-
Journal of Bone and Mineral Research :... Mar 2003Gnathodiaphyseal dysplasia (GDD) is a syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of jawbones. Although some cases...
Gnathodiaphyseal dysplasia (GDD) is a syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of jawbones. Although some cases of this syndrome exist in families with autosomal dominant inheritance, the underlying gene has never been identified. We analyzed a large four-generation family with GDD by linkage analysis using genomic DNA from nine affected and six nonaffected family members. A genome-wide search using a set of highly polymorphic microsatellite markers showed evidence for linkage to chromosome 11p14.3-15.1. Two-point linkage analysis of microsatellite markers spanning this locus resulted in a maximum logarithm of odds (LOD) score of 2.70 with a recombination fraction (theta) of 0 at D11S1755, D11S1759, and D11S915, and a maximum LOD score of 3.01 at D11S4114 was obtained in multipoint linkage analysis. Haplotype analysis detected no recombination between GDD and six closely linked markers (D11S928, D11S1755, D11S4114, D11S1759, D11S915, and D11S929) and established the candidate interval of 8.7 cM on chromosome 11p for GDD. Although GDD has been considered to be a variation of osteogenesis imperfecta (MIM 166260), our results indicate that this syndrome is a new and distinct disease entity from other systemic bone diseases. Furthermore, these genetic markers are useful for presymptomatic diagnosis of GDD in some families and for identification of the GDD gene.
Topics: Bone Diseases; Chromosome Mapping; Chromosomes, Human, Pair 11; Female; Genes, Dominant; Genetic Linkage; Humans; Jaw Diseases; Lod Score; Male; Pedigree
PubMed: 12619924
DOI: 10.1359/jbmr.2003.18.3.413 -
American Journal of Human Genetics Jun 1998There is genetic predisposition associated with >=10% of all cancer of the prostate (CaP). By means of a genomewide search on a selection of 47 French and German...
There is genetic predisposition associated with >=10% of all cancer of the prostate (CaP). By means of a genomewide search on a selection of 47 French and German families, parametric and nonparametric linkage (NPL) analysis allowed identification of a locus, on chromosome 1q42.2-43, carrying a putative predisposing gene for CaP (PCaP). The primary localization was confirmed with several markers, by use of three different genetic models. We obtained a maximum two-point LOD score of 2.7 with marker D1S2785. Multipoint parametric and NPL analysis yielded maximum HLOD and NPL scores of 2.2 and 3.1, respectively, with an associated P value of . 001. Homogeneity analysis with multipoint LOD scores gave an estimate of the proportion of families with linkage to this locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, the 9/47 families with early-onset CaP at age <60 years gave multipoint LOD and NPL scores of 3.31 and 3.32, respectively, with P = .001.
Topics: Age of Onset; Chromosome Mapping; Chromosomes, Human, Pair 1; Genetic Heterogeneity; Genetic Linkage; Genetic Predisposition to Disease; Genotype; Humans; Lod Score; Male; Microsatellite Repeats; Prostatic Neoplasms
PubMed: 9585607
DOI: 10.1086/301879 -
Human Genomics Nov 2003There is now a wide choice of software available for linkage analysis. The most well known packages are briefly reviewed here. The package with the most extensive range... (Review)
Review
There is now a wide choice of software available for linkage analysis. The most well known packages are briefly reviewed here. The package with the most extensive range of analyses is GENEHUNTER, but for many of its functions there are other programs with better performance. These include FASTLINK and VITESSE for parametric analysis ALLEGRO and MERLIN for non-parametric analysis and SOLAR for variance components analysis. The computational limits of current approaches can be improved with SIMWALK2 and the promising new SUPERLINK program. Directions for future work include improved user interfaces and consensus formats for data input and exchange.
Topics: Algorithms; Computer Systems; Data Collection; Genes, Recessive; Genetic Linkage; Genetic Markers; Haplotypes; Humans; Lod Score; Microsatellite Repeats; Pedigree; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable; Regression Analysis; Software
PubMed: 15601534
DOI: 10.1186/1479-7364-1-1-63 -
Genomics Aug 1989A total of 63 families with Huntington disease (HD) were examined for linkage between HD and G8 (D4S10). The families included 57 Caucasian, four Black American, and two...
A total of 63 families with Huntington disease (HD) were examined for linkage between HD and G8 (D4S10). The families included 57 Caucasian, four Black American, and two Japanese. The combined maximum lod score was 87.69 at theta = 0.04 (99% confidence interval 0.018-0.071). The maximum frequency of recombination was 0.03 in males and 0.05 in females. Fifty-seven families gave positive lod scores; five small families gave mildly negative lod scores. The maximum likelihood estimate of alpha, the proportion of linked loci, was 1.0 with a lower 99% confidence interval of 0.88. These data suggest that there is only one HD locus, although a second rare locus cannot be ruled out.
Topics: Computers; Female; Genetic Linkage; Genetic Markers; Haplotypes; Humans; Huntington Disease; Lod Score; Male; Polymorphism, Restriction Fragment Length; Recombination, Genetic
PubMed: 2571579
DOI: 10.1016/0888-7543(89)90062-1 -
Human Heredity 2008To detect the positions of disease loci, lod scores are calculated at multiple chromosomal positions given trait and marker data on members of pedigrees. Exact lod score...
