Parametric and Nonparametric Multipoint Linkage Analysis with Imprinting and Two-locus-trait Models: Application to Mite Sensitization

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2000 May 5

PMID 10796874

Citations 74

Authors

K Strauch

R Fimmers

T Kurz

K A Deichmann

T F Wienker

M P Baur

Affiliations

Soon will be listed here.

Abstract

We present two extensions to linkage analysis for genetically complex traits. The first extension allows investigators to perform parametric (LOD-score) analysis of traits caused by imprinted genes-that is, of traits showing a parent-of-origin effect. By specification of two heterozygote penetrance parameters, paternal and maternal origin of the mutation can be treated differently in terms of probability of expression of the trait. Therefore, a single-disease-locus-imprinting model includes four penetrances instead of only three. In the second extension, parametric and nonparametric linkage analysis with two trait loci is formulated for a multimarker setting, optionally taking imprinting into account. We have implemented both methods into the program GENEHUNTER. The new tools, GENEHUNTER-IMPRINTING and GENEHUNTER-TWOLOCUS, were applied to human family data for sensitization to mite allergens. The data set comprises pedigrees from England, Germany, Italy, and Portugal. With single-disease-locus-imprinting MOD-score analysis, we find several regions that show at least suggestive evidence for linkage. Most prominently, a maximum LOD score of 4.76 is obtained near D8S511, for the English population, when a model that implies complete maternal imprinting is used. Parametric two-trait-locus analysis yields a maximum LOD score of 6.09 for the German population, occurring exactly at D4S430 and D18S452. The heterogeneity model specified for analysis alludes to complete maternal imprinting at both disease loci. Altogether, our results suggest that the two novel formulations of linkage analysis provide valuable tools for genetic mapping of multifactorial traits.

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References

Strauch K, Fimmers R, Windemuth C, Hahn A, Wienker T, Baur M . Linkage analysis with adequate modeling of a parent-of-origin effect. Genet Epidemiol. 1999; 17 Suppl 1:S331-6. DOI: 10.1002/gepi.1370170756. View

Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A . A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996; 380(6570):152-4. DOI: 10.1038/380152a0. View

Kruglyak L, Lander E . Faster multipoint linkage analysis using Fourier transforms. J Comput Biol. 1998; 5(1):1-7. DOI: 10.1089/cmb.1998.5.1. View

Barnes K, Marsh D . The genetics and complexity of allergy and asthma. Immunol Today. 1998; 19(7):325-32. DOI: 10.1016/s0167-5699(97)01241-3. View

Greenberg D, Abreu P, Hodge S . The power to detect linkage in complex disease by means of simple LOD-score analyses. Am J Hum Genet. 1998; 63(3):870-9. PMC: 1377386. DOI: 10.1086/301997. View

Abel L . Two-locus developments of the weighted pairwise correlation method for linkage analysis. Genet Epidemiol. 1998; 15(5):491-510. DOI: 10.1002/(SICI)1098-2272(1998)15:5<491::AID-GEPI4>3.0.CO;2-3. View

Durner M, Vieland V, Greenberg D . Further evidence for the increased power of LOD scores compared with nonparametric methods. Am J Hum Genet. 1999; 64(1):281-9. PMC: 1377726. DOI: 10.1086/302181. View

Cox N, Frigge M, Nicolae D, Concannon P, Hanis C, Bell G . Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nat Genet. 1999; 21(2):213-5. DOI: 10.1038/6002. View

Howard T, Wiesch D, Koppelman G, Postma D, Meyers D, Bleecker E . Genetics of allergy and bronchial hyperresponsiveness. Clin Exp Allergy. 1999; 29 Suppl 2:86-9. DOI: 10.1046/j.1365-2222.1999.00015.x. View

10.

Paterson A, Naimark D, Petronis A . The analysis of parental origin of alleles may detect susceptibility loci for complex disorders. Hum Hered. 1999; 49(4):197-204. DOI: 10.1159/000022875. View

11.

Abreu P, Greenberg D, Hodge S . Direct power comparisons between simple LOD scores and NPL scores for linkage analysis in complex diseases. Am J Hum Genet. 1999; 65(3):847-57. PMC: 1377991. DOI: 10.1086/302536. View

12.

Smith C . TESTING FOR HETEROGENEITY OF RECOMBINATION FRACTION VALUES IN HUMAN GENETICS. Ann Hum Genet. 1963; 27:175-82. DOI: 10.1111/j.1469-1809.1963.tb00210.x. View

13.

Elston R, Stewart J . A general model for the genetic analysis of pedigree data. Hum Hered. 1971; 21(6):523-42. DOI: 10.1159/000152448. View

14.

Ott J . Linkage analysis and family classification under heterogeneity. Ann Hum Genet. 1983; 47(4):311-20. DOI: 10.1111/j.1469-1809.1983.tb01001.x. View

15.

Risch N . Segregation analysis incorporating linkage markers. I. Single-locus models with an application to type I diabetes. Am J Hum Genet. 1984; 36(2):363-86. PMC: 1684434. View

16.

Lathrop G, Lalouel J, Julier C, Ott J . Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984; 81(11):3443-6. PMC: 345524. DOI: 10.1073/pnas.81.11.3443. View

17.

Clerget-Darpoux F, Bonaiti-Pellie C, Hochez J . Effects of misspecifying genetic parameters in lod score analysis. Biometrics. 1986; 42(2):393-9. View

18.

Lander E, Green P . Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci U S A. 1987; 84(8):2363-7. PMC: 304651. DOI: 10.1073/pnas.84.8.2363. View

19.

Greenberg D, Hodge S . Linkage analysis under "random" and "genetic" reduced penetrance. Genet Epidemiol. 1989; 6(1):259-64. DOI: 10.1002/gepi.1370060145. View

20.

Greenberg D . Inferring mode of inheritance by comparison of lod scores. Am J Med Genet. 1989; 34(4):480-6. DOI: 10.1002/ajmg.1320340406. View