Showing papers by "Michael Boehnke published in 1996"

Affected-sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations.

Abstract: We describe an extension of Risch's [(1990a,b) Am J Hum Genet 46:222-228, 229-241] method of linkage detection and exclusion for complex genetic traits. The method uses interval mapping to infer disease locus identity-by-descent (IBD) sharing for affected sib pairs (ASPs) based on marker information for the ASP and other genotyped family members. The method is likelihood based, and makes use of Risch's parameterization in terms of recurrence risk ratios for relatives. We describe specific linkage detection and exclusion tests for use as genome screening tools to prioritize genomic regions for further study. We also examine issues of optimal study design. We advocate initially typing a large panel of ASPs (and no additional family members) with a map of genetic markers evenly spaced at 10-20-cM intervals. We recommend a screening procedure that 1) investigates further all regions with maximum lod scores greater than 1 and 2) excludes from consideration those regions that result in lod scores less than -2 at the smallest genetic effect that is viewed as important to detect. Further investigation of an interval might include typing other available families or family members, typing additional markers in the interval, and carrying out further statistical analyses. This strategy is efficient in the number of genotypings required and focuses attention on regions most likely to harbor a disease gene with a substantial impact on disease risk, while resulting in the pursuit of a manageable number of false-positive linkage results. Modification may be required if insufficient ASPs are available or if families come from a significantly admixed population.

Affected-Sib-Pair Interval Mapping and Exclusion for Complex Genetic Traits:

Abstract: We describe an extension of Risch’s [(1990a,b) Am J Hum Genet 46:222-228, 229-2411 method of linkage detection and exclusion for complex genetic traits. The method uses interval mapping to infer disease locus identity-by-descent (IBD) sharing for affected sib pairs (ASPs) based on marker information for the ASP and other genotyped family members. The method is likelihood based, and makes use of Risch’s parameterization in terms of recurrence risk ratios for relatives. We describe specific linkage detection and exclusion tests for use as genome screening tools to prioritize genomic regions for further study. We also examine issues of optimal study design. We advocate initially typing a large panel of ASPs (and no additional family members) with a map of genetic markers evenly spaced at 10-20-cM intervals. We recommend a screening procedure that 1) investigates further all regions with maximum lod scores greater than 1 and 2) excludes from consideration those regions that result in lod scores less than -2 at the smallest genetic effect that is viewed as important to detect. Further investigation of an interval might include typing other available families or family members, typing additional markers in the interval, and carrying out further statistical analyses. This strategy is efficient in the number of genotypings required and focuses attention on regions most likely to harbor a disease gene with a substantial impact on disease risk, while resulting in the pursuit of a manageable number of false-positive linkage results. Modification may be required if insufficient ASPs are available or if families come from a significantly admixed population. 0 1996 Wiley-Liss, Inc.

Selected locus and multiple panel models for radiation hybrid mapping.

Abstract: We develop two new types of models for whole-genome radiation hybrid mapping using the general multipoint framework. The first, selected locus models, are appropriate for mapping markers in the region of a selectable locus that was used in creation of the hybrids. The models allow for strong retention of the selectable locus, with retention rates decreasing with increasing distance from the selectable locus in both directions. We illustrate the application of these models with 10 chromosome 17 sequence-tagged site (STS) markers and the thymidine kinase (TK) locus typed on a whole-genome hybrid panel in which TK was used in the selection process. The second set of models are appropriate when loci typed on two or more independent panels are to be used to build maps. Maps can be built assuming interlocus distances are independent or proportional between the panels, and the hypothesis of proportional distances can be tested. We illustrate the application of these models by using 27 chromosome 21 STS markers typed on two hybrid panels created with radiation doses of approximately 10,000 and approximately 50,000 Rads.

Identifying marker typing incompatibilities in linkage analysis.

Abstract: A common problem encountered in linkage analyses is that execution of the computer program is halted because of genotypes in the data that are inconsistent with Mendelian inheritance. Such inconsistencies may arise because of pedigree errors or errors in typing. In some cases, the source of the inconsistencies is easily identified by examining the pedigree. In others, the error is not obvious, and substantial time and effort are required to identify the responsible genotypes. We have developed two methods for automatically identifying those individuals whose genotypes are most likely the cause of the inconsistencies. First, we calculate the posterior probability of genotyping error for each member of the pedigree, given the marker data on all pedigree members and allowing anyone in the pedigree to have an error. Second, we identify those individuals whose genotypes could be solely responsible for the inconsistency in the pedigree. We illustrate these methods with two examples: one a pedigree error, the second a genotyping error. These methods have been implemented as a module of the pedigree analysis program package MENDEL.

Linkage Study of Best‘s Vitelliform Macular Dystrophy (VMD2) in a Large North American Family

Abstract: Best’s vitelliform macular dystrophy (VMD2) is an autosomal dominant retinal dystrophy for which the underlying biochemical cause is unknown. We used 11 genetic markers in the vicinity of the VMD2 gene in our study of a large North American family in which macular dystrophy characteristics overlap the broad definition of Best’s disease. Significant evidence for linkage was found for markers D11S956 (ao‘= 5.88, Θ = 0.04) and FCER1B (ao‘ = 4.31, Θ = 0.00). Recombination events localized the disease gene to the 5-cM interval D11S956-UGB, a genetic inclusion interval that substantially overlaps the VMD2 inclusion interval defined by recombinants at FCER1B and UGB observed by other research groups. The resulting exclusion of ROM 1 from the genetic inclusion interval eliminates ROM1 defects as a possible cause of the disease in this family. Linkage studies of many families, including those that share most but not all features with classical Best’s disease, will be needed to properly evaluate genetic heterogeneity and the range of phenotypic variation that can result from VMD2 defects.

Lod score curves for phase-unknown matings

Abstract: For a phase-unknown nuclear family, we show that the likelihood and lod score are unimodal, and we describe conditions under which the maximum occurs at recombination fraction theta = 0, theta = 1/2, and 0 < theta < 1/2. These simply stated necessary and sufficient conditions seem to have escaped the notice of previous statistical geneticists.