Non-additive association analysis using proxy phenotypes identifies novel cattle syndromes

Mammalian species carry similar to 100 loss-of-function variants per individual(1,2), where similar to 1-5 of these impact essential genes and cause embryonic lethality or severe disease when homozygous(3). The functions of the remainder are more difficult to resolve, although the assumption is that these variants impact fitness in less manifest ways. Here we report one of the largest sequence-resolution screens of cattle to date, targeting discovery and validation of non-additive effects in 130,725 animals. We highlight six novel recessive loci with impacts generally exceeding the largest-effect variants identified from additive genome-wide association studies, presenting analogs of human diseases and hitherto-unrecognized disorders. These loci present compelling missense (PLCD4, MTRF1 and DPF2), premature stop (MUS81) and splice-disrupting (GALNT2 and FGD4) mutations, together explaining substantial proportions of inbreeding depression. These results demonstrate that the frequency distribution of deleterious alleles segregating in selected species can afford sufficient power to directly map novel disorders, presenting selection opportunities to minimize the incidence of genetic disease.

Automated summary

The study reports the discovery of six new recessive loci in cattle, with impacts generally exceeding known largest-effect variants, playing a significant role in explaining inbreeding depression. The results demonstrate that the frequency distribution of deleterious alleles can help directly map novel disorders and provide opportunities to reduce the incidence of genetic diseases.