Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Abstract

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Fig. 1. Flowchart depicting the study design to detect homozygosity deficit in 1.52 million North-Western Europeans.

We looked for a strong deficit of homozygosity (10% or less of predicted homozygotes based on observed heterozygote frequency and the assumption of Hardy-Weinberg equilibrium within populations) among protein-altering sequence variants in a meta-analysis of 1.52 million individuals from six populations. We tested 75,178 moderate-impact and 3024 pLOF single variants for the deficit of homozygosity based on the imputation of variants detected by whole-genome sequencing of individuals from all of the populations. Additionally, a gene-based test (geneLOF) for the deficit of homozygosity was performed, where we were able to test 2757 genes for deficit of homozygosity. To estimate a false discovery rate, we divided the fraction of intergenic sequence variants with strong deficits of homozygosity by that of protein-altering sequence variants to determine a cutpoint value for expected homozygous count to detect a strong deficit of homozygosity at an FDR < 10%.

Fig. 2. False discovery rate (FDR) for a strong deficit of homozygosity relative to intergenic variants in the combined set of 1.52 million individuals of North-Western European descent (Denmark, Finland, Iceland, Norway, Sweden, and the UK).

After binning variants based on the expected number of homozygotes and functional impact, the fraction of protein-altering variants with a strong deficit of homozygosity (f_pav) in each bin was compared to that of intergenic variants (f_intergenic) to estimate an FDR (FDR = f_intergenic/f_pav). One minus the FDR estimates the fraction of homozygous deficit variants within each bin due to negative selection (1 - FDR = positive predictive power (PPV) = 1 - f_intergenic/f_pav). FDR confidence intervals were calculated using the AECI method.