Polygenic risk and the development and course of asthma: an analysis of data from a four-decade longitudinal study

Abstract

Background: Genome-wide association studies (GWAS) have discovered genetic variants that predispose individuals to asthma. To integrate these new discoveries with emerging models of asthma pathobiology, we aimed to test how genetic discoveries relate to developmental and biological characteristics of asthma.

Methods: In this prospective longitudinal study, we investigated a multilocus profile of genetic risk derived from published GWAS of asthma case status. We then tested associations between this genetic risk score and developmental and biological characteristics of asthma in participants enrolled in a population-based long-running birth cohort, the Dunedin Multidisciplinary Health and Development Study (n=1037). We used data on asthma onset, asthma persistence, atopy, airway hyper-responsiveness, incompletely reversible airflow obstruction, and asthma-related school and work absenteeism and hospital admissions obtained during nine prospective assessments spanning the ages of 9 to 38 years. Analyses included cohort members of European descent from whom genetic data had been obtained.

Findings: Of the 880 cohort members included in our analysis, those at higher genetic risk developed asthma earlier in life than did those with lower genetic risk (hazard ratio [HR] 1·12, 95% CI 1·01-1·26). Of cohort members with childhood-onset asthma, those with higher genetic risk were more likely to develop life-course-persistent asthma than were those with a lower genetic risk (relative risk [RR] 1·36, 95% CI 1·14-1·63). Participants with asthma at higher genetic risk more often had atopy (RR 1·07, 1·01-1·14), airway hyper-responsiveness (RR 1·16, 1·03-1·32), and incompletely reversible airflow obstruction (RR 1·28, 1·04-1·57) than did those with a lower genetic risk. They were also more likely to miss school or work (incident rate ratio 1·38, 1·02-1·86) and be admitted to hospital (HR 1·38, 1·07-1·79) because of asthma. Genotypic information about asthma risk was independent of and additive to information derived from cohort members' family histories of asthma.

Interpretation: Our findings confirm that GWAS discoveries for asthma are associated with a childhood-onset phenotype. Genetic risk assessments might be able to predict which childhood-onset asthma cases remit and which become life-course-persistent, who might develop impaired lung function, and the burden of asthma in terms of missed school and work and hospital admissions, although these predictions are not sufficiently sensitive or specific to support immediate clinical translation.

Funding: US National Institute on Aging and UK Medical Research Council.

Figure 1. Cohort members at higher genetic risk were more likely to develop asthma ever and did so earlier in life

Children at higher genetic risk were more likely to develop asthma through age 38 years and did so earlier in life (Hazard Ratio (HR)=1.12 [1.01–1.26]). Hazards were estimated using a Cox regression model testing association between the continuous genetic risk score and timing of asthma onset. The Cox model was adjusted for sex. Panel A plots Kaplan-Meier Survival Curves for asthma onset among girls and boys in the Dunedin cohort. Panels B and C plot the same data separately for girls and boys with genetic risk scores below the cohort mean (low genetic risk) and cohort members with genetic risk scores above the cohort mean (high genetic risk). Risk tables provide number at risk at birth and ages 7, 15, 21, 26, 32, and 38 years.

Figure 2. Cohort members at higher genetic risk were more likely to develop life-course-persistent asthma

Panel A graphs the genetic association with risk of developing life-course-persistent asthma in the full cohort (N=880; RR=1.36 [1.14–1.63]). Panel B graphs the genetic association with life-course-persistent asthma among the subset of cohort members who onset with asthma by age 13 years (n=187; RR=1.20 [1.05–1.38]). Error bars reflect 95% confidence intervals for point estimates. The genetic risk score is the count of risk alleles standardized to have mean=0 and standard deviation=1.

Figure 3. Asthma cases at higher genetic risk were more likely to manifest atopy, airway hyperresponsiveness, and incompletely reversible airflow obstruction

Panel A illustrates overlap among different biological chracteristics of asthma. Across 3 decades of follow-up (between ages 9 and 38 years), n=236 asthma cases manifested atopy during follow-up; n=160 manifested airway hyperresponsiveness; and n=76 manifested incompletely reversible airflow obstruction. Panel B graphs mean genetic risk within subgroups of asthma cases defined by atopic status, airway hyperresponsiveness, and incompletely reversible airflow obstruction. Asthma cases with no atopy who manifested airway hyperresponsiveness or incompletely reversible airflow obstruction are grouped together due to the small number of cases in each cell. Error bars reflect standard errors for subgroup means. The genetic risk score is the count of risk alleles standardized to have mean=0 and standard deviation=1.

Figure 3. Asthma cases at higher genetic risk were more likely to manifest atopy, airway hyperresponsiveness, and incompletely reversible airflow obstruction

Panel A illustrates overlap among different biological chracteristics of asthma. Across 3 decades of follow-up (between ages 9 and 38 years), n=236 asthma cases manifested atopy during follow-up; n=160 manifested airway hyperresponsiveness; and n=76 manifested incompletely reversible airflow obstruction. Panel B graphs mean genetic risk within subgroups of asthma cases defined by atopic status, airway hyperresponsiveness, and incompletely reversible airflow obstruction. Asthma cases with no atopy who manifested airway hyperresponsiveness or incompletely reversible airflow obstruction are grouped together due to the small number of cases in each cell. Error bars reflect standard errors for subgroup means. The genetic risk score is the count of risk alleles standardized to have mean=0 and standard deviation=1.