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

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 ¼ 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; h 2 g ¼ 25.6%) than for AOA (onset at ages between 20 and 60 years; h 2 g ¼ 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 (h 2 g ¼ 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 ¼ 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 ¼ 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.

Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective

“…Dupuytren's disease, which has a prevalence of more than 30% in some Northern European ethnicities, although it is lower in most of the world by 1-3 levels of magnitude, is an interesting example that was examined in this research. The alleles were randomly distributed throughout the model genome; these results are consistent with GWAS findings for asthma [53,98], schizophrenia [99], and other diseases [4].…”

GSDMAdrives the most replicated association with asthma in naïve CD4+T cells

“…The association between asthma and the 17q12-21 locus was first established in childhood asthma 6 and was then confirmed to be mainly driven by individuals with the early-onset form of the disease. 13,14 Using a familial cohort with a mean age of onset of seven and 22 years old for probands and other family members respectively can be considered a caveat for the study of this locus, principally since gene expression counts and DNA methylation levels are changing over time. However, the genetic association was replicated in a previous study performed with the SLSJ asthma cohort 11 and analyses using the imputed data in this study show similar results when taking account of all samples or only those with age of onset under 17 years old.…”

“…Since the association between genetic variants and the disease occurring at the 17q12-21 locus is mainly driven by individuals with early-onset asthma, 13,14 correlation analyses were performed with DNA methylation levels from different mother-child duos for the two CpGs included in the significant mQTLs at GSDMA TSS. Analyses were between unaffected mother and affected child duos, all asthma status mother and affected child duos and affected mother and affected child duos to demonstrate the possible heritability of these DNA methylation levels.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12] Even though this locus was associated with this disease without considering any specific age of onset as it was done using the Saguenay-Lac-Saint-Jean (SLSJ) asthma familial cohort before, 11 it is principally with the condition of childhood. 13,14 Several studies explored the complex interactions between SNPs, gene expressions and epigenetic modifications at this locus, primarily focusing on the levels of expressed ORMDL3 and GSDMB. 12,[15][16][17][18][19][20][21][22][23][24][25] Given that DNA methylation and gene expression signals are cell-type specific, 26,27 isolated materials such as lymphocytes from blood [17][18][19][20][21] and, to a lesser extent, bronchial epithelial cells from biopsies of bronchi or bronchoalveolar lavages 15,16 have been used in a number of studies to investigate such interactions.…”

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

“…Consistent with this notion, estimates for the heritability of asthma have ranged between 35% and 95% 3 , although those based on twin studies have been lower 4 . Genome-wide association studies (GWAS) have confirmed the contribution of genetic factors to risk of asthma, with over 140 susceptibility loci having been identified thus far [5][6][7][8][9][10][11][12][13] . However, the risk alleles, most of which are common in the population, still only explain a small fraction of the overall heritability for asthma [5][6][7] .…”