Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene

BMC Genomics

Hannes Lohi²  Anita M. Oberbauer³  Tarja S. Jokinen¹  Ranno Viitmaa¹  Elisa M. Nevalainen²  Päivi Jokinen²  Osmo Hakosalo²  Meharji Arumilli²  Janelle M. Belanger³  Eija H. Seppälä²  Lotta L. E. Koskinen² 

[1] Department of Clinical Veterinary Sciences, University of Helsinki, Helsinki, Finland;Folkhälsan Institute of Genetics, Helsinki, Finland;Department of Animal Science, University of California Davis, Davis, California, USA

关键词: SNP;    Resequencing;    GWAS;    ADAM23;    Dog;    Epilepsy;   

Others  :  1216169
DOI  :  10.1186/s12864-015-1651-9

 received in 2014-10-27, accepted in 2015-05-20,  发布年份 2015

【 摘 要 】

Background

Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37.

Results

We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (p _c  = 2.9e–07, p _GWAS  = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (p _raw  = 2.76e–15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49–0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy.

Conclusions

These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.

【 授权许可】

   
2015 Koskinen et al.

【 图 表 】

Fig. 1.

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【 参考文献 】

• [1]Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde BW et al.. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010; 51(4):676-685.
• [2]Berendt M, Gullov CH, Christensen SL, Gudmundsdottir H, Gredal H, Fredholm M et al.. Prevalence and characteristics of epilepsy in the Belgian shepherd variants Groenendael and Tervueren born in Denmark 1995–2004. Acta Vet Scand. 2008; 50:51. BioMed Central Full Text
• [3]Hildebrand MS, Dahl HH, Damiano JA, Smith RJ, Scheffer IE, Berkovic SF. Recent advances in the molecular genetics of epilepsy. J Med Genet. 2013; 50(5):271-279.
• [4]Ekenstedt KJ, Oberbauer AM. Inherited epilepsy in dogs. Top Companion Anim Med. 2013; 28(2):51-58.
• [5]Lohi H, Young EJ, Fitzmaurice SN, Rusbridge C, Chan EM, Vervoort M et al.. Expanded repeat in canine epilepsy. Science. 2005; 307(5706):81.
• [6]Melville SA, Wilson CL, Chiang CS, Studdert VP, Lingaas F, Wilton AN. A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs. Genomics. 2005; 86(3):287-294.
• [7]Katz ML, Khan S, Awano T, Shahid SA, Siakotos AN, Johnson GS. A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun. 2005; 327(2):541-547.
• [8]Awano T, Katz ML, O’Brien DP, Sohar I, Lobel P, Coates JR et al.. A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Mol Genet Metab. 2006; 89(3):254-260.
• [9]Awano T, Katz ML, O’Brien DP, Taylor JF, Evans J, Khan S et al.. A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis. Mol Genet Metab. 2006; 87(4):341-348.
• [10]Sanders DN, Farias FH, Johnson GS, Chiang V, Cook JR, O’Brien DP et al.. A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Mol Genet Metab. 2010; 100(4):349-356.
• [11]Farias FH, Zeng R, Johnson GS, Wininger FA, Taylor JF, Schnabel RD et al.. A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers. Neurobiol Dis. 2011; 42(3):468-474.
• [12]Wohlke A, Philipp U, Bock P, Beineke A, Lichtner P, Meitinger T et al.. A one base pair deletion in the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrier. PLoS Genet. 2011; 7(10):e1002304.
• [13]Seppala EH, Jokinen TS, Fukata M, Fukata Y, Webster MT, Karlsson EK et al.. LGI2 truncation causes a remitting focal epilepsy in dogs. PLoS Genet. 2011; 7(7):e1002194.
• [14]Seppala EH, Koskinen LL, Gullov CH, Jokinen P, Karlskov-Mortensen P, Bergamasco L et al.. Identification of a novel idiopathic epilepsy locus in Belgian Shepherd dogs. PLoS One. 2012; 7(3):e33549.
• [15]Oberbauer AM, Belanger JM, Grossman DI, Regan KR, Famula TR. Genome-wide linkage scan for loci associated with epilepsy in Belgian shepherd dogs. BMC Genet. 2010; 11:35. BioMed Central Full Text
• [16]Viitmaa R, Cizinauskas S, Orro T, Niilo-Rama M, Gordin E, Lohi H et al.. Phenotype, inheritance characteristics, and risk factors for idiopathic epilepsy in Finnish Spitz dogs. J Am Vet Med Assoc. 2013; 243(7):1001-1009.
• [17]Bielfelt SW, Redman HC, McClellan RO. Sire- and sex-related differences in rates of epileptiform seizures in a purebred beagle dog colony. Am J Vet Res. 1971; 32(12):2039-2048.
