Heterozygosity mapping for human dominant trait variants

Abstract

Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. We confirm existence of this phenomenon in sequence data with known dominant pathogenic variants obtained on family members and in unrelated population controls. A computer-based approach to estimating empirical significance levels associated with our test statistics shows genome-wide p-values smaller than 0.05 for many but not all of the individuals carrying a pathogenic variant.

Keywords: ALSPAC; computer simulation; gene mapping; genetic association analysis; sequence variants.

Figure 1

Stage 1 heterozygosity rate, H (y‐axis), plotted against marker positions (x‐axis) surrounding a pathogenic BRCA2 mutation in three females affected with breast cancer in family S. The x‐axis scale is the distance in kb from the pathogenic BRCA2 mutation

Figure 2

Stage 1 heterozygosity rate, H (y‐axis), plotted against marker positions (x‐axis) surrounding a pathogenic BRCA2 mutation in a control individual, that is, the first individual in our unpublished collection of family members affected with psoriasis. The x‐axis scale is the distance in kb from the pathogenic BRCA2 mutation

Figure 3

Receiver operating characteristic curve based on results of Table 3. The graph shows y = sensitivity plotted against x = 1 − specificity. The area under the curve is AUC =0.85