Use of MRI in genetic studies of endometriosis.
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Endometriosis↗
Biomedical subjects
D E Weeks
Publications and source records attributed to D E Weeks.
Analysis of bipolar disorder using affected relatives.
We have analyzed the GAW10 data from several studies of bipolar affective disorder (BPAD) using the software packages SimIBD and SIMWALK2. SimIBD implements a simulation-based affected-pedigree-member (APM) statistic, called SimAPM, as well as an APM-like statistic, also called SimIBD, that measures identical-by-descent (IBD) sharing. SIMWALK2 uses Markov chain Monte Carlo techniques to compute several IBD-based statistics on the degree of marker-allele clustering among all affected relatives. We have found no strong evidence of linkage to either chromosome 5 or 18. However, we did find that several markers showed p-values less than 0.01 and may deserve further study.
Alleles↗
Analysis of a complex oligogenic disease.
Our analysis of GAW10 problem 2 data set consisted of linear regression analysis followed by linkage analysis. The linear regression analysis allowed some exploration of the relationships between the quantitative variables. Furthermore, it isolated some of the components of certain quantitative variables that were not due to a major locus and facilitated the linkage analysis that followed. For the linkage analysis, we used MAPMAKER/SIBS and the SIBPAL program from S.A.G.E. We found linkage of Q4 to chromosome 8. Analysis using the residuals of Q1 and Q3 showed linkage to chromosomes 5 and 4, respectively.
Female↗
A linkage study across the T cell receptor A and T cell receptor B loci in families with rheumatoid arthritis.
OBJECTIVE: To examine whether the T cell receptor (TCR) A or TCRB loci exhibit linkage with disease in multiplex rheumatoid arthritis (RA) families. METHODS: A linkage study was performed in 184 RA families from the UK Arthritis and Rheumatism Council Repository, each containing at least 1 affected sibpair. The microsatellites D14S50, TCRA, and D14S64 spanning the TCRA locus and D7S509, Vbeta6.7, and D7S688 spanning the TCRB locus were used as DNA markers. The subjects were genotyped using a semiautomated polymerase chain reaction-based method. Two-point and multipoint linkage analyses were performed. RESULTS: Nonparametric single-marker likelihood odds (LOD) scores were 0.49 (P = 0.07) for D14S50, 0.65 (P = 0.04) for TCRA, 0.07 (P = 0.29) for D14S64, 0.01 (P = 0.43) for D7S509, 0.0 (P = 0.50) for Vbeta6.7, and 0.0 (P = 0.50) for D7S688. By multipoint analysis, there was no evidence of linkage at TCRB (LOD score 0), and the maximum LOD score at the TCRA locus was 0.37 (at D14S50). The presence of a susceptibility locus (LOD score < -2.0) was excluded, with lambda > or = 1.8 at TCRA and > or = 1.4 at TCRB. CONCLUSION: These linkage studies provide no significant evidence of a major germline-encoded TCRA or TCRB component of susceptibility to RA.
Alleles↗
Comparison of nonparametric statistics for detection of linkage in nuclear families: single-marker evaluation.
We have evaluated 23 different statistics, from a total of 10 popular software packages for model-free linkage analysis of nuclear-family data, by applying them to single-marker data simulated under several two-locus disease models. The statistics that we examined fall into two broad categories: (1) those that test directly for increased identity-by-state or identity-by-descent sharing (by use of the programs APM, Genetic Analysis System [GAS] SIBSTATE and SIBDES, SAGE SIBPAL, ERPA, SimIBD, and Genehunter NPL) and (2) those that are based on likelihood-ratio tests and that report LOD scores (by use of the programs Splink, SIBPAIR, Mapmaker/Sibs, ASPEX, and GAS SIBMLS). For each of eight two-locus disease models, we analyzed six data sets; the first three data sets consisted of two-child families with both sibs affected and zero, one, or both parents typed, whereas the other three data sets consisted of four-child families with at least two affected sibs and zero, one, or both parents typed. We report false-positive rates, overall rank by power, and the power for each statistic. We give rough recommendations regarding which programs provide the most powerful tests for linkage, as well as the programs to be avoided under certain conditions. For the likelihood-ratio-based statistics, we examined the effects of various treatments of sibships with multiple affected individuals. Finally, we explored the use of some simple two-of-three composite statistics and found that such tests are of only marginal benefit over the most powerful single statistic.
