Genome-wide association identifies multiple genomic regions associated with susceptibility to and control of ovine lentivirus

Abstract

Background: Like human immunodeficiency virus (HIV), ovine lentivirus (OvLV) is macrophage-tropic and causes lifelong infection. OvLV infects one quarter of U.S. sheep and induces pneumonia and body condition wasting. There is no vaccine to prevent OvLV infection and no cost-effective treatment for infected animals. However, breed differences in prevalence and proviral concentration have indicated a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 variants in OvLV susceptibility. The objective here was to identify additional loci associated with odds and/or control of OvLV infection.

Methodology/principal findings: This genome-wide association study (GWAS) included 964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes. Analytic models accounted for breed and age, as well as genotype. This approach identified TMEM154 (nominal P=9.2×10(-7); empirical P=0.13), provided 12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P<1 × 10(-5)). Rapid decline of linkage disequilibrium with distance suggested many regions included few genes each. Genes in regions associated with odds of infection included DPPA2/DPPA4 (empirical P=0.006), and SYTL3 (P=0.051). Genes in regions associated with control of infection included a zinc finger cluster (ZNF192, ZSCAN16, ZNF389, and ZNF165; P=0.001), C19orf42/TMEM38A (P=0.047), and DLGAP1 (P=0.092).

Conclusions/significance: These associations provide targets for mutation discovery in sheep susceptibility to OvLV. Aside from TMEM154, these genes have not been associated previously with lentiviral infection in any species, to our knowledge. Further, data from other species suggest functional hypotheses for future testing of these genes in OvLV and other lentiviral infections. Specifically, SYTL3 binds and may regulate RAB27A, which is required for enveloped virus assembly of human cytomegalovirus. Zinc finger transcription factors have been associated with positive selection for repression of retroviral replication. DLGAP1 binds and may regulate DLG1, a known regulator of HIV infectivity.

Figure 1. Manhattan plot for susceptibility to OvLV.

The Manhattan plot shows nominal P-values from association with serological status by chromosomal position. Representative data from the all-breeds, additive mode of inheritance analysis are shown. The top red line shows a genome-wide significance threshold defined by nominal P-values of 1x10^-6, which is P = 0.05/50,000. The lower blue line shows a genome-wide suggestive significance threshold defined by 1x10^-5.

Figure 2. Manhattan plot for control of OvLV infection.

The Manhattan plot shows nominal P-values from association with proviral concentration by chromosomal position. Representative data from the Rambouillet, dominant mode of inheritance analysis are shown. The top red line shows a genome-wide significance threshold defined by nominal P-values of 1x10^-6, which is P = 0.05/50,000. The lower blue line shows a genome-wide suggestive significance threshold defined by nominal P-values of 1x10^-5.