Characterization of a 320-kb region containing the HEXA gene on bovine chromosome 10 and analysis of its association with BSE susceptibility.
Bovine spongiform encephalopathy (BSE) belongs to a group of neurodegenerative diseases known as transmissible prion diseases. Recently, variants in the promoter region of the prion protein (PRNP) gene have been shown to have a considerable effect on the susceptibility to BSE. However, a previous genome scan revealed other putative BSE-susceptibility loci. Here, we analysed such a region on BTA10, which contains the functional candidate gene HEXA. Three hundred and twenty kilobases that, besides HEXA, also contain ARIH1, BRUNOL6 and PARP6 were characterized and screened for polymorphisms. Genotyping of 38 SNPs in Holstein-Friesian animals from the UK (350 diseased and 270 controls) revealed two intronic SNPs that were associated with BSE incidence, with experiment-wise P-values of 3.5 x 10(-3) and 7.7 x 10(-3) respectively. Both SNPs were in strong linkage disequilibrium and the rare alleles had a protective effect. These alleles were contained in a haplotype dubbed 'UK-protective' that was significantly overrepresented in the controls with a permuted P-value of 2 x 10(-3). An association study in German Holstein animals (73 diseased and 627 controls) revealed an opposite effect of the 'UK-protective' haplotype in this population, i.e. it was overrepresented in the diseased animals, although not significant after correction for multiple testing. These findings indicate a causal variant for BSE susceptibility on BTA10 in linkage disequilibrium with the markers studied. Candidate gene analyses of the surrounding region and additional association studies will help to clarify the origin of the protective effects and to identify causal variants for BSE susceptibility on BTA10.
Institute of Animal Breeding, Technical University of Munich, Hochfeldweg 1, 85354 Freising-Weihenstephan, Germany. katrin.juling@tierzucht.tum.de
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K
Juling
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Schwarzenbacher
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Frankenberg
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Ziegler
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Groschup
J L
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Williams
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Fries
D000818:Animals; D002417:Cattle / Q000235:genetics*; D022202:Chromosomes, Artificial, Bacterial; D033481:Chromosomes, Mammalian / Q000235:genetics; D016643:Encephalopathy, Bovine Spongiform / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015698:Genomic Library; D006239:Haplotypes; D054818:Hexosaminidase A / Q000235:genetics*; D007438:Introns; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
D054818:Hexosaminidase A