Linkage Analysis as an Approach for Disease-related Loci Identification
Nowak Dorota M. 1, Pitarque Jose A. 2, Molinari Andrea 2, Bejjani Bassem A. 3, Gajecka Marzena 1*
1Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
2Department of Ophthalmology, Hospital Metropolitano, Quito, Ecuador
3Revemic Systems, Spokane, Washington, USA
*e-mail: gamar@man.poznan.pl
Received:
(Received: 10 February 2012; accepted: 6 June 2012; published online: 23 August 2012)
DOI: 10.12921/cmst.2012.18.02.95-101
OAI: oai:lib.psnc.pl:415
Abstract:
Extensive progress in human genetics and clinical diagnostics allowed identification of the majority of genetically-related diseases. Still, the genes responsible for numerous diseases have not been recognized and frequently the disease etiology remains unknown. This is true for keratoconus, the study subject of this article. Therefore, before mutation analysis or other sequence variant assessment, it is essential to identify the chromosomal region, where a gene
or genes causing the disease phenotype are located. To achieve that, advanced bioinformatics methods are applied to data obtained from molecular research to narrow the chromosomal region containing the disease locus.
Key words:
References:
[1] N.E. Morton, Sequential tests for the detection of linkage. Am. J. Hum. Genet. 7, 277-318 (1955).
[2] E. Lander, L. Kruglyak, Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241-247 (1995).
[3] L. Kruglyak, M.J. Daly, M.P. Reeve-Daly, E.S. Lander, Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347-1363 (1996).
[4] A. Kong, N.J. Cox, Allele-sharing models: LOD scores and accurate linkage tests. Am. J. Hum. Genet. 61, 1179-1188 (1997).
[5] D.F. Gudbjartsson, T. Thorvaldsson, A. Kong, G. Gunnarsson, A. Ingolfsdottir, Allegro version 2. Nat. Genet. 37, 1015-1016 (2005).
[6] Y.S. Rabinowitz, Keratoconus. Surv Ophthalmol 42, 297- 319 (1998).
[7] D.M. Nowak, M. Gajecka, The genetics of keratoconus. Middle East Afr J Ophthalmol 18, 2-6 (2011).
[8] P.L. Jacq, Y. Sale, B. Cochener, P. Lozach, J. Colin, Keratoconus, changes in corneal topography and allergy. Study of 3 groups of patients. J Fr Ophtalmol 20, 97-102 (1997).
[9] A.R. Gasset, W.L. Houde, M. Garcia-Bengochea, Hard contact lens wear as an environmental risk in keratoconus. Am. J. Ophthalmol. 85, 339-341 (1978).
[10] R.J. Harrison, P.T. Klouda, D.L. Easty, M. Manku, J. Charles, C.M. Stewart, Association between keratoconus and atopy. Br J Ophthalmol 73, 816-822 (1989).
[11] A. Rahi, P. Davies, M. Ruben, D. Lobascher, J. Menon, Keratoconus and coexisting atopic disease. Br J Ophthalmol 61, 761-764 (1977).
[12] L. Wachtmeister, S.O. Ingemansson, E. Möller, Atopy and HLA antigens in patients with keratoconus. Acta Ophthalmol (Copenh) 60, 113-122 (1982).
[13] K.P. Burdon, D.J. Coster, J.C. Charlesworth, R.A. Mills, K.J. Laurie, C. Giunta, A.W. Hewitt, P. Latimer, J.E. Craig, Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci. Hum. Genet. 124, 379-386 (2008).
[14] H. Hutchings, H. Ginisty, M. Le Gallo, D. Levy, F. Stoësser, J.F. Rouland, J.L. Arné, M.H. Lalaux, P. Calvas, M.P. Roth, A. Hovnanian, F. Malecaze, Identification of a new locus for isolated familial keratoconus at 2p24. J. Med. Genet. 42, 88-94 (2005).
[15] S. Kim, J. Mok, H. Kim, C.K. Joo, Association of -31T>C and -511 C>T polymorphisms in the interleukin 1 beta (IL1B) promoter in Korean keratoconus patients. Mol. Vis. 14, 2109-2116 (2008).