Adult↗
True and false positive peaks in genomewide scans: applications of length-biased sampling to linkage mapping.
Disease-susceptibility loci are now being mapped via genomewide scans in which a linkage statistic is computed at each of a large number of markers. Such disease-susceptibility loci may be identified via a peak in the test statistic when the latter is plotted against the genetic map. In this paper we establish, by appealing to renewal theory, that true positive peaks are expected to be longer than false positive peaks. These results are verified by a realistic simulation of a genomewide linkage study based on the affected-sib-pair design. Since longer peaks are more likely to contain a gene of interest than are shorter peaks, these differences may aid in linkage mapping, justifying assignment of lower priority to shorter peaks. However, since these differences are generally small, statistics based on both peak length and height may not be much more powerful than those based on height alone. The results presented here also provide a theoretical framework for methods that use the length of shared haplotypes in populations to map disease genes.
Chromosome Mapping↗
Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10.
Hypertension is a significant risk factor for heart attack and stroke and represents a major public health burden because of its high prevalence (e.g. 15-20% of the European and American populations). Although blood pressure is known to have a strong genetic determination, the genes responsible for susceptibility to essential hypertension are mostly unknown. Loci involved in blood pressure regulation have been found by linkage in experimental hereditary hypertensive rat strains, but their relationship to human hypertension has not been extensively investigated. One of the principal blood pressure loci has been mapped to rat chromosome 10 and we have undertaken an investigation of the homologous region on human chromosome 17 in familial essential hypertension. Affected sib-pair analysis and parametric analysis with ascertainment correction gave significant evidence of linkage ( P <0.0001 in some analyses) near two closely linked microsatellite markers, D17S183 and D17S934, that reside 18 cM proximal to the ACE locus in the homology region. Our results indicate that chromosome 17q could contain a susceptibility locus for human hypertension and show that comparative mapping may be a useful approach for identification of such loci in humans.
Animals↗
Nonparametric simulation based linkage statistics for general pedigrees.
A common strategy for testing for linkage without posing a disease model is to test for increased marker similarity among the affected pedigree members. We developed a simulation based statistic, SimIBD, which measures marker similarity in terms of identity-by-descent (IBD) when it can be determined whether or not the alleles are IBD, and in terms of the probability of the alleles being IBD when it cannot be determined. The SimIBD statistic is not only more powerful than its precursor, the affected-pedigree-member (APM) method, but it is also less sensitive to the misspecification of marker allele frequencies.
Alleles↗
A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel's syndrome.
Terminal keratinocyte differentiation involves coordinated expression of several functionally interdependent genes, many of which have been mapped to the epidermal differentiation complex (EDC) on chromosome 1q21. We have identified linkage of Vohwinkel's syndrome in an extended pedigree to markers flanking the EDC region with a maximum multipoint lod score of 14.3. Sequencing of the loricrin gene revealed an insertion that shifts the translation frame of the C-terminal Gly- and Gln/Lys-rich domains, and is likely to impair cornification. Our findings provide the first evidence for a defect in an EDC gene in human disease, and disclose novel insights into perturbations of cornified cell envelope formation.
Amino Acid Sequence↗
Influence of the HLA-DRB1 locus on susceptibility and severity in rheumatoid arthritis.
