title: Estimating heritability of drug-induced liver injury from common variants and implications for future study designs.
abstract: Recent genome-wide association studies identified certain human leukocyote antigen (HLA) alleles as the major risk factors of drug-induced liver injuries (DILI). While these alleles often cause large relative risk, their predictive values are quite low due to low prevalence of idiosyncratic DILI. Finding additional risk factors is important for precision medicine. However, optimal design of further genetic studies is hindered by uncertain overall heritability of DILI. This is a common problem for low-prevalence pharmacological traits, since it is difficult to obtain clinical outcome data in families. Here we estimated the heritability (h(2)) of DILI from case-control genome-wide single nucleotide polymorphism data using a method based on random effect models. We estimated the proportion of h(2) captured by common SNPs for DILI to be between 0.3 and 0.5. For co-amoxiclav induced DILI, chromosome 6 explained part of the heritability, indicating additional contributions from common variants yet to be found. We performed simulations to assess the robustness of the h(2) estimate with limited sample size under low prevelance, a condition typical to studies on idiosyncratic pharmacological traits. Our findings suggest that common variants outside of HLA contribute to DILI susceptability; therefore, it is valuable to conduct further GWAS with expanded case collection.
authors.affiliation: 1] Department of Biomedical Informatics, Columbia University, New York, NY [2].
authors.forename: Casey Lynnette
authors.initials: CL
authors.lastname: Overby
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, NY.
authors.forename: George
authors.initials: G
authors.lastname: Hripcsak
authors.affiliation: 1] Department of Biomedical Informatics, Columbia University, New York, NY [2] Department of Systems Biology, Columbia University, New York, NY [3] JP Sulzberger Columbia Genome Center, Columbia University, New York, NY.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000009:adverse effects / Q000627:therapeutic use; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005436:Floxacillin / Q000009:adverse effects / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D065093:beta-Lactamase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D065093:beta-Lactamase Inhibitors; D005436:Floxacillin; D019980:Amoxicillin-Potassium Clavulanate Combination