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Volumn 9, Issue 6, 1998, Pages 578-594

Linkage disequilibrium mapping of complex disease: Fantasy or reality?

Author keywords

[No Author keywords available]

Indexed keywords

ALLELE; GENE LINKAGE DISEQUILIBRIUM; GENE MAPPING; GENETIC DISORDER; GENETIC HETEROGENEITY; POPULATION GENETICS; PRIORITY JOURNAL; REVIEW;

EID: 0032403973     PISSN: 09581669     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0958-1669(98)80135-3     Document Type: Article
Times cited : (303)

References (156)
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    • Linkage disequilibrium and gene mapping an empirical least-squares approach
    • of special interest. This paper presents a multilocus approach to LD mapping based on identity by descent inference from multiple loci jointly. The author theoretically divides chromosomes into those with any 'D' allele and those without a 'D' allele, thus in theory allowing for allelic heterogeneity, though as with any LD method, the power is very adversely affected when the allelic complexity is great.
    • Lazzeroni L. Linkage disequilibrium and gene mapping an empirical least-squares approach. of special interest Am J Hum Genet. 62:1998;159-170 This paper presents a multilocus approach to LD mapping based on identity by descent inference from multiple loci jointly. The author theoretically divides chromosomes into those with any 'D' allele and those without a 'D' allele, thus in theory allowing for allelic heterogeneity, though as with any LD method, the power is very adversely affected when the allelic complexity is great.
    • (1998) Am J Hum Genet , vol.62 , pp. 159-170
    • Lazzeroni, L.1
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    • A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation suggesting multiple susceptibility loci
    • of special interest
    • Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajärvi R, Juovinen H, Kokko Sahin ML, Väisänen L, et al. A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation suggesting multiple susceptibility loci. of special interest Am J Hum Genet. 1998; This study highlights some of the ups and downs of LD mapping in extreme population isolates. In this case, several issues of more general concern are pointed out, and potential solutions are proposed. This is useful reading for anyone working in extremely small expanded populations.
    • (1998) Am J Hum Genet
    • Hovatta, I.1    Varilo, T.2    Suvisaari, J.3    Terwilliger, J.D.4    Ollikainen, V.5    Arajärvi, R.6    Juovinen, H.7    Kokko Sahin, M.L.8    Väisänen, L.9
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    • Human genome diversity - A project?
    • of outstanding interest. The authors comment on the feasibility, viability, and political considerations involved in the proposed human genome diversity project. Clearly, investigations of human population history and variation are critical to the future of enetic epidemiology and one identification, and this review covers some subtle important considerations in very eloquent style.
    • Harding RM, Sajantila A. Human genome diversity - a project? of outstanding interest Nat Genet. 18:1998;307-308 The authors comment on the feasibility, viability, and political considerations involved in the proposed human genome diversity project. Clearly, investigations of human population history and variation are critical to the future of enetic epidemiology and one identification, and this review covers some subtle important considerations in very eloquent style.
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    • Harding, R.M.1    Sajantila, A.2
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    • Multilocus genotypes, a tree of individuals, and human evolutionary history
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    • Use of siblings as controls in case-control association studies
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    • Genetic association mapping based on discordant sib pairs: The discordant alleles test
    • Boehnke M, Langefeld CD. Genetic association mapping based on discordant sib pairs: the discordant alleles test. Am J Hum Genet. 62:1998;950-961.
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    • Incorporating genotype of relatives into a test of linkage disequilibrium
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    • Transmission/disequilibrium tests for multiallelic loci
    • Sham P. Transmission/disequilibrium tests for multiallelic loci. Am J Hum Genet. 61:1997;774-777.
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    • Transmission-disequilibrium tests for quantitative traits
    • Allison DB. Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet. 60:1997;676-690.
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    • Transmission/disequilibrium test for quantitative trait loci
