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American Journal of Human Genetics May 1992Linkage analyses were performed in 11 families with X-linked Menkes disease. In each family more than one affected patient had been diagnosed. Forty informative meioses...
Linkage analyses were performed in 11 families with X-linked Menkes disease. In each family more than one affected patient had been diagnosed. Forty informative meioses were tested using 11 polymorphic DNA markers. From two-point linkage analyses high lod scores are seen for DXS146 (pTAK-8; maximal lod score 3.16 at recombination fraction [theta] = .0), for DXS1 (p-8; maximal lod score 3.44 at theta = .0), for PGK1 (maximal lod score 2.48 at theta = .0), and for DXS3 (p19-2; maximal lod score 2.90 at theta = .0). This indicates linkage to the pericentromeric region. Multilocus linkage analyses of the same data revealed a peak for the location score between DXS146(pTAK-8) and DXYS1X(pDP34). The most likely location is between DXS159 (cpX289) and DXYS1X(pDP34). Odds for this location relative to the second-best-supported region, between DXS146(pTAK-8) and DXS159 (cpX289), are better than 74:1. Visualization of individual recombinant X chromosomes in two of the Menkes families showed the Menkes locus to be situated between DXS159(cpX289) and DXS94(pXG-12). Combination of the present results with the reported absence of Menkes symptoms in male patients with deletions in Xq21 leads to the conclusion that the Menkes locus is proximal to DXSY1X(pDP34) and located in the region Xq12 to Xq13.3.
Topics: Female; Genetic Linkage; Genetic Markers; Humans; Lod Score; Male; Menkes Kinky Hair Syndrome; Pedigree; Recombination, Genetic; X Chromosome
PubMed: 1570830
DOI: No ID Found -
American Journal of Human Genetics Oct 1995To investigate the genetic component of multifactorial diseases such as type 1 (insulin-dependent) diabetes mellitus (IDDM), models involving the joint action of several...
To investigate the genetic component of multifactorial diseases such as type 1 (insulin-dependent) diabetes mellitus (IDDM), models involving the joint action of several disease loci are important. These models can give increased power to detect an effect and a greater understanding of etiological mechanisms. Here, we present an extension of the maximum lod score method of N. Risch, which allows the simultaneous detection and modeling of two unlinked disease loci. Genetic constraints on the identical-by-descent sharing probabilities, analogous to the "triangle" restrictions in the single-locus method, are derived, and the size and power of the test statistics are investigated. The method is applied to affected-sib-pair data, and the joint effects of IDDM1 (HLA) and IDDM2 (the INS VNTR) and of IDDM1 and IDDM4 (FGF3-linked) are assessed with relation to the development of IDDM. In the presence of genetic heterogeneity, there is seen to be a significant advantage in analyzing more than one locus simultaneously. Analysis of these families indicates that the effects at IDDM1 and IDDM2 are well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 follow a heterogeneity model.
Topics: Diabetes Mellitus, Type 1; Humans; Likelihood Functions; Lod Score; Models, Genetic
PubMed: 7573054
DOI: No ID Found -
American Journal of Human Genetics Jun 1999One of the major challenges facing genome-scan studies to discover disease genes is the assessment of the genomewide significance. The assessment becomes particularly...
One of the major challenges facing genome-scan studies to discover disease genes is the assessment of the genomewide significance. The assessment becomes particularly challenging if the scan involves a large number of markers collected from a relatively small number of meioses. Typically, this assessment has two objectives: to assess genomewide significance under the null hypothesis of no linkage and to evaluate true-positive and false-positive prediction error rates under alternative hypotheses. The distinction between these goals allows one to formulate the problem in the well-established paradigm of statistical hypothesis testing. Within this paradigm, we evaluate the traditional criterion of LOD score 3.0 and a recent suggestion of LOD score 3.6, using the Monte Carlo simulation method. The Monte Carlo experiments show that the type I error varies with the chromosome length, with the number of markers, and also with sample sizes. For a typical setup with 50 informative meioses on 50 markers uniformly distributed on a chromosome of average length (i.e., 150 cM), the use of LOD score 3.0 entails an estimated chromosomewide type I error rate of.00574, leading to a genomewide significance level >.05. In contrast, the corresponding type I error for LOD score 3.6 is.00191, giving a genomewide significance level of slightly <.05. However, with a larger sample size and a shorter chromosome, a LOD score between 3.0 and 3.6 may be preferred, on the basis of proximity to the targeted type I error. In terms of reliability, these two LOD-score criteria appear not to have appreciable differences. These simulation experiments also identified factors that influence power and reliability, shedding light on the design of genome-scan studies.
