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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.

Genome-Wide Association Identifies Multiple Genomic Regions Associated with Susceptibility to and Control of Ovine Lentivirus