Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

Manuel A R Ferreira; Riddhima Mathur; Judith M Vonk; Agnieszka Szwajda; Ben Brumpton; Raquel Granell; Bronwyn K Brew; Vilhelmina Ullemar; Yi Lu; Yunxuan Jiang; 23andMe Research Team; eQTLGen Consortium; BIOS Consortium; Patrik K E Magnusson; Robert Karlsson; David A Hinds; Lavinia Paternoster; Gerard H Koppelman; Catarina Almqvist

doi:10.1016/j.ajhg.2019.02.022

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.

Authors

Manuel A R Ferreira¹, Riddhima Mathur², Judith M Vonk³, Agnieszka Szwajda⁴, Ben Brumpton⁵, Raquel Granell⁶, Bronwyn K Brew⁴, Vilhelmina Ullemar⁴, Yi Lu⁴, Yunxuan Jiang⁷; 23andMe Research Team⁷; eQTLGen Consortium⁸; BIOS Consortium⁹; Patrik K E Magnusson⁴, Robert Karlsson⁴, David A Hinds⁷, Lavinia Paternoster⁶, Gerard H Koppelman¹⁰, Catarina Almqvist¹¹

Affiliations

¹ Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia. Electronic address: manuel.ferreira@qimrberghofer.edu.au.
² Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
³ Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen 9713, the Netherlands; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen 9713, the Netherlands.
⁴ Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm 171 77, Sweden.
⁵ Medical Reserve Corps Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol BS8 1TH, UK; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norges Teknisk-Naturvitenskapelige Universitet, Norwegian University of Science and Technology, Trondheim 7491, Norway; Clinic of Thoracic and Occupational Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim 7030, Norway.
⁶ Medical Reserve Corps Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol BS8 1TH, UK.
⁷ 23andMe, Mountain View, California 94041, USA.
⁸ Collaborators of the eQTLGen Consortium are listed at the end of the manuscript.
⁹ A full list of members appears at the end of the paper.
¹⁰ Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen 9713, the Netherlands; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen 9713, the Netherlands.
¹¹ Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm 171 77, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 171 76, Sweden.

Abstract

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h²_g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h²_g = 10.6%). The genetic correlation (r_g) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h²_g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.

Keywords: GWAS; age; allergy; asthma; genetic; genome; heritability; onset; overlap; risk.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Age of Onset
Alleles
Asthma / genetics*
Child
Child, Preschool
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Hypersensitivity
Infant
Infant, Newborn
Male
Middle Aged
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Risk Factors
United Kingdom
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding