title: Haplotype misclassification resulting from statistical reconstruction and genotype error, and its impact on association estimates.
abstract: Haplotypes are an important concept for genetic association studies, but involve uncertainty due to statistical reconstruction from single nucleotide polymorphism (SNP) genotypes and genotype error. We developed a re-sampling approach to quantify haplotype misclassification probabilities and implemented the MC-SIMEX approach to tackle this as a 3 x 3 misclassification problem. Using a previously published approach as a benchmark for comparison, we evaluated the performance of our approach by simulations and exemplified it on real data from 15 SNPs of the APM1 gene. Misclassification due to reconstruction error was small for most, but notable for some, especially rarer haplotypes. Genotype error added misclassification to all haplotypes resulting in a non-negligible drop in sensitivity. In our real data example, the bias of association estimates due to reconstruction error alone reached -48.2% for a 1% genotype error, indicating that haplotype misclassification should not be ignored if high genotype error can be expected. Our 3 x 3 misclassification view of haplotype error adds a novel perspective to currently used methods based on genotype intensities and expected number of haplotype copies. Our findings give a sense of the impact of haplotype error under realistic scenarios and underscore the importance of high-quality genotyping, in which case the bias in haplotype association estimates is negligible.
authors.affiliation: Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lamina
authors.forename: Helmut
authors.initials: H
authors.lastname: Küchenhoff
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Bernhard
authors.initials: B
authors.lastname: Paulweber
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Margret R
authors.initials: MR
authors.lastname: Hoehe
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.forename: Iris M
authors.initials: IM
authors.lastname: Heid
mesh_terms: D052242:Adiponectin / Q000235:genetics; D015992:Body Mass Index; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D012680:Sensitivity and Specificity
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin