title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US National Institute on Aging and UK Medical Research Council.
authors.affiliation: Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA; Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA. Electronic address: dbelsky@duke.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Belsky
authors.affiliation: Division of Respirology, Department of Medicine, DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Sears
authors.affiliation: Department of Preventive and Social Medicine, School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hancox
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA; Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
authors.forename: Honalee
authors.initials: H
authors.lastname: Harrington
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA; Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
authors.forename: Renate
authors.initials: R
authors.lastname: Houts
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA; Department of Psychology and Neuroscience, Duke University, Durham, NC, USA; Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Moffitt
authors.affiliation: Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA; Department of Psychology and Neuroscience, Duke University, Durham, NC, USA; Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Sugden
authors.affiliation: Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA; Department of Psychology and Neuroscience, Duke University, Durham, NC, USA; Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Williams
authors.affiliation: Department of Preventive and Social Medicine, School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Richie
authors.initials: R
authors.lastname: Poulton
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA; Department of Psychology and Neuroscience, Duke University, Durham, NC, USA; Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: Avshalom
authors.initials: A
authors.lastname: Caspi
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000235:genetics*; D002648:Child; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D055815:Young Adult