Probability of Detection of Genotyping Errors and Mutations as Inheritance Inconsistencies in Nuclear-Family Data

Abstract

Gene-mapping studies routinely rely on checking for Mendelian transmission of marker alleles in a pedigree, as a means of screening for genotyping errors and mutations, with the implicit assumption that, if a pedigree is consistent with Mendel's laws of inheritance, then there are no genotyping errors. However, the occurrence of inheritance inconsistencies alone is an inadequate measure of the number of genotyping errors, since the rate of occurrence depends on the number and relationships of genotyped pedigree members, the type of errors, and the distribution of marker-allele frequencies. In this article, we calculate the expected probability of detection of a genotyping error or mutation as an inheritance inconsistency in nuclear-family data, as a function of both the number of genotyped parents and offspring and the marker-allele frequency distribution. Through computer simulation, we explore the sensitivity of our analytic calculations to the underlying error model. Under a random-allele-error model, we find that detection rates are 51%-77% for multiallelic markers and 13%-75% for biallelic markers; detection rates are generally lower when the error occurs in a parent than in an offspring, unless a large number of offspring are genotyped. Errors are especially difficult to detect for biallelic markers with equally frequent alleles, even when both parents are genotyped; in this case, the maximum detection rate is 34% for four-person nuclear families. Error detection in families in which parents are not genotyped is limited, even with multiallelic markers. Given these results, we recommend that additional error checking (e.g., on the basis of multipoint analysis) be performed, beyond routine checking for Mendelian consistency. Furthermore, our results permit assessment of the plausibility of an observed number of inheritance inconsistencies for a family, allowing the detection of likely pedigree-rather than genotyping-errors in the early stages of a genome scan. Such early assessments are valuable in either the targeting of families for resampling or discontinued genotyping.

Population differences in the International Multi‐Centre ADHD Gene Project

“…The final dataset for association analysis included 674 families that contained 156 sporadic Mendelian errors from 987 autosomal markers. The overall detection rate of Mendelian errors is therefore 0.02%, which is consistent with the estimated efficiency of SNP markers [13-75%; Douglas et al, 2002] to detect such errors by identification of Mendelian errors and an estimated overall genotype error rate o0.065%. Pedigree errors may be explained by the complicated procedures inherent within a large international cooperative process.…”

The impact of data quality on the identification of complex disease genes: experience from the Family Blood Pressure Program

“…Theoretically, only 51 -77% of the error can be detected for multiallelic markers such as STR, and these rates are even lower for biallelic markers such as SNPs. 29 Most errordetecting algorithms identify only errors that lead to blatant inheritance inconsistencies. By using a multipoint method, Mendelian-consistent genotyping errors most likely to affect linkage analysis can also be detected.…”

The impact of genotyping error on haplotype reconstruction and frequency estimation

“…Methods which incorporate both familial transmission and genotype frequencies, thereby combining the benefits of error detection, segregation patterns and underlying haplotype frequencies, but which are as yet undeveloped, could favour trios and yield more efficient and accurate methods for cataloguing LD patterns. Moreover, methods for explicit detection and modelling of genotype error within the full distribution of possible haplotypes, similar to the approaches recently developed for markers in linkage equilibrium, 24,33 could significantly increase the accuracy of family designs.…”