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Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping.

ABSTRACT: To test the usefulness of linkage disequilibrium for gene mapping, we compared physical distances and linkage disequilibrium among eight RFLPs in the neurofibromatosis 1 (NF1) region. Seven of the polymorphisms span most of the NF1 gene, while the remaining polymorphism lies approximately 70 kb 3' to a stop codon in exon 49. By using Centre d'Etude du Polymorphisme Humain (CEPH) kindreds, 91-110 unrelated parents were genotyped. A high degree of disequilibrium is maintained among the seven intragenic polymorphisms (r > .82, P < 10(-7)), even though they are separated by as much as 340 kb. The 3' polymorphism is only 68 kb distal to the next polymorphism, but disequilibrium between the 3' polymorphism and all others is comparatively low (magnitude of 4 < .33, P values .27-.001). This result was replicated in three sets of unrelated kindreds: the Utah CEPH families, the non-Utah CEPH families, and an independent set of NF1 families. Trigenic, quadrigenic, three-locus, and four-locus disequilibrium measures were also estimated. There was little evidence of higher-order linkage disequilibrium. As expected for a disease with multiple mutations, no disequilibrium was observed between the disease gene and any of the RFLPs. The observed pattern of high disequilibrium within the gene and a loss of disequilibrium 3' to the stop codon could have implications for gene mapping studies. These are discussed, and guidelines for linkage disequilibrium studies are suggested.

SUBMITTER: Jorde LB

PROVIDER: S-EPMC1682302 | biostudies-other | 1993 Nov

REPOSITORIES: biostudies-other

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Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping.

Jorde L B LB Watkins W S WS Viskochil D D O'Connell P P Ward K K

American journal of human genetics 19931101 5

To test the usefulness of linkage disequilibrium for gene mapping, we compared physical distances and linkage disequilibrium among eight RFLPs in the neurofibromatosis 1 (NF1) region. Seven of the polymorphisms span most of the NF1 gene, while the remaining polymorphism lies approximately 70 kb 3' to a stop codon in exon 49. By using Centre d'Etude du Polymorphisme Humain (CEPH) kindreds, 91-110 unrelated parents were genotyped. A high degree of disequilibrium is maintained among the seven intra ...[more]

PMID: 8105688

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Project description:Association studies are widely seen as the most promising approach for finding polymorphisms that influence genetically complex traits, such as common diseases and responses to their treatment. Considerable interest has therefore recently focused on the development of methods that efficiently screen genomic regions or whole genomes for gene variants associated with complex phenotypes. One key element in this search is the use of linkage disequilibrium to gain maximal information from typing a selected subset of highly informative single-nucleotide polymorphism (SNP) markers, now often called "tagging SNPs" (tSNPs). Probably the most common approach to linkage-disequilibrium gene mapping involves a three-step program: (1) characterization of the haplotype structure in candidate genes or genomic regions of interest, (2) identification of tSNPs sufficient to represent the most common haplotypes, and (3) typing of tSNPs in clinical material. Early definitions of tSNPs focused on the amount of haplotype diversity that they explained. To select tSNPs that would have maximal power in a genetic association study, however, we have developed optimization criteria based on the r2 measure of association and have compared these with other criteria based on the haplotype diversity. To evaluate the full program and to assess how well the selected tags are likely to perform, we have determined the haplotype structure and have assessed tSNPs in the SCN1A gene, an important candidate gene for sporadic epilepsy. We find that as few as four tSNPs are predicted to maintain a consistently high r2 value with all other common SNPs in the gene, indicating that the tags could be used in an association study with only a modest reduction in power relative to direct assays of all common SNPs. This implies that very large case-control studies can be screened for variation in hundreds of candidate genes with manageable experimental effort, once tSNPs are identified. However, our results also show that tSNPs identified in one population may not necessarily perform well in another, indicating that the preliminary study to identify tSNPs and the later case-control study should be performed in the same population. Our results also indicate that tSNPs will not easily identify discrepant SNPs, which lie on importantly discriminating but apparently short genealogical branches. This could significantly complicate tagging approaches for phenotypes influenced by variants that have experienced positive selection.

Dataset Information

Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping.

Publications

Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping.

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