    • of special interest. The future of human gene mapping is undoubtedly going to focus more on quantitative variation and less on qualitative variation. To this end, the development of statistical methods, such as this one, to extended the current thinking to quantitative phenotypes is critical.
    • Rabinowitz D. Transmission/disequilibrium test for quantitative trait loci. of special interest Hum Hered. 47:1997;342-350 The future of human gene mapping is undoubtedly going to focus more on quantitative variation and less on qualitative variation. To this end, the development of statistical methods, such as this one, to extended the current thinking to quantitative phenotypes is critical.
    • (1997) Hum Hered , vol.47 , pp. 342-350
    • Rabinowitz, D.1
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    • True and false positive peaks in genome-wide scans: Applications of length-biased sampling to linkage mapping
    • of special interest. In this paper, relevant to association mapping, the general theory of the expected distribution of true and false positive shared segments is derived, and it is shown that the length of a haplotype is not so useful a measure of significance as the haplotype frequency in the population, as 25% of the false positive (assuming there are false positive IBD segments shared) will be longer than the true positives.
    • Terwilliger JD, Shannon WD, Lathrop GM, Nolan JP, Goldin LR, Chase GA, Weeks DE. True and false positive peaks in genome-wide scans: applications of length-biased sampling to linkage mapping. of special interest Am J Hum Genet. 61:1997;430-438 In this paper, relevant to association mapping, the general theory of the expected distribution of true and false positive shared segments is derived, and it is shown that the length of a haplotype is not so useful a measure of significance as the haplotype frequency in the population, as 25% of the false positive (assuming there are false positive IBD segments shared) will be longer than the true positives.
    • (1997) Am J Hum Genet , vol.61 , pp. 430-438
    • Terwilliger, J.D.1    Shannon, W.D.2    Lathrop, G.M.3    Nolan, J.P.4    Goldin, L.R.5    Chase, G.A.6    Weeks, D.E.7
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    • Tests for linkage and association in nuclear families
    • Martin ER, Kaplan NL, Weir BS. Tests for linkage and association in nuclear families. Am J Hum Genet. 61:1997;439-448.
    • (1997) Am J Hum Genet , vol.61 , pp. 439-448
    • Martin, E.R.1    Kaplan, N.L.2    Weir, B.S.3
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    • Combining information within and between pedigrees for mapping complex traits
    • Teng J, Siegmund D. Combining information within and between pedigrees for mapping complex traits. Am J Hum Genet. 60:1997;979-992.
    • (1997) Am J Hum Genet , vol.60 , pp. 979-992
    • Teng, J.1    Siegmund, D.2
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    • Mapping of complex traits by single-nucleotide polymorphisms
    • of special interest. Although it is unfortunate that the authors stress the issue of the diallelic single nucleotide polymorphisms in this manuscript, the general theory is a very useful means of combining linkage and association methods in a single statistical framework. This area of research will become more and more important with time, whether or not SNP markers become the markers of choice.
    • Zhao LP, Aragaki C, Hsu L, Quiaoit F. Mapping of complex traits by single-nucleotide polymorphisms. of special interest Am J Hum Genet. 63:1998;225-240 Although it is unfortunate that the authors stress the issue of the diallelic single nucleotide polymorphisms in this manuscript, the general theory is a very useful means of combining linkage and association methods in a single statistical framework. This area of research will become more and more important with time, whether or not SNP markers become the markers of choice.
    • (1998) Am J Hum Genet , vol.63 , pp. 225-240
    • Zhao, L.P.1    Aragaki, C.2    Hsu, L.3    Quiaoit, F.4
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    • Genomewide transmission/disequilibrium testing - Consideration of the genotype relative risks at disease loci
    • Camp NJ. Genomewide transmission/disequilibrium testing - consideration of the genotype relative risks at disease loci. Am J Hum Genet. 61:1997;1424-1430.
    • (1997) Am J Hum Genet , vol.61 , pp. 1424-1430
    • Camp, N.J.1
  • 96
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    • Algorithms and inferences: The challenge of multifactorial diseases
    • of outstanding interest. In this paper, Elston's perspectives on the hot topics of the day are explained in a very clear and intuitive manner. While this paper focuses on linkage analysis in complex disease, it gets to the heart of some important philosophical issues about how to interpret the results of a linkage and by extension an association study from his own unique perspective.
