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Mapping a disease locus by allelic association

Mapping a disease locus by allelic association
Mapping a disease locus by allelic association

Allelic association provides a means to map disease genes that, in a dense map of polymorphic markers, has considerably higher resolution than linkage methods. We describe here a composite likelihood estimate of location for a disease gene against a high-resolution marker map by using allele frequencies at linked loci. Data may be family-based, as in the transmission disequilibrium test, or from a case-control study. χ2 tests, logarithm of odds, standard errors, and information weights are provided. The method is illustrated by analysis of published cystic fibrosis haplotypes, in which ΔF508 is more accurately localized than by other association studies. This differs from current approaches by adopting a more general Malecot model for isolation by distance, where distance here is between marker and disease locus, allowance for errors in the map and model, and freedom from assumptions about demography, systematic pressures, and the ratio of physical to genetic distance. When these assumptions are introduced the number of generations since the original mutation may be estimated, but this is not required to determine location and its standard error, so that evidence from allelic association may be efficiently combined with linkage evidence to identify a region for positional cloning of a disease gene.

Cystic fibrosis, Disease gene mapping, Malecot model
0027-8424
1741-1745
Collins, A.
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Morton, N. E.
c668e2be-074a-4a0a-a2ca-e8f51830ebb7
Collins, A.
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Morton, N. E.
c668e2be-074a-4a0a-a2ca-e8f51830ebb7

Collins, A. and Morton, N. E. (1998) Mapping a disease locus by allelic association. Proceedings of the National Academy of Sciences, 95 (4), 1741-1745. (doi:10.1073/pnas.95.4.1741).

Record type: Article

Abstract

Allelic association provides a means to map disease genes that, in a dense map of polymorphic markers, has considerably higher resolution than linkage methods. We describe here a composite likelihood estimate of location for a disease gene against a high-resolution marker map by using allele frequencies at linked loci. Data may be family-based, as in the transmission disequilibrium test, or from a case-control study. χ2 tests, logarithm of odds, standard errors, and information weights are provided. The method is illustrated by analysis of published cystic fibrosis haplotypes, in which ΔF508 is more accurately localized than by other association studies. This differs from current approaches by adopting a more general Malecot model for isolation by distance, where distance here is between marker and disease locus, allowance for errors in the map and model, and freedom from assumptions about demography, systematic pressures, and the ratio of physical to genetic distance. When these assumptions are introduced the number of generations since the original mutation may be estimated, but this is not required to determine location and its standard error, so that evidence from allelic association may be efficiently combined with linkage evidence to identify a region for positional cloning of a disease gene.

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More information

Published date: 17 February 1998
Keywords: Cystic fibrosis, Disease gene mapping, Malecot model

Identifiers

Local EPrints ID: 470928
URI: http://eprints.soton.ac.uk/id/eprint/470928
ISSN: 0027-8424
PURE UUID: fd12c7b5-29e4-48d9-aafc-2bdff2fbab64
ORCID for A. Collins: ORCID iD orcid.org/0000-0001-7108-0771

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Date deposited: 21 Oct 2022 16:33
Last modified: 17 Mar 2024 02:37

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Contributors

Author: A. Collins ORCID iD
Author: N. E. Morton

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