Assessing the impact of non-differential genotyping errors on rare variant tests of association

Abstract

Background/aims: We aim to quantify the effect of non-differential genotyping errors on the power of rare variant tests and identify those situations when genotyping errors are most harmful.

Methods: We simulated genotype and phenotype data for a range of sample sizes, minor allele frequencies, disease relative risks and numbers of rare variants. Genotype errors were then simulated using five different error models covering a wide range of error rates.

Results: Even at very low error rates, misclassifying a common homozygote as a heterozygote translates into a substantial loss of power, a result that is exacerbated even further as the minor allele frequency decreases. While the power loss from heterozygote to common homozygote errors tends to be smaller for a given error rate, in practice heterozygote to homozygote errors are more frequent and, thus, will have measurable impact on power.

Conclusion: Error rates from genotype-calling technology for next-generation sequencing data suggest that substantial power loss may be seen when applying current rare variant tests of association to called genotypes.

Fig. 1

An example of how the power for each of the four methods diminishes as the error level increases in error model 5 for one choice of simulation settings (high sample size, low number of SNVs, low MAF and high relative risk). Heterozygote to homozygote error rates are 10 times larger than homozygote to heterozygote error rates. The margin of error is ≤1.41% in all cases.