    • Elston RC. Algorithms and inferences: the challenge of multifactorial diseases. of outstanding interest Am J Hum Genet. 60:1997;255-262 In this paper, Elston's perspectives on the hot topics of the day are explained in a very clear and intuitive manner. While this paper focuses on linkage analysis in complex disease, it gets to the heart of some important philosophical issues about how to interpret the results of a linkage and by extension an association study from his own unique perspective.
    • (1997) Am J Hum Genet , vol.60 , pp. 255-262
    • Elston, R.C.1
  • 97
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    • Significance levels in complex inheritance
    • of outstanding interest. In the field of human genetics, it would be irresponsible to highly recommend the treatises on interpretation of significance testing by Elston [96] and Kruglyak [36] and not to suggest just as strongly that one read Newton Morton's opinions on the subject. Especially in the area of association mapping, these insights are useful to understand in developing your own opinions about interpretation.
    • Morton NE. Significance levels in complex inheritance. of outstanding interest Am J Hum Genet. 62:1998;690-697 In the field of human genetics, it would be irresponsible to highly recommend the treatises on interpretation of significance testing by Elston [96] and Kruglyak [36] and not to suggest just as strongly that one read Newton Morton's opinions on the subject. Especially in the area of association mapping, these insights are useful to understand in developing your own opinions about interpretation.
    • (1998) Am J Hum Genet , vol.62 , pp. 690-697
    • Morton, N.E.1
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    • Review of 'Statistical evidence: A likelihood paradigm' by Richard Royal
    • of outstanding interest. This is an excellent review of an excellent book - it is strongly recommended that both the review and the book be read by anyone changed with interpreting results of an association study or linkage analysis. This review and book are further complements to the papers of Morton [97], Elston [96], and Kruglyak [36] listed above, and is highly recommend reading for everyone. Read them all and make your own interpretations.
    • Vieland VJ, Hodge SE. Review of 'Statistical evidence: a likelihood paradigm' by Richard Royal. of outstanding interest Am J Hum Genet. 63:1998;283-288 This is an excellent review of an excellent book - it is strongly recommended that both the review and the book be read by anyone changed with interpreting results of an association study or linkage analysis. This review and book are further complements to the papers of Morton [97], Elston [96], and Kruglyak [36] listed above, and is highly recommend reading for everyone. Read them all and make your own interpretations.
    • (1998) Am J Hum Genet , vol.63 , pp. 283-288
    • Vieland, V.J.1    Hodge, S.E.2
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    • Optimal strategies for mapping complex diseases in the presence of multiple loci
    • Goldgar DE, Easton DF. Optimal strategies for mapping complex diseases in the presence of multiple loci. Am J Hum Genet. 60:1997;1222-1232.
    • (1997) Am J Hum Genet , vol.60 , pp. 1222-1232
    • Goldgar, D.E.1    Easton, D.F.2
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    • A new five-year plan for the US Human Genome Project
    • Collins F, Galas D. A new five-year plan for the US Human Genome Project. Science. 262:1993;43-46.
    • (1993) Science , vol.262 , pp. 43-46
    • Collins, F.1    Galas, D.2
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    • Variations on a theme: Cataloging human DNA sequence variation
    • Collins F, Guyer M, Chakravarti A. Variations on a theme: cataloging human DNA sequence variation. Science. 278:1997;1580-1581.
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    • Haplotype analysis of hemochromatosis: Evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes
    • of outstanding interest. This paper discusses the evolution of the hemochromatosis locus, and evaluates a number of different statistical methods for detection of LD and its application to estimation of the map position of a disease gene. In the case, a disease is analyzed for which almost all disease alleles in the population are identical by descent from a common ancestor. Multi-locus methods are emphasized.
