Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma

• Published in: Nature communications Vol. 11; no. 1; p. 1776
• Main Authors: Han, Yi, Jia, Qiong, Jahani, Pedram Shafiei, Hurrell, Benjamin P., Pan, Calvin, Huang, Pin, Gukasyan, Janet, Woodward, Nicholas C., Eskin, Eleazar, Gilliland, Frank D., Akbari, Omid, Hartiala, Jaana A., Allayee, Hooman
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-04-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/43; 631/208/205/2138; 631/250/248; 64; 64/60; 692/699/1785/31; 692/699/249/2510/31; Adult; Aged; Allergens; Animal models; Animals; Antibodies; Architecture; Asthma; Asthma - genetics; Asthma - immunology; Bioinformatics; Case-Control Studies; CD52 Antigen - genetics; CD52 Antigen - immunology; Chromatin; Consortia; Female; Gene loci; Genetic analysis; Genetic Predisposition to Disease - epidemiology; Genome-Wide Association Study; Genomes; Health risk assessment; Humanities and Social Sciences; Humans; Hypersensitivity; Immune system; Immune System - cytology; Immune System - pathology; Immunology; Lymphocytes - metabolism; Male; Men; Mice; Middle Aged; multidisciplinary; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Respiratory diseases; Respiratory tract; Risk analysis; Risk Factors; Science; Science (multidisciplinary); Sex; Sex Factors; United Kingdom - epidemiology; United Kingdom
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15649-3

Asthma is a chronic and genetically complex respiratory disease that affects over 300 million people worldwide. Here, we report a genome-wide analysis for asthma using data from the UK Biobank and the Trans-National Asthma Genetic Consortium. We identify 66 previously unknown asthma loci and demonstrate that the susceptibility alleles in these regions are, either individually or as a function of cumulative genetic burden, associated with risk to a greater extent in men than women. Bioinformatics analyses prioritize candidate causal genes at 52 loci, including
CD52
, and demonstrate that asthma-associated variants are enriched in regions of open chromatin in immune cells. Lastly, we show that a murine anti-CD52 antibody mimics the immune cell-depleting effects of a clinically used human anti-CD52 antibody and reduces allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma and provide important insight into the immunological and sex-specific relevance of asthma-associated risk variants.
Asthma is a common disease of the airways for which numerous genetic loci have been identified. Here, Han et al. carry out a genome-wide analysis for asthma to identify additional loci, report sex-stratified and genetic risk score analyses, and functionally follow-up one locus using a murine model of airway hyperreactivity.