Genome-wide association studies for multiple diseases of the German Shepherd Dog

Springer Science and Business Media LLC - Tập 23 - Trang 203-211 - 2011
Kate L. Tsai1, Rooksana E. Noorai1, Alison N. Starr-Moss1, Pascale Quignon2,3, Caitlin J. Rinz1, Elaine A. Ostrander2, Jörg M. Steiner4, Keith E. Murphy1, Leigh Anne Clark1
1Department of Genetics and Biochemistry, College of Agriculture, Forestry and Life Sciences, Clemson University, Clemson, USA
2Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, USA
3Institut de Génétique et Développement de Rennes, CNRS-UMR6061, Université de Rennes 1, Rennes Cedex, France
4Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, USA

Tóm tắt

The German Shepherd Dog (GSD) is a popular working and companion breed for which over 50 hereditary diseases have been documented. Herein, SNP profiles for 197 GSDs were generated using the Affymetrix v2 canine SNP array for a genome-wide association study to identify loci associated with four diseases: pituitary dwarfism, degenerative myelopathy (DM), congenital megaesophagus (ME), and pancreatic acinar atrophy (PAA). A locus on Chr 9 is strongly associated with pituitary dwarfism and is proximal to a plausible candidate gene, LHX3. Results for DM confirm a major locus encompassing SOD1, in which an associated point mutation was previously identified, but do not suggest modifier loci. Several SNPs on Chr 12 are associated with ME and a 4.7 Mb haplotype block is present in affected dogs. Analysis of additional ME cases for a SNP within the haplotype provides further support for this association. Results for PAA indicate more complex genetic underpinnings. Several regions on multiple chromosomes reach genome-wide significance. However, no major locus is apparent and only two associated haplotype blocks, on Chrs 7 and 12 are observed. These data suggest that PAA may be governed by multiple loci with small effects, or it may be a heterogeneous disorder.