[16] F. Brancati, E.M. Valente, A. Sarkozy, J. Fehèr, M. Castori, P. Del Duca, R. Mingarelli, A. Pizzuti, B. Dallapiccola, A locus for autosomal dominant keratoconus maps to human chromosome 3p14-q13. J. Med. Genet. 41, 188-192 (2004).
[17] Y.G. Tang, Y.S. Rabinowitz, K.D. Taylor, X. Li, M. Hu, Y. Picornell, H. Yang, Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1. Genet. Med. 7, 397-405 (2005).
[18] L. Bisceglia, P. De Bonis, C. Pizzicoli, L. Fischetti, A. Laborante, M. Di Perna, F. Giuliani, N. Delle Noci, L. Buzzonetti, L. Zelante, Linkage analysis in keratoconus: replication of locus 5q21.2 and identification of other suggestive Loci. Invest. Ophthalmol. Vis. Sci. 50, 1081-1086 (2009).
[19] X. Li, Y.S. Rabinowitz, Y.G. Tang, Y. Picornell, K.D. Taylor, M. Hu, H. Yang, Two-stage genome-wide linkage scan in keratoconus sib pair families. Invest. Ophthalmol. Vis. Sci. 47, 3791-3795 (2006).
[20] M. Gajecka, U. Radhakrishna, D. Winters, S.K. Nath, M. Rydzanicz, U. Ratnamala, K. Ewing, A. Molinari, J.A. Pitarque, K. Lee, S.M. Leal, B.A. Bejjani, Localization of a gene for keratoconus to a 5.6-Mb interval on 13q32, Invest. Ophthalmol. Vis. Sci. 50, 1531-1539 (2009).
[21] P. Liskova, P.G. Hysi, N. Waseem, N.D. Ebenezer, S.S. Bhattacharya, S.J. Tuft, Evidence for keratoconus susceptibility locus on chromosome 14: a genome-wide linkage screen using single-nucleotide polymorphism markers. Arch. Ophthalmol. 128 1191-1195 (2010).
[22] A.E. Hughes, D.P. Dash, A.J. Jackson, D.G. Frazer, G. Silvestri, Familial keratoconus with cataract: linkage to the long arm of chromosome 15 and exclusion of candidate genes. Invest. Ophthalmol. Vis. Sci. 44, 5063-5066 (2003).
[23] H. Tyynismaa, P. Sistonen, S. Tuupanen, T. Tervo, A. Dammert, T. Latvala, T. Alitalo, A locus for autosomal dominant keratoconus: linkage to 16q22.3-q23.1 in Finnish families. Invest. Ophthalmol. Vis. Sci. 43, 3160-3164 (2002).
[24] A. Hameed, S. Khaliq, M. Ismail, K. Anwar, N.D. Ebenezer, T. Jordan, S.Q. Mehdi, A.M. Payne, S.S. Bhattacharya, A novel locus for Leber congenital amaurosis (LCA4) with anterior keratoconus mapping to chromosome 17p13. Invest. Ophthalmol. Vis. Sci. 41, 629-633 (2000).
[25] J. Fullerton, P. Paprocki, S. Foote, D.A. Mackey, R. Williamson, S. Forrest, Identity-by-descent approach to gene localisation in eight individuals affected by keratoconus from north-west Tasmania, Australia. Hum. Genet. 110, 462-470 (2002).
[26] J.E. Wigginton, G.R. Abecasis, PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 21, 3445-3447 (2005).
[27] E. Sobel, K. Lange, Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am. J. Hum. Genet. 58, 1323-1337 (1996).
[28] E.M. Lange, K. Lange, Powerful allele sharing statistics for nonparametric linkage analysis. Hum. Hered. 57 49-58 (2004).
[29] N. Mukhopadhyay, L. Almasy, M. Schroeder, W.P. Mulvihill, D.E. Weeks, Mega2: data-handling for facilitating genetic linkage and association analyses. Bioinormatics 21, 2556-2557 (2005).
[30] T.C. Matise, F. Chen, W. Chen, F.M. De La Vega, M. Hansen, C. He, F.C.L. Hyland, G.C. Kennedy, X. Kong, S.S. Murray, J.S. Ziegle, W.C.L. Stewart, S. Buyske, A second-generation combined linkage physical map of the human genome. Genome Res. 17, 1783-1786 (2007).
