The Journal of allergy and clinical immunology | 2021
Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors.
Abstract
BACKGROUND\nWhile numerous genetic loci associated atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited.\n\n\nOBJECTIVE\nThis study aims to determine if polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. We also explicitly test the value of including genome wide association studies (GWASs) of related allergic phenotypes and known filaggrin (FLG) loss-of-function (LOF) variants.\n\n\nMETHODS\nAD PRSs were constructed for 1,619 European American (EA) individuals from the Atopic Dermatitis Research Network (ADRN) using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations.\n\n\nRESULTS\nGenetic scores derived from the AD-only GWAS were predictive of AD cases (PRSAD: OR [95% CI] = 1.70 [1.49, 1.93]). Accuracy was first improved when PRSs were built off the larger atopy GWAS (PRSAD+: OR = 2.16 [1.89, 2.47]) and further improved when including FLG LOF mutations (PRSAD++: OR = 3.23 [2.57, 4.07]). Importantly, while all three PRSs correlated with AD severity, the best prediction was from PRSAD++ which distinguished individuals with severe AD from controls with OR = 3.86 [2.77, 5.36].\n\n\nCONCLUSION\nWe demonstrate how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high-risk for developing disease and specifically severe disease.\n\n\nCLINICAL IMPLICATION\nA genetic risk model combining AD and atopy related genetic variants with FLG loss-of-function indicators could identify high-risk neonates for targeted therapies to prevent the onset (or severity) of AD.