To detect the positions of disease loci, lod scores are calculated at multiple chromosomal positions given trait and marker data on members of pedigrees. Exact lod score calculations are often impossible when the size of the pedigree and the number of markers are both large. In this case, a Markov Chain Monte Carlo (MCMC) approach provides an approximation. However, to provide accurate results, mixing performance is always a key issue in these MCMC methods. In this paper, we propose two methods to improve MCMC sampling and hence obtain more accurate lod score estimates in shorter computation time. The first improvement generalizes the block-Gibbs meiosis (M) sampler to multiple meiosis (MM) sampler in which multiple meioses are updated jointly, across all loci. The second one divides the computations on a large pedigree into several parts by conditioning on the haplotypes of some 'key' individuals. We perform exact calculations for the descendant parts where more data are often available, and combine this information with sampling of the hidden variables in the ancestral parts. Our approaches are expected to be most useful for data on a large pedigree with a lot of missing data.
Topics: Computational Biology; Genetic Linkage; Genetic Markers; Haplotypes; Humans; Lod Score; Markov Chains; Meiosis; Pedigree; Recombination, Genetic
PubMed: 17934317
DOI: 10.1159/000109731 -
American Journal of Hematology Jul 2007Red blood cell (RBC) count and size are major criteria for evaluating anemia and related hematology disease diagnoses. While environmental factors influence RBC count...
Red blood cell (RBC) count and size are major criteria for evaluating anemia and related hematology disease diagnoses. While environmental factors influence RBC count (RBCC) and size, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), studies have indicated that each of these measures has a substantial genetic component. So far, no linkage analysis or genome scan has been reported. We carried out 10 cM genome-wide scans on RBCC, MCV, and MCH in a community-based Caucasian cohort, the Framingham Heart Study, using 325 pedigrees with 1,144 individuals genotyped and phenotyped. Using variance-component linkage methods, heritabilities were estimated as 56, 52, and 52% after covariate adjusted for RBCC, MCV, and MCH, respectively. For RBCC, we found a maximum LOD score of 3.2 on chromosome 19, 24 cM (7.0 Mbp). Near this region, there lie a few important candidate genes, including erythropoietin receptor and erythroid Krüppel-like factor. For linkage analyses for MCV and MCH, there were coinciding maximized LOD scores on chromosome 11, 9 cM (5.2 Mbp) with values of 3.8 and 3.6, respectively. Under the peak resides the hemoglobin beta cluster - several beta-like genes, which are important candidates for RBC size. In subsequent analyses, we excluded individuals with low MCV to assess the possible influence of beta-thalassemia carriers, and there continued to be evidence for linkage in the same region on chromosome 11p15 (LOD scores of 2.6 and 2.7 for MCV and MCH, respectively). For MCV, we also identified a new region on chromosome 6q24 with a LOD score of 2.9. These findings suggest that further studies are warranted to identify potential causal genetic variants for RBC size and count and related erythrocyte indices.
Topics: Adolescent; Adult; Aged; Cell Size; Child; Child, Preschool; Chromosomes, Human; Erythrocyte Count; Erythrocytes; Genome, Human; Health Surveys; Heart; Humans; Lod Score; Middle Aged
PubMed: 17211848
DOI: 10.1002/ajh.20868 -
Molecular Vision May 2009To evaluate the clinical, histopathologic, and genetic characteristics of a microphthalmia pedigree.
PURPOSE
To evaluate the clinical, histopathologic, and genetic characteristics of a microphthalmia pedigree.
METHODS
A five-generation Chinese family with microphthalmia was recruited. Clinical and histological examinations were performed in the affected patients and their family members. Cyrillic software was used to map the pedigree. Genomic DNA was extracted from peripheral blood, and linkage analysis was performed using short tandem repeat polymorphism markers. Two-point LOD scores were calculated using the MLINK program.
RESULTS
Microphthalmia was inherited in an autosomal dominant manner in this family. All nine affected members had hyperopia (mean: +8.00 diopters) and physiologically reduced axis oculi (mean: 19.29 mm) with a visual acuity of less than 0.5. Refractory angle-closure glaucoma occurred in three of them and atrophia bulbi in two. Histological examination showed diffuse degenerated collagen fibers in the scleral stroma. Two-point LOD score linkage analysis excluded all known genetic loci associated with simple microphthalmia in all patients.
CONCLUSIONS
Simple microphthalmia was dominantly inherited in this Chinese pedigree with typical phenotypes, which resulted in severe visual deterioration by middle age. A novel locus is predicted to be responsible for the microphthalmia in this family, which may prove a high genetic heterogeneity in microphthalmia.
Topics: Adolescent; Adult; Aged; Child; China; Family; Female; Genes, Dominant; Histocytochemistry; Humans; Karyotyping; Lod Score; Male; Microphthalmos; Microsatellite Repeats; Middle Aged; Pedigree; Polymerase Chain Reaction
PubMed: 19452014
DOI: No ID Found -
American Journal of Human Genetics Jan 1999Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal...
Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.
Topics: Adolescent; Adult; Alleles; Child; Child, Preschool; Chromosome Mapping; Chromosomes, Human, Pair 9; Consanguinity; Female; Genotype; Histiocytosis, Non-Langerhans-Cell; Homozygote; Humans; Infant; Lod Score; Male; Microsatellite Repeats; Pakistan; Pedigree
PubMed: 9915955
DOI: 10.1086/302187 -
Genetics May 1995
Topics: DNA; Female; Genetic Diseases, Inborn; Genetic Linkage; Genetics, Medical; History, 20th Century; Humans; Likelihood Functions; Lod Score; Male; Recombination, Genetic
PubMed: 7635310
DOI: 10.1093/genetics/140.1.7 -
American Journal of Human Genetics Nov 2001
Topics: Alleles; Bias; Chromosome Mapping; Humans; Lod Score; Matched-Pair Analysis; Nuclear Family; Probability
PubMed: 11590550
DOI: 10.1086/324268