[31] D.E. Weeks, E. Sobel, J.R. O’Connell, K. Lange, Computer programs for multilocus haplotyping of general pedigrees. Am. J. Hum. Genet. 56, 1506-1507 (1995).
[32] H. Thiele, P. Nürnberg, HaploPainter: a tool for drawing pedigrees with complex haplotypes. Bioinformatics 21, 1730-1732 (2005).
Extensive progress in human genetics and clinical diagnostics allowed identification of the majority of genetically-related diseases. Still, the genes responsible for numerous diseases have not been recognized and frequently the disease etiology remains unknown. This is true for keratoconus, the study subject of this article. Therefore, before mutation analysis or other sequence variant assessment, it is essential to identify the chromosomal region, where a gene
or genes causing the disease phenotype are located. To achieve that, advanced bioinformatics methods are applied to data obtained from molecular research to narrow the chromosomal region containing the disease locus.
Key words:
References:
[1] N.E. Morton, Sequential tests for the detection of linkage. Am. J. Hum. Genet. 7, 277-318 (1955).
[2] E. Lander, L. Kruglyak, Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241-247 (1995).
[3] L. Kruglyak, M.J. Daly, M.P. Reeve-Daly, E.S. Lander, Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347-1363 (1996).
[4] A. Kong, N.J. Cox, Allele-sharing models: LOD scores and accurate linkage tests. Am. J. Hum. Genet. 61, 1179-1188 (1997).
[5] D.F. Gudbjartsson, T. Thorvaldsson, A. Kong, G. Gunnarsson, A. Ingolfsdottir, Allegro version 2. Nat. Genet. 37, 1015-1016 (2005).
[6] Y.S. Rabinowitz, Keratoconus. Surv Ophthalmol 42, 297- 319 (1998).
[7] D.M. Nowak, M. Gajecka, The genetics of keratoconus. Middle East Afr J Ophthalmol 18, 2-6 (2011).
[8] P.L. Jacq, Y. Sale, B. Cochener, P. Lozach, J. Colin, Keratoconus, changes in corneal topography and allergy. Study of 3 groups of patients. J Fr Ophtalmol 20, 97-102 (1997).
[9] A.R. Gasset, W.L. Houde, M. Garcia-Bengochea, Hard contact lens wear as an environmental risk in keratoconus. Am. J. Ophthalmol. 85, 339-341 (1978).
[10] R.J. Harrison, P.T. Klouda, D.L. Easty, M. Manku, J. Charles, C.M. Stewart, Association between keratoconus and atopy. Br J Ophthalmol 73, 816-822 (1989).
[11] A. Rahi, P. Davies, M. Ruben, D. Lobascher, J. Menon, Keratoconus and coexisting atopic disease. Br J Ophthalmol 61, 761-764 (1977).
[12] L. Wachtmeister, S.O. Ingemansson, E. Möller, Atopy and HLA antigens in patients with keratoconus. Acta Ophthalmol (Copenh) 60, 113-122 (1982).
[13] K.P. Burdon, D.J. Coster, J.C. Charlesworth, R.A. Mills, K.J. Laurie, C. Giunta, A.W. Hewitt, P. Latimer, J.E. Craig, Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci. Hum. Genet. 124, 379-386 (2008).
[14] H. Hutchings, H. Ginisty, M. Le Gallo, D. Levy, F. Stoësser, J.F. Rouland, J.L. Arné, M.H. Lalaux, P. Calvas, M.P. Roth, A. Hovnanian, F. Malecaze, Identification of a new locus for isolated familial keratoconus at 2p24. J. Med. Genet. 42, 88-94 (2005).
[15] S. Kim, J. Mok, H. Kim, C.K. Joo, Association of -31T>C and -511 C>T polymorphisms in the interleukin 1 beta (IL1B) promoter in Korean keratoconus patients. Mol. Vis. 14, 2109-2116 (2008).
[16] F. Brancati, E.M. Valente, A. Sarkozy, J. Fehèr, M. Castori, P. Del Duca, R. Mingarelli, A. Pizzuti, B. Dallapiccola, A locus for autosomal dominant keratoconus maps to human chromosome 3p14-q13. J. Med. Genet. 41, 188-192 (2004).
[17] Y.G. Tang, Y.S. Rabinowitz, K.D. Taylor, X. Li, M. Hu, Y. Picornell, H. Yang, Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1. Genet. Med. 7, 397-405 (2005).