Tài liệu tham khảo

Andresen E, Willeberg P (1976) Pituitary dwarfism in German shepherd dogs: additional evidence of simple, autosomal recessive inheritance. Nord Vet Med 28:481–486 Averill DR Jr (1973) Degenerative myelopathy in the aging German shepherd dog: clinical and pathologic findings. J Am Vet Med Assoc 162:1045–1051 Awano T, Johnson GS, Wade CM, Katz ML, Johnson GC, Taylor JF, Perloski M, Biagi T, Baranowska I, Long S, March PA, Olby NJ, Shelton GD, Khan S, O’Brien DP, Lindblad-Toh K, Coates JR (2009) Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 106:2794–2799 Bach I, Rhodes SJ, Pearse RV II, Heinzel T, Gloss B, Scully KM, Sawchenko PE, Rosenfeld MG (1995) P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc Natl Acad Sci USA 92:2720–2724 Barclay KB, Haines DM (1994) Immunohistochemical evidence for immunoglobulin and complement deposition in spinal cord lesions in degenerative myelopathy in German shepherd dogs. Can J Vet Res 58:20–24 Barnes A, O’Neill T, Kennedy LJ, Short AD, Catchpole B, House A, Binns M, Fretwell N, Day MJ, Ollier WE (2009) Association of canine anal furunculosis with TNFA is secondary to linkage disequilibrium with DLA-DRB1*. Tissue Antigens 73:218–224 Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57:289–300 Bhangoo APS, Hunter CS, Savage JJ, Anhalt H, Pavlakis S, Walvoord EC, Ten S, Rhodes SJ (2006) Clinical case seminar: a novel LHX3 mutation presenting as combined pituitary hormonal deficiency. J Clin Endocr Metab 91:747–753 Clark LA, Wahl JM, Steiner JM, Zhou W, Ji W, Famula TR, Williams DA, Murphy KE (2005) Linkage analysis and gene expression profile of pancreatic acinar atrophy in the German shepherd dog. Mamm Genome 16:955–962 Coates JR, March PA, Oglesbee M, Ruaux CG, Olby NJ, Berghaus RD, O’Brien DP, Keating JH, Johnson GS, Williams DA (2007) Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs. J Vet Intern Med 21:1323–1331 Colvin SC, Malik RE, Showalter AD, Sloop KW, Rhodes SJ (2011) Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo. Proc Natl Acad Sci USA 108:173–178 Cox VS, Wallace LJ, Anderson VE, Rushmer RA (1980) Hereditary esophageal dysfunction in the miniature Schnauzer dog. Am J Vet Res 41:326–330 Drögemüller C, Becker D, Brunner A, Haase B, Kircher P, Seeliger F, Fehr M, Baumann U, Lindblad-Toh K, Leeb T (2009) A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta. PLoS Genet 5:e1000579 Gill JL, Tsai KL, Krey C, Noorai RE, Vanbellinghen JF, Garosi LS, Shelton GD, Clark LA, Harvey RJ (2011) A canine BCAN microdeletion associated with episodic falling syndrome. Neurobiol Dis. doi:10.1016/j.nbd.2011.07.014 Goldbecker WM, Hart EH (1967) This is the German shepherd. T.F.H Publications Inc., Jersey City Greer KA, Wong AK, Liu H, Famula TR, Pedersen NC, Ruhe A, Wallace M, Neff MW (2010) Necrotizing meningoencephalitis of Pug dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis. Tissue Antigens 76:110–118 Guilford WG (1990) Megaesophagus in the dog and cat. Semin Vet Med Surg (Small Anim) 5:37–45 Hall EJ, Bond PM, McLean C, Batt RM, McLean L (1991) A survey of the diagnosis and treatment of canine exocrine pancreatic insufficiency. J Small Anim Pract 32:613–619 Hanson JM, Mol JA, Leegwater PA, Kooistra HS, Meji BP (2006) The leukemia inhibitory factor receptor gene is not involved in the etiology of pituitary dwarfism in German shepherd dogs. Res Vet Sci 81:316–320 Hong H, Su Z, Ge W, Shi L, Perkins R, Fang H, Xu J, Chen JJ, Han T, Kaput J, Fuscoe JC, Tong W (2008) Assessing batch effects of genotype calling algorithm BRLMM for the Affymetrix GeneChip human mapping 500 K array set using 270 HapMap samples. BMC Bioinformatics 9:S17 Hughes AM, Jokinen P, Bannasch DL, Lohi H, Oberbauer AM (2010) Association of a dog leukocyte antigen class II haplotype with hypoadrenocorticism in Nova Scotia duck tolling retrievers. Tissue Antigens 75:684–690 Johnston PE, Barrie JA, McCulloch MC, Anderson TJ, Griffiths IR (2000) Central nervous system pathology in 25 dogs with chronic degenerative radiculomyelopathy. Vet Rec 146:629–633 Karlsson EK, Baranowska I, Wade CM, Salmon Hillbertz NH, Zody MC, Anderson N, Biagi TM, Patterson N, Pielberg GR, Kulbokas EJ 3rd, Comstock KE, Keller ET, Mesirov JP, von Euler H, Kämpe O, Hedhammar A, Lander ES, Andersson G, Andersson L, Lindblad-Toh K (2007) Efficient mapping of Mendelian traits in dogs through genome-wide association. Nat Genet 39:1321–1328 Kennedy LJ, Davison LJ, Barnes A, Short AD, Fretwell N, Jones CA, Lee AC, Ollier WE, Catchpole B (2006) Identification of susceptibility and protective major histocompatibility complex haplotypes in canine diabetes mellitus. Tissue Antigens 68:467–476 Kooistra HS, Voorhout G, Mol JA, Rijnberk A (2000) Combined pituitary hormone deficiency in German shepherd dogs with dwarfism. Domest Anim Endocrin 19:177–190 Lane PW, Dickie MM (1968) Three recessive mutations producing disproportionate dwarfing in mice: achondroplasia, brachymorphic, and stubby. J Hered 59:300–308 Lantinga-van Leeuwen IS, Kooistra HS, Mol JA, Renier C, Breen M, van Oost BA (2000a) Cloning, characterization, and physical mapping of the canine Prop-1 gene (PROP1): exclusion as a candidate gene for combined pituitary hormone deficiency in German shepherd dogs. Cytogenet Cell Genet 88:140–144 Lantinga-van Leeuwen