Dataset Information

Deviations from hardy-weinberg equilibrium in parental and unaffected sibling genotype data.

ABSTRACT:

Background

Genotyping error can increase both type I and II errors. In order to elucidate potential genotyping errors, data quality control often includes testing genotype data for deviations from Hardy-Weinberg Equilibrium (HWE).

Methods

The Hardy-Weinberg Disequilibrium (HWD) coefficient and the ability to reject the null hypothesis of HWE were calculated analytically for genotype data from parents and unaffected siblings of affected probands.

Results

Genotype data from parents and unaffected siblings display deviations from HWE when functional or markers in LD with functional locus are tested. For the parental genotype data all deviations from HWE are negative, indicating an excess of heterozygous genotypes with the strongest deviations from HWE observed for the multiplicative model. In contrast, for affected proband genotype data, there is no deviation from HWE under the multiplicative model and the deviations from HWE for the recessive model are positive. For the unaffected sibling data, patterns of deviation from HWE are similar to those observed in the proband data with the exception of the multiplicative model where the HWD coefficient although close to 0 can be either positive or negative depending on the allele frequency.

Conclusion

Deviations from HWE in parental and unaffected sibling genotype data could be due to an association with the functional locus. However these deviations for genotypic relative risk < or =2.0 are not large and therefore the power to detect them is usually low. Testing for deviations from HWE in parental and unaffected sibling genotype data is still beneficial for quality control even though functional loci, in parental and unaffected sibling genotype data, can produce an association signal.

SUBMITTER: Li B

PROVIDER: S-EPMC2798818 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Departure from Hardy Weinberg Equilibrium (HWE) may occur due to a variety of causes, including purifying selection, inbreeding, population substructure, copy number variation or genotyping error. We searched for specific characteristics of HWE-departure due to genotyping error. Methods: Genotypes of a random set of genetic variants were obtained from the Exome Aggregation Consortium (ExAC) database. Variants with <80% successful genotypes or with minor allele frequency (MAF) <1% were excluded. HWE-departure (d-HWE) was considered significant at p < 10E-05 and classified as d-HWE with loss of heterozygosity (LoH d-HWE) or d-HWE with excess heterozygosity (gain of heterozygosity: GoH d-HWE). Missing genotypes, variant type (single nucleotide polymorphism (SNP) vs. insertion/deletion); MAF, standard deviation (SD) of MAF across populations (MAF-SD) and copy number variation were evaluated for association with HWE-departure. Results: The study sample comprised 3,204 genotype distributions. HWE-departure was observed in 134 variants: LoH d-HWE in 41 (1.3%), GoH d-HWE in 93 (2.9%) variants. LoH d-HWE was more likely in variants located within deletion polymorphisms (p < 0.001) and in variants with higher MAF-SD (p = 0.0077). GoH d-HWE was associated with low genotyping rate, with variants of insertion/deletion type and with high MAF (all at p < 0.001). In a sub-sample of 2,196 variants with genotyping rate >98%, LoH d-HWE was found in 29 (1.3%) variants, but no GoH d-HWE was detected. The findings of the non-random distribution of HWE-violating SNPs along the chromosome, the association with common deletion polymorphisms and indel-variant type, and the finding of excess heterozygotes in genomic regions that are prone to cross-hybridization were confirmed in a large sample of short variants from the 1,000 Genomes Project. Conclusions: We differentiated between two types of HWE-departure. GoH d-HWE was suggestive for genotyping error. LoH d-HWE, on the contrary, pointed to natural variabilities such as population substructure or common deletion polymorphisms.