[18] L. Bisceglia, P. De Bonis, C. Pizzicoli, L. Fischetti, A. Laborante, M. Di Perna, F. Giuliani, N. Delle Noci, L. Buzzonetti, L. Zelante, Linkage analysis in keratoconus: replication of locus 5q21.2 and identification of other suggestive Loci. Invest. Ophthalmol. Vis. Sci. 50, 1081-1086 (2009).
[19] X. Li, Y.S. Rabinowitz, Y.G. Tang, Y. Picornell, K.D. Taylor, M. Hu, H. Yang, Two-stage genome-wide linkage scan in keratoconus sib pair families. Invest. Ophthalmol. Vis. Sci. 47, 3791-3795 (2006).
[20] M. Gajecka, U. Radhakrishna, D. Winters, S.K. Nath, M. Rydzanicz, U. Ratnamala, K. Ewing, A. Molinari, J.A. Pitarque, K. Lee, S.M. Leal, B.A. Bejjani, Localization of a gene for keratoconus to a 5.6-Mb interval on 13q32, Invest. Ophthalmol. Vis. Sci. 50, 1531-1539 (2009).
[21] P. Liskova, P.G. Hysi, N. Waseem, N.D. Ebenezer, S.S. Bhattacharya, S.J. Tuft, Evidence for keratoconus susceptibility locus on chromosome 14: a genome-wide linkage screen using single-nucleotide polymorphism markers. Arch. Ophthalmol. 128 1191-1195 (2010).
[22] A.E. Hughes, D.P. Dash, A.J. Jackson, D.G. Frazer, G. Silvestri, Familial keratoconus with cataract: linkage to the long arm of chromosome 15 and exclusion of candidate genes. Invest. Ophthalmol. Vis. Sci. 44, 5063-5066 (2003).
[23] H. Tyynismaa, P. Sistonen, S. Tuupanen, T. Tervo, A. Dammert, T. Latvala, T. Alitalo, A locus for autosomal dominant keratoconus: linkage to 16q22.3-q23.1 in Finnish families. Invest. Ophthalmol. Vis. Sci. 43, 3160-3164 (2002).
[24] A. Hameed, S. Khaliq, M. Ismail, K. Anwar, N.D. Ebenezer, T. Jordan, S.Q. Mehdi, A.M. Payne, S.S. Bhattacharya, A novel locus for Leber congenital amaurosis (LCA4) with anterior keratoconus mapping to chromosome 17p13. Invest. Ophthalmol. Vis. Sci. 41, 629-633 (2000).
[25] J. Fullerton, P. Paprocki, S. Foote, D.A. Mackey, R. Williamson, S. Forrest, Identity-by-descent approach to gene localisation in eight individuals affected by keratoconus from north-west Tasmania, Australia. Hum. Genet. 110, 462-470 (2002).
[26] J.E. Wigginton, G.R. Abecasis, PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 21, 3445-3447 (2005).
[27] E. Sobel, K. Lange, Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am. J. Hum. Genet. 58, 1323-1337 (1996).
[28] E.M. Lange, K. Lange, Powerful allele sharing statistics for nonparametric linkage analysis. Hum. Hered. 57 49-58 (2004).
[29] N. Mukhopadhyay, L. Almasy, M. Schroeder, W.P. Mulvihill, D.E. Weeks, Mega2: data-handling for facilitating genetic linkage and association analyses. Bioinormatics 21, 2556-2557 (2005).
[30] T.C. Matise, F. Chen, W. Chen, F.M. De La Vega, M. Hansen, C. He, F.C.L. Hyland, G.C. Kennedy, X. Kong, S.S. Murray, J.S. Ziegle, W.C.L. Stewart, S. Buyske, A second-generation combined linkage physical map of the human genome. Genome Res. 17, 1783-1786 (2007).
[31] D.E. Weeks, E. Sobel, J.R. O’Connell, K. Lange, Computer programs for multilocus haplotyping of general pedigrees. Am. J. Hum. Genet. 56, 1506-1507 (1995).
[32] H. Thiele, P. Nürnberg, HaploPainter: a tool for drawing pedigrees with complex haplotypes. Bioinformatics 21, 1730-1732 (2005).
