Genome-wide association study of susceptibility to infection by Mycobacterium avium subspecies paratuberculosis in Holstein cattle.

Fazli Alpay,Xianwei Shi,Mamat H Kamalludin,Xixia Huang,Yalda Zare,Brian W Kirkpatrick,Michael T Collins,George E Shook

doi:10.1371/journal.pone.0111704

Abstract

Paratuberculosis, or Johne's disease, is a chronic, granulomatous, gastrointestinal tract disease of cattle and other ruminants caused by the bacterium Mycobacterium avium, subspecies paratuberculosis (MAP). Control of Johne's disease is based on programs of testing and culling animals positive for infection with MAP while concurrently modifying management to reduce the likelihood of infection. The current study is motivated by the hypothesis that genetic variation in host susceptibility to MAP infection can be dissected and quantifiable associations with genetic markers identified. For this purpose, a case-control, genome-wide association study was conducted using US Holstein cattle phenotyped for MAP infection using a serum ELISA and/or fecal culture test. Cases included cows positive for either serum ELISA, fecal culture or both. Controls consisted of animals negative for the serum ELISA test or both serum ELISA and fecal culture when both were available. Controls were matched by herd and proximal birth date with cases. A total of 856 cows (451 cases and 405 controls) were used in initial discovery analyses, and an additional 263 cows (159 cases and 104 controls) from the same herds were used as a validation data set. Data were analyzed in a single marker analysis controlling for relatedness of individuals (GRAMMAR-GC) and also in a Bayesian analysis in which multiple marker effects were estimated simultaneously (GenSel). For the latter, effects of non-overlapping 1 Mb marker windows across the genome were estimated. Results from the two discovery analyses were generally concordant; however, discovery results were generally not well supported in analysis of the validation data set. A combined analysis of discovery and validation data sets provided strongest support for SNPs and 1 Mb windows on chromosomes 1, 2, 6, 7, 17 and 29.

Highlights

Paratuberculosis, or Johne’s disease, is a chronic, granulomatous, gastrointestinal tract disease of cattle and other ruminants caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP)
Calves less than 6 months of age are generally considered to be at the greatest risk of becoming infected with MAP [2], but clinical signs of infection usually do not appear until second or third lactation [3]
Control programs for paratuberculosis have been established in some nations including Australia [4], Norway [5], Iceland [6], Japan [7], the Netherlands [8] and the United States [9]

Summary

Introduction

Paratuberculosis, or Johne’s disease, is a chronic, granulomatous, gastrointestinal tract disease of cattle and other ruminants caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP). The clinical signs of disease in cattle are pipestream diarrhea, weight loss, edema due to hypoproteinemia caused by protein-losing enteropathy [1]. Even if not showing clinical signs of disease, MAP test-positive cows produce less milk and are culled earlier in their productive life [2]. The disease occurs worldwide in dairy cattle and other ruminants. The reported herd-based prevalence of MAP infection varies between European countries and is greater than 60% in some regions according to a recent review [10]. Recent estimates suggest that 68% of US dairy herds [11] and 7.9% of US beef herds have infected animals [12]. The economic impact of paratuberculosis on the US dairy industry has been estimated to be from US $200 million to $1.5 billion annually [14, 15]. An additional concern is the potential zoonotic role of MAP in Crohn’s disease in humans, which at the current time remains uncertain [16]

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Methods

Results