We examined HLA-DR genotype risk in 288 patients with rheumatoid arthritis who were carefully categorized for disease severity. Five hundred ethnically-matched bone-marrow donors were controls. A hierarchy of positive allelic associations was noted with DRB1*0401 (p < 10(-38), *0404,8 (p < 10(-43), *0405 (p < 10(-8), *10 (p < 10(-3) and *0101,2 (p < 10(-2), while DRB1*0403 was negatively associated (p = 0.02). The DRB1 genotype relative risks (and 95% CIs) for RA were: *0404,5,8/*0404,5,8 = 36.2 (15-87), *0401/*0404,5,8 = 31.3 (18-55), *401/*0401 = 18.8 (11-35), *0101,2/*0404,5,8 = 6.0 (2-14), *0101,2/*0401 = 6.4 (3-12), *0101,2/*0101,2 = 1.3 (0.3-6), *10/*0404,5,8 = 27.8 (5-148), *10/*0401 = 20.8 (5-89), *10/*0101,2 = 22.3 (5-96), *0404,5,8/DRX = 5.0 (3-8), *0401/DRX = 4.7 (3-7), *0101,2/DRX = 2.3 (1.4-4), *10/DRX = 3.4 (0.8-14). No significant correlation of DRB1 genotypes was found with severity of RA as judged by nodules or articular erosions.
Arthritis, Rheumatoid↗
Nonparametric simulation-based statistics for detecting linkage in general pedigrees.
We present here four nonparametric statistics for linkage analysis that test whether pairs of affected relatives share marker alleles more often than expected. These statistics are based on simulating the null distribution of a given statistic conditional on the unaffecteds' marker genotypes. Each statistic uses a different measure of marker sharing: the SimAPM statistic uses the simulation-based affected-pedigree-member measure based on identity-by-state (IBS) sharing. The SimKIN (kinship) measure is 1.0 for identity-by-descent (IBD) sharing, 0.0 for no IBD status sharing, and the kinship coefficient when the IBD status is ambiguous. The simulation-based IBD (SimIBD) statistic uses a recursive algorithm to determine the probability of two affecteds sharing a specific allele IBD. The SimISO statistic is identical to SimIBD, except that it also measures marker similarity between unaffected pairs. We evaluated our statistics on data simulated under different two-locus disease models, comparing our results to those obtained with several other nonparametric statistics. Use of IBD information produces dramatic increases in power over the SimAPM method, which uses only IBS information. The power of our best statistic in most cases meets or exceeds the power of the other nonparametric statistics. Furthermore, our statistics perform comparisons between all affected relative pairs within general pedigrees and are not restricted to sib pairs or nuclear families.
Algorithms↗
DNA profile match probabilities in a subdivided population: when can subdivision be ignored?
Li and Chakravarti [Li, C.C. & Chakravarti, A. (1994) Hum. Hered. 44, 100-109] compared the probability (MO) of a random match between the two DNA profiles of a pair of individuals drawn from a random-mating population to the probability (MF) of the match between a pair of random individuals drawn from a subdivided population. The level of heterogeneity in this subdivided population is measured by the parameter F, where there is no subdivision when F = 0 and increasing values of F indicate increasing subdivisions. Li and Chakravarti concluded that it is conservative to use the match probability MO, which is derived under the assumption that the two individuals are drawn from a homogeneous random-mating population without subdivision. However, MO may not be always greater than MF, even for biologically reasonable values of F. We explore here those mathematical conditions under which MO is less than MF, and we find that MO is not conservative mainly when there is an allele with a much higher frequency than all the other alleles. When empirical data for both variable number of tandem repeat (VNTR) and short tandem repeat (STR) systems are evaluated, we find that in the majority of cases MO represents a conservative probability of a match, and so the subdivision of human populations may usually be ignored for a random match, although not, of course, for relatives. Loci for which MO is not conservative should be avoided for forensic inference.
Alleles↗
A high-resolution genetic linkage map of the pericentromeric region of the human X chromosome.
