalia; Wenbo Tang; Christopher Oldmeadow; Qing Duan; Kim de Jong; Mary K Wojczynski; Xin-Qun Wang; Raymond Noordam; Fernando Pires Hartwig; Victoria E Jackson; Tianyuan Wang; Ma'en Obeidat; Brian D Hobbs; Tianxiao Huan; Hongsheng Gui; Margaret M Parker; Donglei Hu; Lauren S Mogil; Gleb Kichaev; Jianping Jin; Mariaelisa Graff; Tamara B Harris; Ravi Kalhan; Susan R Heckbert; Lavinia Paternoster; Kristin M Burkart; Yongmei Liu; Elizabeth G Holliday; James G Wilson; Judith M Vonk; Jason L Sanders; R Graham Barr; Renée de Mutsert; Ana Maria Baptista Menezes; Hieab H H Adams; Maarten van den Berge; Roby Joehanes; Albert M Levin; Jennifer Liberto; Lenore J Launer; Alanna C Morrison; Colleen M Sitlani; Juan C Celedón; Stephen B Kritchevsky; Rodney J Scott; Kaare Christensen; Jerome I Rotter; Tobias N Bonten; Fernando César Wehrmeister; Yohan Bossé; Shujie Xiao; Sam Oh; Nora Franceschini; Jennifer A Brody; Robert C Kaplan; Kurt Lohman; Mark McEvoy; Michael A Province; Frits R Rosendaal; Kent D Taylor; David C Nickle; L Keoki Williams; Esteban G Burchard; Heather E Wheeler; Don D Sin; Vilmundur Gudnason; Kari E North; Myriam Fornage; Bruce M Psaty; Richard H Myers; George O'Connor; Torben Hansen; Cathy C Laurie; Patricia A Cassano; Joohon Sung; Woo Jin Kim; John R Attia; Leslie Lange; H Marike Boezen; Bharat Thyagarajan; Stephen S Rich; Dennis O Mook-Kanamori; Bernardo Lessa Horta; André G Uitterlinden; Hae Kyung Im; Michael H Cho; Guy G Brusselle; Sina A Gharib; Josée Dupuis; Ani Manichaikul; Stephanie J London Journal: Nat Commun Date: 2018-07-30 Impact factor: 14.919