• [18]Sagane K, Ishihama Y, Sugimoto H. LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11. Int J Biol Sci. 2008; 4(6):387-396.
• [19]Fukata Y, Lovero KL, Iwanaga T, Watanabe A, Yokoi N, Tabuchi K et al.. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci U S A. 2010; 107(8):3799-3804.
• [20]Ottman R. Autosomal dominant partial epilepsy with auditory features. GeneReviews. Pagon RA, Adam MP, Bird TD, editors. University of Washington, Seattle, Seattle (WA); 1993.
• [21]Senechal KR, Thaller C, Noebels JL. ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. Hum Mol Genet. 2005; 14(12):1613-1620.
• [22]Novak U. ADAM proteins in the brain. J Clin Neurosci. 2004; 11(3):227-235.
• [23]Owuor K, Harel NY, Englot DJ, Hisama F, Blumenfeld H, Strittmatter SM. LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology. Mol Cell Neurosci. 2009; 42(4):448-457.
• [24]Mitchell KJ, Pinson KI, Kelly OG, Brennan J, Zupicich J, Scherz P et al.. Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet. 2001; 28(3):241-249.
• [25]Canine genetic studies. http://www. koirangeenit.fi/english/ webcite
• [26]Rincon G, Tengvall K, Belanger JM, Lagoutte L, Medrano JF, Andre C et al.. Comparison of buccal and blood-derived canine DNA, either native or whole genome amplified, for array-based genome-wide association studies. BMC Res Notes. 2011; 4:226. BioMed Central Full Text
• [27]Oberbauer AM, Grossman DI, Eggleston ML, Irion DN, Schaffer AL, Pedersen NC et al.. Alternatives to blood as a source of DNA for large-scale scanning studies of canine genome linkages. Vet Res Commun. 2003; 27(1):27-38.
• [28]Purcell S, Cherny SS, Sham PC. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003; 19(1):149-150.
• [29]Lequarre AS, Andersson L, Andre C, Fredholm M, Hitte C, Leeb T et al.. LUPA: a European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs. Vet J. 2011; 189(2):155-159.
• [30]Aulchenko YS, Ripke S, Isaacs A, van Duijn CM. GenABEL: an R library for genome-wide association analysis. Bioinformatics. 2007; 23(10):1294-1296.
• [31]Amin N, van Duijn CM, Aulchenko YS. A genomic background based method for association analysis in related individuals. PLoS One. 2007; 2(12):e1274.
• [32]Thompson EA, Shaw RG. Pedigree analysis for quantitative traits: variance components without matrix inversion. Biometrics. 1990; 46(2):399-413.
• [33]Hytonen MK, Arumilli M, Lappalainen AK, Kallio H, Snellman M, Sainio K et al.. A novel GUSB mutation in Brazilian terriers with severe skeletal abnormalities defines the disease as mucopolysaccharidosis VII. PLoS One. 2012; 7(7):e40281.
• [34]FASTX-Toolkit. http://hannonlab. cshl.edu/fastx_toolkit/index.html webcite
• [35]Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010; 26(5):589-595.
• [36]Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N et al.. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-2079.
• [37]McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al.. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-1303.
• [38]DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C et al.. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43(5):491-498.
• [39]Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38(16):e164.
• [40]Thorvaldsdottir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013; 14(2):178-192.
• [41]Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G et al.. Integrative genomics viewer. Nat Biotechnol. 2011; 29(1):24-26.
• [42]Cooper GM, Stone EA, Asimenos G, Green ED, Batzoglou S et al.. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005; 15(7):901-913.
• [43]Ensembl. www. ensembl.org webcite
• [44]UCSC Genome Browser. http://genome. ucsc.edu webcite
• [45]Miller W, Rosenbloom K, Hardison RC, Hou M, Taylor J, Raney B et al.. 28-way vertebrate alignment and conservation track in the UCSC Genome Browser. Genome Res. 2007; 17(12):1797-1808.
• [46]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al.. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-575.
• [47]PLINK v. 1.07. http://pngu. mgh.harvard.edu/purcell/plink/ webcite
• [48]Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21(2):263-265.