A 2cM genome-wide scan of European Holstein cattle affected by classical BSE.
BACKGROUND
Classical bovine spongiform encephalopathy (BSE) is an acquired prion disease that is invariably fatal in cattle and has been implicated as a significant human health risk. Polymorphisms that alter the prion protein of sheep or humans have been associated with variations in transmissible spongiform encephalopathy susceptibility or resistance. In contrast, there is no strong evidence that non-synonymous mutations in the bovine prion gene (PRNP) are associated with classical BSE disease susceptibility. However, two bovine PRNP insertion/deletion polymorphisms, one within the promoter region and the other in intron 1, have been associated with susceptibility to classical BSE. These associations do not explain the full extent of BSE susceptibility, and loci outside of PRNP appear to be associated with disease incidence in some cattle populations. To test for associations with BSE susceptibility, we conducted a genome wide scan using a panel of 3,072 single nucleotide polymorphism (SNP) markers on 814 animals representing cases and control Holstein cattle from the United Kingdom BSE epidemic.


RESULTS
Two sets of BSE affected Holstein cattle were analyzed in this study, one set with known family relationships and the second set of paired cases with controls. The family set comprises half-sibling progeny from six sires. The progeny from four of these sires had previously been scanned with microsatellite markers. The results obtained from the current analysis of the family set yielded both some supporting and new results compared with those obtained in the earlier study. The results revealed 27 SNPs representing 18 chromosomes associated with incidence of BSE disease. These results confirm a region previously reported on chromosome 20, and identify additional regions on chromosomes 2, 14, 16, 21 and 28. This study did not identify a significant association near the PRNP in the family sample set. The only association found in the PRNP region was in the case-control sample set and this was not significant after multiple test correction. The genome scan of the case-control animals did not identify any associations that passed a stringent genome-wide significance threshold.


CONCLUSIONS
Several regions of the genome are statistically associated with the incidence of classical BSE in European Holstein cattle. Further investigation of loci on chromosomes 2, 14, 16, 20, 21 and 28 will be required to uncover any biological significance underlying these marker associations.
Murdoch
Brenda M
BM
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada.
Clawson
Michael L
ML
Laegreid
William W
WW
Stothard
Paul
P
Settles
Matthew
M
McKay
Stephanie
S
Prasad
Aparna
A
Wang
Zhiquan
Z
Moore
Stephen S
SS
Williams
John L
JL
D000818:Animals; D016022:Case-Control Studies; D002417:Cattle / Q000235:genetics*; D016643:Encephalopathy, Bovine Spongiform / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000662:veterinary*; D005838:Genotype; D054643:INDEL Mutation; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D006113:United Kingdom / Q000453:epidemiology
D005819:Genetic Markers