Topics: Chromosome Mapping; False Negative Reactions; False Positive Reactions; Genetic Diseases, Inborn; Humans; Lod Score; Monte Carlo Method
PubMed: 10330362
DOI: 10.1086/512072 -
Methods (San Diego, Calif.) Feb 2011In 1999 a meeting took place at the Jackson Laboratory, a large mouse research centre in Bar Harbor, Maine, to consider the value of systematically collecting phenotypes... (Review)
Review
In 1999 a meeting took place at the Jackson Laboratory, a large mouse research centre in Bar Harbor, Maine, to consider the value of systematically collecting phenotypes on inbred strains of mice (Paigen and Eppig (2000) [1]). The group concluded that cataloguing the extensive phenotypic diversity present among laboratory mice, and in particular providing the research community with data from cohorts of animals, phenotyped according to standardized protocols, was essential if we were to take advantage of the possibilities of mouse genetics. Beginning with the collection of basic physiological, biochemical and behavioral data on nine commonly used inbred strains, the project has expanded so that by the beginning of 2010 data for 178 strains had been collected, with 105 phenotype projects yielding over 2000 different measurements (Bogue et al. (2007) [2].
Topics: Animals; Chromosome Mapping; Crosses, Genetic; Genome; Inbreeding; Lod Score; Mice; Mice, Inbred Strains; Phenotype; Quantitative Trait Loci
PubMed: 20643209
DOI: 10.1016/j.ymeth.2010.07.007 -
Genetic Epidemiology Jul 2001Multipoint lod scores are typically calculated for a grid of locus positions, moving the putative disease locus across a fixed map of genetic markers. Changing the order...
Multipoint lod scores are typically calculated for a grid of locus positions, moving the putative disease locus across a fixed map of genetic markers. Changing the order of a set of markers and/or the distances between the markers can make a substantial difference in the resulting lod score curve and the location and height of its maximum. The typical approach of using the best maximum likelihood marker map is not easily justified if other marker orders are nearly as likely and give substantially different lod score curves. To deal with this problem, we propose three weighted multipoint lod score statistics that make use of information from all plausible marker orders. In each of these statistics, the information conditional on a particular marker order is included in a weighted sum, with weight equal to the posterior probability of that order. We evaluate the type 1 error rate and power of these three statistics on the basis of results from simulated data, and compare these results to those obtained using the best maximum likelihood map and the map with the true marker order. We find that the lod score based on a weighted sum of maximum likelihoods improves on using only the best maximum likelihood map, having a type 1 error rate and power closest to that of using the true marker order in the simulation scenarios we considered.
Topics: Bias; Chromosome Mapping; Data Interpretation, Statistical; Genetic Diseases, Inborn; Genetic Markers; Humans; Likelihood Functions; Lod Score; Models, Genetic; Pedigree
PubMed: 11443732
DOI: 10.1002/gepi.1016 -
Arthritis and Rheumatism Aug 2004Studies investigating hand osteoarthritis (OA) as a single entity have not shown strong linkage of the disease with any chromosomal sites. We undertook this study to...
OBJECTIVE
Studies investigating hand osteoarthritis (OA) as a single entity have not shown strong linkage of the disease with any chromosomal sites. We undertook this study to test our hypothesis that phenotypes of hand OA may show stronger linkage than has been shown for overall hand OA.
METHODS
We performed a factor analysis on measures of hand OA to determine patterns of disease. Using the joint regions identified by this analysis, we performed a genome-wide linkage analysis for OA susceptibility loci using 426 original cohort members and 790 offspring cohort members in 267 pedigrees. Radiographic OA features evaluated included the Kellgren/Lawrence score, osteophytes, and joint space narrowing. Prior to linkage analysis, standardized residuals were computed from regression analysis of each phenotype on age. This was performed separately for each sex and cohort. The variance component model (GeneHunter) was then applied to the normalized scores of the residuals of both sexes and cohorts.
RESULTS
There was evidence suggestive of linkage (logarithm of odds [LOD] score >1.5) at 16 sites. Four of these sites had LOD scores >3.0. Two of these sites (identified in the full sample) included a linkage region for OA of the distal interphalangeal (DIP) joint on chromosome 7 (155 cM; LOD score 3.06) and a linkage region for OA of the first carpometacarpal (CMC) joint on chromosome 15 (81 cM; LOD score 6.25). The other 2 sites (identified in women) included a linkage region for OA of the DIP joint on chromosome 1 (202 cM; LOD score 3.03) and a linkage region for OA of the first CMC joint on chromosome 20 (4 cM; LOD score 3.74).
CONCLUSION
These data suggest that several chromosomes contain hand OA susceptibility genes and that a joint-specific approach may be more rewarding than a global approach to the genetics of hand OA. Further investigation of these regions is warranted using finer maps and other populations.
Topics: Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 20; Chromosomes, Human, Pair 7; Factor Analysis, Statistical; Genetic Linkage; Genetic Predisposition to Disease; Hand; Humans; Lod Score; Osteoarthritis; Radiography
PubMed: 15334462
DOI: 10.1002/art.20445 -
American Journal of Medical Genetics Jan 1995Darier disease is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion. Recent data have provided evidence for linkage of the Darier...
