PT  - JOURNAL ARTICLE
AU  - Konrad J. Karczewski
AU  - Laura D. Gauthier
AU  - Mark J. Daly
TI  - Technical artifact drives apparent deviation from Hardy-Weinberg equilibrium at CCR5-∆32 and other variants in gnomAD
AID  - 10.1101/784157
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 784157
4099  - http://biorxiv.org/content/early/2019/10/02/784157.short
4100  - http://biorxiv.org/content/early/2019/10/02/784157.full
AB  - Following an earlier report suggesting increased mortality due to homozygosity at the CCR5-∆32 allele1, Wei and Nielsen recently suggested a deviation from Hardy-Weinberg Equilibrium (HWE) observed in public variant databases as additional supporting evidence for this hypothesis2. Here, we present a re-analysis of the primary data underlying this variant database and identify a pervasive genotyping artifact, especially present at long insertion and deletion polymorphisms. Specifically, very low levels of contamination can affect the variant calling likelihood models, leading to the misidentification of homozygous individuals as heterozygous, and thereby creating an apparent depletion of homozygous calls, which is especially prominent at large insertions and deletions. The deviation from HWE observed at CCR5-∆32 is a consequence of this specific genotyping error mode rather than a signature of selective pressure at this locus.