IS, Mol JA, Kooistra HS, Rijnberk A, Breen M, Renier C, van Oost BA (2000b) Cloning of the canine gene encoding transcription factor Pit-1 and its exclusion as a candidate gene in a canine model of pituitary dwarfism. Mamm Genome 11:31–36 Moeller EM, Steiner JM, Clark LA, Murphy KE, Famula TR, Williams DA, Stankovics ME, Vose AS (2002) Inheritance of pancreatic acinar atrophy in German shepherd dogs. Am J Vet Res 63(10):1429–1434 Moody JA, Clark LA, Murphy KE (2006) Working dogs: history and applications. In: Ostrander EA, Giger U, Lindblad-Toh K (eds) The dog and its genome. Cold Spring Harbor Laboratory Press, Woodbury, pp 1–18 Netchine I, Sobrier ML, Krude H, Schnabel D, Maghnie M, Marcos E, Duriez B, Cacheux V, Moers A, Goossens M, Grüters A, Amselem S (2000) Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 25:182–186 Osborne CA, Clifford DH, Jessen C (1967) Hereditary esophageal achalasia in dogs. J Am Vet Med Assoc 151:572–581 Pfaeffle RW, Savage JJ, Hunter CS, Palme C, Ahlmann M, Kumar P, Bellone J, Schoenau E, Korsch E, Brämswig JH, Stobbe HM, Blum WF, Rhodes SJ (2007) Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. J Clin Endocrinol Metab 92:1909–1919 Pfister K, Rossi GL, Freudiger U, Bigler B (1980) Morphological studies in dogs with chronic pancreatic insufficiency. Virchows Arch A 386:91–105 Proschowsky HF, Fredholm M (2007) Exocrine pancreatic insufficiency in the Eurasian dog breed–inheritance and exclusion of two candidate genes. Anim Genet 38:171–173 Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575 Räihä M, Westermarck E (1989) The signs of pancreatic degenerative atrophy in dogs and the role of external factors in the ethiology of the disease. Acta Vet Scand 30:447–452 Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H, Pearce K, Hall CM, Shaikh G, Gerrelli D, Grueters A, Krude H, Dattani MT (2008) Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 17:2150–2159 Reynaud R, Saveanu A, Barlier A, Enjalbert A, Brue T (2004) Pituitary hormone deficiencies due to transcription factor gene alterations. Growth Horm IGF Res 14:442–448 Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng H-X, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston SM, Berger R, Tanzi RE, Halperin JJ, Herzfeldt B, Van den Bergh R, Hung W-Y, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak–Vance MA, Haines J, Rouleau GA, Gusella JS, Horvitz HR, Brown RH Jr (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62 Schmutz SM, Berryere TG (2007) The genetics of cream coat color in dogs. J Hered 98:544–548 Sheng HZ, Zhadanov AB, Mosinger B Jr, Fujii T, Bertuzzi S, Grinberg A, Lee EJ, Huang SP, Mahon KA, Westphal H (1996) Specification of pituitary cell lineages by the LIM homeobox gene LHX3. Science 272:1004–1007 Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao K, Zhu L, Padhukasahasram B, Karlins E, Davis S, Jones PG, Quignon P, Johnson GS, Parker HG, Fretwell N, Mosher DS, Lawler DF, Satyaraj E, Nordborg M, Lark KG, Wayne RK, Ostrander EA (2007) A single IGF1 allele is a major determinant of small size in dogs. Science 316:112–115 van Oost BA, Versteeg SA, Imholz S, Kooistra HS (2002) Exclusion of the lim homeodomain gene LHX4 as a candidate gene for pituitary dwarfism in German shepherd dogs. Mol Cell Endocrinol 197:57–62 Voorbij AM, Leegwater PA, Kooistra HS (2010) Hypopituitarism associated dwarfism in German shepherds, saarloos wolf dogs and Czechoslovakian wolf dogs. Access to genetic testing. Tijdschr Diergeneeskd 135:950–954 Wahl JM, Clark LA, Skalli O, Ambrus A, Rees CA, Mansell JL, Murphy KE (2008) Analysis of gene transcript profiling and immunobiology in Shetland sheepdogs with dermatomyositis. Vet Dermatol 19:52–58 Westermarck E (1980) The hereditary nature of canine pancreatic degenerative atrophy in the German shepherd dog. Acta Vet Scand 21:389–394 Westermarck E, Batt RM, Valliant C, Wiberg M (1993) Sequential study of pancreatic structure and function during development of pancreatic acinar atrophy in a German shepherd dog. Am J Vet Res 54:1088–1094 Westermarck E, Saari SA, Wiberg ME (2010) Heritability of exocrine pancreatic insufficiency in German shepherd dogs. J Vet Intern Med 24:450–452 Wiberg ME (2004) Pancreatic acinar atrophy in German shepherd dogs and rough-coated collies. Etiopathogenesis, diagnosis and treatment. A review Vet Q 26:61–75 Wiberg ME, Westermarck E (2002) Subclinical exocrine pancreatic insufficiency in dogs. J Am Vet Med Assoc 220:1183–1187 Wiberg ME, Saari SA, Westermarck E (1999) Exocrine pancreatic atrophy in German shepherd dogs and rough coated collies: an end result of lymphocytic pancreatitis. Vet Pathol 36:530–541 Wilbe M, Jokinen P, Hermanrud C, Kennedy LJ, Strandberg E, Hansson-Hamlin H, Lohi H, Andersson G (2009) MHC class II polymorphism is associated with a canine SLE-related disease complex. Immunogenetics 61:557–564 Wilbe M, Jokinen P, Truvé K, Seppala EH, Karlsson EK, Biagi T, Hughes A, Bannasch D, Andersson G, Hansson-Hamlin H, Lohi H, Lindblad-Toh K (2010) Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Nat Genet 42:250–254 Williams DA, Batt RM (1988) Sensitivity and specificity of radioimmunoassay of serum trypsin-like immunoreactivity for the diagnosis of canine exocrine pancreatic insufficiency. J Am Vet Med Assoc 192:195–201