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Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

ABSTRACT: Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

SUBMITTER: Ferreira MAR

PROVIDER: S-EPMC7367489 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Ferreira Manuel A R MAR Vonk Judith M JM Baurecht Hansjörg H Marenholz Ingo I Tian Chao C Hoffman Joshua D JD Helmer Quinta Q Tillander Annika A Ullemar Vilhelmina V Lu Yi Y Grosche Sarah S Rüschendorf Franz F Granell Raquel R Brumpton Ben M BM Fritsche Lars G LG Bhatta Laxmi L Gabrielsen Maiken E ME Nielsen Jonas B JB Zhou Wei W Hveem Kristian K Langhammer Arnulf A Holmen Oddgeir L OL Løset Mari M Abecasis Gonçalo R GR Willer Cristen J CJ Emami Nima C NC Cavazos Taylor B TB Witte John S JS Szwajda Agnieszka A Hinds David A DA Hübner Norbert N Weidinger Stephan S Magnusson Patrik Ke PK Jorgenson Eric E Karlsson Robert R Paternoster Lavinia L Boomsma Dorret I DI Almqvist Catarina C Lee Young-Ae YA Koppelman Gerard H GH

PLoS genetics 20200630 6

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earli ...[more]

PMID: 32603359

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Project description:Background & aimsEarly-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.MethodsWe studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.ResultsOverall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.ConclusionsIn an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

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Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Publications

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

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