Shared and Distinct Genetic Risk Factors for Childhood Onset and Adult Onset Asthma: Genome- and Transcriptome-wide Studies

Abstract

14 15 16 We detected 61 independent asthma loci: 23 were childhood onset specific, one was 33 adult onset specific, and 37 were shared. Nineteen loci were associated with age of 34 asthma onset. Genes at the childhood onset loci were most highly expressed in skin, 35 blood and small intestine; genes at the adult onset loci were most highly expressed in 36 lung, blood, small intestine and spleen. PrediXcan identified 113 unique candidate 37 genes at 22 of the 61 GWAS loci. 38 Interpretation 39Genetic risk factors for adult onset asthma are largely a subset of the genetic risk for 40 childhood onset asthma but with overall smaller effects, suggesting a greater role for 41 non-genetic risk factors in adult onset asthma. In contrast, the onset of disease in 42 childhood is associated with additional genes with relatively large effect sizes, and SNP-43 based heritability estimates that are over 3-times larger than for adult onset disease. 44Combined with gene expression and tissue enrichment patterns, we suggest that the 45 establishment of disease in children is driven more by dysregulated allergy and 46 epithelial barrier function genes whereas the etiology of adult onset asthma is more 47 lung-centered and environmentally determined, but with immune mediated mechanisms 48 driving disease progression in both children and adults. 49 50

Multi-omics co-localization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus

“…In contrast, 66 co-localizations were specific to childhood onset asthma, and were associated with 11 genes ( ACO2, ERBB2, FGFR4, FLG, FLG-AS1, FRK, GSTO2, IRF5, ORMDL3, PMM1, POLI ) and 27 CpG sites. The larger number of co-localizations for childhood onset asthma relative to adult onset asthma is consistent with the previous observation that genes at the childhood onset asthma loci were most highly expressed in skin, an epithelial cell type [12].…”

“…To test this hypothesis, we extracted summary statistics from the largest GWASs of adult onset and childhood onset asthma to date [12], and tested each for co-localization with genetic variants associated with gene expression, DNA methylation, and asthma, using moloc , a Bayesian statistical strategy that allows the integration and co-localization of more than two molecular traits [15]. We performed a separate co-localization test in each of the four conditions using variants from the GWASs of adult onset and childhood onset asthma separately.…”

“…Although these resources have provided important insights into the interpretation of GWAS results, they do not include all cell types relevant to all diseases or information on environmental exposures that influence disease outcomes. As a result, annotations of asthma GWAS variants have been largely limited to studies in cell lines, blood (immune) cells, and whole lung tissue [10–12].…”

Neonatal genetics of gene expression reveal the origins of autoimmune and allergic disease risk

“…At the CCL20 locus, the reQTL (rs13034664) in PHA-stimulated T cells colocalised with childhoodonset asthma 41 (Figure 4A, Figure S6). CCL20 encodes a C-C chemokine ligand that binds to a G protein-coupled receptor, and elevated CCL20 expression has been shown in airways of patients with chronic obstructive pulmonary disease (COPD) 42 and asthma 43,44 .…”

“…We also downloaded summary statistics of GWAS that were carried out using the ImmunoChip array from the ImmunoBase resource; this array was designed for immunogenetics studies and captured more variants of immune-relevant genetic loci 83 . We had summary statistics for the following immune-mediated diseases: allergic disease (asthma, hay fever, or eczema) 84 , allergic rhinitis 85 , allergic sensitisation 85 , asthma 86 , childhood-onset asthma 41 , adult-onset asthma 41 , inflammatory bowel disease (IBD) including its two subtypes -Crohn's disease and ulcerative colitis 87 , celiac disease 88,89 , autoimmune thyroid disease 90 , juvenile idiopathic arthritis 91 , multiple sclerosis 92 , narcolepsy 93 , primary biliary cirrhosis (PBC) 94,95 , primary sclerosing cholangitis (PSC) 96 , psoriasis 97 , rheumatoid arthritis 98,99 , systemic lupus erythematosus (SLE) 100 , and type 1 diabetes 101,102 . These datasets contained summary statistics obtained using European populations for both significant and non-significant genetic variants, and GRCh37 genomic coordinates were available.…”