On confidence intervals for genotype relative risks and attributable risks from case parent trio designs for candidate-gene studies.

Scherag et al. [Hum Hered 2002;54:210-217] recently proposed point estimates and asymptotic as well as exact confidence intervals for genotype relative risks (GRRs) and the attributable risk (AR) in case parent trio designs using single nucleotide polymorphism (SNP) data. The aim of this study was the investigation of coverage probabilities and bias in estimates if the marker locus is not identical to the disease locus. Using a variety of parameter constellations, including marker allele frequencies identical to and different from the SNP at the disease locus, we performed an analytical study to quantify the bias and a Monte-Carlo simulation study for quantifying both bias and coverage probabilities. No bias was observed if marker and trait locus coincided. Two parameters had a strong impact on coverage probabilities of confidence intervals and bias in point estimates if they did not coincide: the linkage disequilibrium (LD) parameter delta and the allele frequency at the marker SNP. If marker allele frequencies were different from the allele frequencies at the functional SNP, substantial biases occurred. Further, if delta between the marker and the disease locus was lower than the maximum possible delta, estimates were also biased. In general, biases were towards the null hypothesis for both GRRs and AR. If one GRR was not increased, as e.g. in a recessive genetic model, biases away from the null could be observed. If both GRRs were in identical directions and if both were substantially larger than 1, the bias always was towards the null. When applying point estimates and confidence intervals for GRRs and AR in candidate gene studies, great care is needed. Effect estimates are substantially biased towards the null if either the allele frequencies at the marker SNP and the true disease locus are different or if the LD between the marker SNP and the disease locus is not at its maximum. A bias away from the null occurs only in uncommon study situations; it is small and can therefore be ignored for applications.