Darier disease is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion. Recent data have provided evidence for linkage of the Darier disease locus to 12q23-24.1 in British families. We have carried out linkage analysis using the 12q markers D12S58, D12S84, D12S79, D12S86, PLA2, and D12S63 in 6 Canadian families. Pairwise linkage analysis generated positive lod scores at all 6 markers at various recombination fractions, and each family showed positive lod scores with more than one marker. The peak lod score in the multipoint analysis (Zmax) was 5.5 in the interval between markers D12S58 and D12S84. These positive lod scores in North American families of varied European ancestry confirm the location of the Darier disease gene, and suggest genetic homogeneity. The future identification and sequencing of the gene responsible for Darier disease should lead to improved understanding of the disease and of keratinocyte adhesion in general.
Topics: Adolescent; Adult; Chromosome Mapping; Chromosomes, Human, Pair 12; Darier Disease; Female; Genes, Dominant; Genetic Linkage; Humans; Keratins; Lod Score; Male; Middle Aged; Pedigree
PubMed: 7537018
DOI: 10.1002/ajmg.1320550312 -
American Journal of Human Genetics Aug 2003Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the...
Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.
Topics: Adolescent; Adult; Age of Onset; Aged; Australia; Child; Chromosome Mapping; Chromosomes, Human, Pair 1; Humans; Lod Score; Melanoma; Middle Aged; Pedigree; Skin Neoplasms
PubMed: 12844286
DOI: 10.1086/377140 -
American Journal of Human Genetics Sep 1999Several methods have been proposed for linkage analysis of complex traits with unknown mode of inheritance. These methods include the LOD score maximized over disease... (Comparative Study)
Comparative Study
Several methods have been proposed for linkage analysis of complex traits with unknown mode of inheritance. These methods include the LOD score maximized over disease models (MMLS) and the "nonparametric" linkage (NPL) statistic. In previous work, we evaluated the increase of type I error when maximizing over two or more genetic models, and we compared the power of MMLS to detect linkage, in a number of complex modes of inheritance, with analysis assuming the true model. In the present study, we compare MMLS and NPL directly. We simulated 100 data sets with 20 families each, using 26 generating models: (1) 4 intermediate models (penetrance of heterozygote between that of the two homozygotes); (2) 6 two-locus additive models; and (3) 16 two-locus heterogeneity models (admixture alpha = 1.0,.7,.5, and.3; alpha = 1.0 replicates simple Mendelian models). For LOD scores, we assumed dominant and recessive inheritance with 50% penetrance. We took the higher of the two maximum LOD scores and subtracted 0.3 to correct for multiple tests (MMLS-C). We compared expected maximum LOD scores and power, using MMLS-C and NPL as well as the true model. Since NPL uses only the affected family members, we also performed an affecteds-only analysis using MMLS-C. The MMLS-C was both uniformly more powerful than NPL for most cases we examined, except when linkage information was low, and close to the results for the true model under locus heterogeneity. We still found better power for the MMLS-C compared with NPL in affecteds-only analysis. The results show that use of two simple modes of inheritance at a fixed penetrance can have more power than NPL when the trait mode of inheritance is complex and when there is heterogeneity in the data set.
Topics: Gene Frequency; Genes, Dominant; Genes, Recessive; Genetic Diseases, Inborn; Genetic Linkage; Genotype; Humans; Likelihood Functions; Lod Score; Models, Genetic; Penetrance; Sensitivity and Specificity; Statistics, Nonparametric
PubMed: 10441591
DOI: 10.1086/302536 -
Journal of Medical Genetics Oct 1983Linkage analysis of 28 genetic markers was undertaken in 108 subjects from 11 families with well-documented, classic, peripheral neurofibromatosis. Fifty-four persons... (Comparative Study)
Comparative Study
Linkage analysis of 28 genetic markers was undertaken in 108 subjects from 11 families with well-documented, classic, peripheral neurofibromatosis. Fifty-four persons were affected in one four-generation family, seven three-generation families, and three two-generation families. Lod scores were calculated using the standard LIPED programme for 49 combinations of theta male and theta female from 0.01 to 0.50. Lod scores excluded close linkage with 16 markers, including most tested on chromosome 1 and HLA on chromosome 6, and were inconclusive for 12 markers, including the secretor locus, closely linked to myotonic dystrophy. Analysis of five informative families resulted in a lod score of +2.2 for close linkage with GC on chromosome 4. However, the lod score for GC in the one additional informative family was negative, so that the final interpolated maximum was Z = 0.89 for theta male = 0.03, theta female = 0.28. Further studies are needed to evaluate this suggestion of linkage and possible genetic heterogeneity.
Topics: Carrier Proteins; Chromosomes, Human, 4-5; Female; Genetic Linkage; Genetic Markers; Humans; Lod Score; Male; Neurofibromatosis 1; Vitamin D-Binding Protein
PubMed: 6417334
DOI: 10.1136/jmg.20.5.334