    • Ajioka RS, Jorde LB, Gruen JR, Yu P, Dimitrova D, Barrow J, Radisky E, Edwards CO, Griffen LM, Kushner JP. Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes. of outstanding interest Am J Genet. 60:1997;1439-1447 This paper discusses the evolution of the hemochromatosis locus, and evaluates a number of different statistical methods for detection of LD and its application to estimation of the map position of a disease gene. In the case, a disease is analyzed for which almost all disease alleles in the population are identical by descent from a common ancestor. Multi-locus methods are emphasized.
    • (1997) Am J Genet , vol.60 , pp. 1439-1447
    • Ajioka, R.S.1    Jorde, L.B.2    Gruen, J.R.3    Yu, P.4    Dimitrova, D.5    Barrow, J.6    Radisky, E.7    Edwards, C.O.8    Griffen, L.M.9    Kushner, J.P.10
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    • Mapping using linkage-disequilibrium estimates: A comparative study
    • of special interest. Another comparison of statistical methods for the analysis of LD for a somewhat more complex genetic disorder than hemochromatosis. In this study, single locus disequilibrium measures are emphasized in a specific applied example from an interesting population dataset.
    • Allamand V, Beckmann JS. Mapping using linkage-disequilibrium estimates: a comparative study. of special interest Hum Hered. 47:1997;237-240 Another comparison of statistical methods for the analysis of LD for a somewhat more complex genetic disorder than hemochromatosis. In this study, single locus disequilibrium measures are emphasized in a specific applied example from an interesting population dataset.
    • (1997) Hum Hered , vol.47 , pp. 237-240
    • Allamand, V.1    Beckmann, J.S.2
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    • Most germ-line mutations in the nevoid basal cell carcinoma lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident
    • Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S, Suthers G, Haites N, Edwards M, Wainwright B, et al. Most germ-line mutations in the nevoid basal cell carcinoma lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. Am J Hum Genet. 60:1997;21-26.
    • (1997) Am J Hum Genet , vol.60 , pp. 21-26
    • Wicking, C.1    Shanley, S.2    Smyth, I.3    Gillies, S.4    Negus, K.5    Graham, S.6    Suthers, G.7    Haites, N.8    Edwards, M.9    Wainwright, B.10
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    • Identification of point mutations in 41 unrelated patients affected with Menkes disease
    • Tumer Z, Lund C, Tolshave J, Vural B, Tonnesen T, Horn N. Identification of point mutations in 41 unrelated patients affected with Menkes disease. Am J Hum Genet. 60:1997;63-71.
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    • Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1A gene
    • Chamberlain ME, Ubagai T, Mudd SH, Levy HL, Chou JY. Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1A gene. Am J Hum Genet. 60:1997;540-546.
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    • Cloning of the human type XVII collagen gene (COL17A1), and detection of novel mutations in generalized atrophic benign epidermolysis bullosa
    • Gatalica B, Pulkkinen L, Li K, Kuokkanen K, Ryynänen M, McGrath J, Uitto J. Cloning of the human type XVII collagen gene (COL17A1), and detection of novel mutations in generalized atrophic benign epidermolysis bullosa. Am J Hum Genet. 60:1997;352-365.
    • (1997) Am J Hum Genet , vol.60 , pp. 352-365
    • Gatalica, B.1    Pulkkinen, L.2    Li, K.3    Kuokkanen, K.4    Ryynänen, M.5    McGrath, J.6    Uitto, J.7
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    • Cystic fibrosis transmembrane-conductance regulator mutations among African Americans
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    • Autosomal recessive Sorsby fundus dystrophy revisited: Evidence for dominant inheritance
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    • The mutational spectrum in Treacher-Collins syndrome reveals a predominance of mutations that create a premature-termination codon
    • Edwards SJ, Gladwin AJ, Dixon MJ. The mutational spectrum in Treacher-Collins syndrome reveals a predominance of mutations that create a premature-termination codon. Am J Hum Genet. 60:1997;515-524.
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    • Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets
    • Holm IA, Huang X, Kunkel LM. Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. Am J Hum Genet. 60:1997;790-797.
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    • Constitutively methylated CpG dinucleotides as mutation hot spots in the retinoblastoma gene (RB1)
    • Mancini D, Singh S, Ainsworth P, Rodenheiser D. Constitutively methylated CpG dinucleotides as mutation hot spots in the retinoblastoma gene (RB1). Am J Hum Genet. 60:1997;80-87.
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    • Characterization of 18 new mutations in COL7A1 in recessive dystrophic epidemolysis bullosa provides evidence for distinct molecular mechanisms underlying defective anchoring fibril formation
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