We generated a high-resolution genetic linkage map of the pericentromeric region of the human X chromosome from approximately Xp11.4 to Xq22. This map contains 41 loci defined by 50 marker systems genotyped in the CEPH families. For this study we have generated 3 new markers (DXS1689, DXS1690, and DXS159) and 2 new primer sequences for previously described markers (PGK1P1 and AR). Using two different mapping algorithms based on genotype data alone, we developed two well-supported framework maps containing 15 and 18 markers with average interval sizes of 2.7 and 1.7 cM. The 18 marker map is [DXS426, PFC]-2.0-DXS255-1.2-DXS991-1.6-AR-1.3-DXS153-2.0-DX S106-1.5-DXS132-0.6- DXS1690-0.8-DXS453-1.4-DXS559-1.5-[PGK1, DXS56]-0.6-DXS1002-1.8-DXYS1X-2.0-DXS3-7.5-DX S458-2.8-DXS454, where the distance between adjacent loci is in centimorgans. As a third approach, we used physical mapping data to define bins for markers; this approach permitted us to place 26 markers on our framework map. Finally, we constructed a map based on the physical order of 35 markers from the fifth international workshop on human X chromosome mapping. A comparison of the physical and genetic maps indicates a relationship of 2 cM per megabase in this region, with two regions of reduced recombination. The first is around the centromere (DXZ1), and the second is in the region around PGK1 (DXS441 to DXS995). Our maps should aid in the fine-mapping of the many disease loci that localize to this region of the X chromosome.
Algorithms↗
The gene for hereditary progressive dystonia with marked diurnal fluctuation maps to chromosome 14q.
Hereditary progressive dystonia with marked diurnal fluctuation (HPD) is a childhood-onset, postural dystonia that is characterized by marked diurnal fluctuation and a dramatic response to levodopa. Recently, the gene for dopa-responsive dystonia (DRD), an autosomal dominant dystonia showing similarly marked response to levodopa, has been mapped to chromosome 14q. Since HPD and DRD share many clinical characteristics, we have analyzed microsatellite polymorphisms in the region of the DRD locus and obtained a maximal lod score of 2.0 at D14S52 without obligate recombination events in the affected individuals. The results strongly suggest that HPD and DRD are to be caused by mutations in the same gene on the long arm of chromosome 14.
Chromosome Mapping↗
Polygenic disease: methods for mapping complex disease traits.
Improved genotyping technology has made it feasible to use a genetic approach to map genes involved in the etiology of common human diseases. We discuss here recent developments in several different statistical approaches to linkage analysis of these traits, including affected-sib-pair methods, the affected-pedigree-member method, regressive models and linkage-disequilibrium-based approaches. We discuss advantages and disadvantages of the various approaches, as well as factors influencing study design and the ability to detect loci. Statistical methodology in this area is advancing rapidly and will help enable the mapping and cloning of loci involved in susceptibility to common multifactorial diseases.
Autistic Disorder↗
The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance.
As genetic marker maps have improved, multipoint linkage analysis has become a crucial part of all disease mapping studies. Paradoxically, multipoint lod scores become increasingly difficult to compute, particularly as the numbers of markers, marker alleles and untyped people increase. We have solved this problem by using a novel set-recording scheme to recode each person's genotype and 'fuzzy inheritance' to infer transmission probabilities. Our approach is implemented in a memory-efficient computer program, VITESSE, for extremely rapid computation of exact multipoint likelihoods. VITESSE enables fast and precise multipoint mapping of disease loci with highly polymorphic markers.
Algorithms↗
Computer programs for multilocus haplotyping of general pedigrees.
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Algorithms↗
Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene.
In the course of a systematic genomic survey, 22 manic-depressive (bipolar) families were examined for linkage to 11 chromosome 18 pericentromeric marker loci, under dominant and recessive models. Overall logarithm of odds score analysis for the pedigree series was not significant under either model, but several families yielded logarithm of odds scores consistent with linkage under dominant or recessive models. Affected sibling pair analysis of these data yielded evidence for linkage (P < 0.001) at D18S21. Affected pedigree member analysis also suggests linkage, with multilocus results for five loci giving P < 0.0001 and P = 0.0007 for weighting functions f(p) = 1 and 1/square root p, respectively, where p is the allele frequency. These results imply a susceptibility gene in the pericentromeric region of chromosome 18, with a complex mode of inheritance. Two plausible candidate genes, a corticotropin receptor and the alpha subunit of a GTP binding protein, have been localized to this region.
Bipolar Disorder↗