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The New England Journal of Medicine Jun 1992Familial Mediterranean fever is an autosomal-recessive disease characterized by acute attacks of fever with sterile peritonitis, pleurisy, or synovitis. The biochemical...
BACKGROUND
Familial Mediterranean fever is an autosomal-recessive disease characterized by acute attacks of fever with sterile peritonitis, pleurisy, or synovitis. The biochemical basis of the disease is unknown, but determining the chromosomal location of the gene for the disorder should be a first step toward defining the biochemical events.
METHODS AND RESULTS
As part of a systematic genome-wide search, we sought evidence of linkage between familial Mediterranean fever and chromosome 16 DNA markers in 27 affected non-Ashkenazi Jewish families from Israel. Two loci from the subtelomeric region of the short arm of chromosome 16 (16p) had lod scores sufficient to establish linkage (a score greater than or equal to 3). One DNA marker (D16S84) gave a maximal lod score of 9.17 (odds of 10(9.17) to 1 in favor of linkage) at a recombination frequency (theta) of 0.04. A probe associated with the hemoglobin alpha complex (5'HVR) gave a maximal lod score of 14.47 at a theta of 0.06. Multipoint linkage analysis indicated that the following was the most likely gene order: the centromere, the gene for familial Mediterranean fever, D16S84, hemoglobin alpha, and the telomere. The maximal multipoint lod score was 19.86. There was a striking degree of homozygosity at chromosome 16p loci in the affected offspring of eight consanguineous couples.
CONCLUSIONS
The gene that causes familial Mediterranean fever in non-Ashkenazi Jews maps to the short arm of chromosome 16.
Topics: Centromere; Chromosome Mapping; Chromosomes, Human, Pair 16; Familial Mediterranean Fever; Genetic Linkage; Genetic Markers; Humans; Jews; Lod Score; Telomere
PubMed: 1579134
DOI: 10.1056/NEJM199206043262301 -
Japanese Journal of Cancer Research :... Nov 2001A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the Sprague-Dawley (SD) strain in Japan, and named the "Nihon" rat in 2000. This...
A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the Sprague-Dawley (SD) strain in Japan, and named the "Nihon" rat in 2000. This study was designed to map the RC susceptibility gene in the Nihon rat using 113 backcross animals. Our present data clearly show that the Nihon gene is genetically linked to interleukin-3 (IL3) gene (chi(2) = 93.6, Lod score = 25.16), lethal (2) giant larvae (LLGL1) locus (chi(2) = 109.0, Lod score = 31.56) and myosin heavy chain, embryonic skeletal muscle (MYHSE) gene (chi(2) = 90.6, Lod score = 23.87), which are located on the distal part of rat chromosome 10. The order of the genes is the Eker (Tsc2) gene (located on the proximal part of rat chromosome 10; human chromosome 16p 13.3)--21.3 cM--IL3 gene (human 5q23-31)--4.4 cM--Nihon gene--0.9 cM--LLGL1 locus (human 17p11.2)--4.4 cM--MYHSE gene (human 17p13.1). We also detected loss of the wild-type allele at the MYHSE locus, fitting Knudson's "two hit" model. Thus, the Nihon rat should have a mutation of a novel tumor suppressor gene related to renal carcinogenesis.
Topics: Animals; Chromosome Mapping; Chromosomes; Crosses, Genetic; Female; Gene Order; Genetic Predisposition to Disease; Humans; Kidney Neoplasms; Lod Score; Male; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley
PubMed: 11714437
DOI: 10.1111/j.1349-7006.2001.tb02133.x -
The Journal of Investigative Dermatology Dec 2002Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p, respectively. To...
Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p, respectively. To investigate the psoriasis susceptibility loci in Chinese Hans, a genome-wide scan was performed with two-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex families. These families were Chinese Hans residing in east and south-east China, comprising 189 affected and 166 unaffected individuals. We detected evidence for linkage at 6p21 (PSORS1) with nonparametric linkage scores > 3 in the range of 39.9-62.3 cM and a maximum multipoint nonparametric linkage score of 4.58 (p=0.000032). Parametric analysis revealed a maximum two-point heterogeneity lod score of 4.30 with 58% as the proportion of linked families (alpha) and a maximum multipoint heterogeneity lod score of 4.25 (alpha=53%) under the assumption of a dominant model. We could not confirm a previous reported locus (PSORS3) on distal chromosome 4q; however, a region of highly suggestive linkage was identified proximal to this proposed locus. Multipoint nonparametric analysis demonstrated nonparametric linkage scores > 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a maximum peak of 3.69 (p=0.00033) at 157.9 cM, which locates D4S413. A maximum multipoint heterogeneity lod score of 2.31 (alpha=46%) was reached at 163.1 cM. With two-point parametric linkage analysis, we observed the highest lod score of 2.43 and heterogeneity lod score of 3.94 (alpha=77%) at marker D4S1597. Our results showed that chromosomes 6p and 4q may contain genes involved in the susceptibility to psoriasis vulgaris in a Chinese Han population. Other regions with weaker evidence for linkage could also hide minor susceptibility genes.
Topics: Adult; Asian People; Chromosomes, Human, Pair 4; Chromosomes, Human, Pair 6; Disease Susceptibility; Female; Genome, Human; Humans; Lod Score; Male; Psoriasis
PubMed: 12485440
DOI: 10.1046/j.1523-1747.2002.19612.x -
American Journal of Human Genetics Dec 1995A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD). We have studied 28 nuclear families...
A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD). We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype, by using 31 polymorphic markers spanning chromosome 18. Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype. The affected-sibpair analyses indicated excess allele sharing for markers on 18p within the region reported previously. The greatest sharing was at D18S37: 64% in bipolar and recurrent unipolar (RUP) sib pairs (P = .0006). In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at three markers on 18q: at D18S41, 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles, and 21 pairs were discordant (P = 0004). The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i.e., those in which the father or one of the father's sibs is affected. In these pedigrees, the greatest allele sharing (81%; P = .00002) and the highest LOD score (3.51; phi = 0.0) were observed at D18S41. Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder. The number of loci involved, and their precise location, require further study..
Topics: Adolescent; Adult; Bipolar Disorder; Chromosome Mapping; Chromosomes, Human, Pair 18; Female; Genetic Linkage; Genotype; Humans; Lod Score; Male
PubMed: 8533768
DOI: No ID Found -
BMC Genetics Dec 2005Linkage disequilibrium (LD) content was calculated for the Genetic Analysis Workshop 14 Affymetrix and Illumina single-nucleotide polymorphism (SNP) genome scans of the...
Linkage disequilibrium (LD) content was calculated for the Genetic Analysis Workshop 14 Affymetrix and Illumina single-nucleotide polymorphism (SNP) genome scans of the Collaborative Study on the Genetics of Alcoholism samples. Pair-wise LD was measured as both D' and r2 on 505 pedigree founder individuals. The r2 estimates were then used to correct the multipoint identity by descent matrix (MIBD) calculation to account for LD and LOD scores on chromosomes 3 and 18 were calculated for COGA's ttdt3 electrophysiological trait using those MIBDs. Extensive LD was observed throughout both marker sets, and it was higher in Affymetrix's more dense SNP map. However, SNP density did not solely account for Affymetrix's higher LD. MIBD estimation procedures assume linkage equilibrium to construct genotypes of non-genotyped pedigree founder individuals, and dense SNP genotyping maps are likely to contain moderate to high LD between markers. LOD score plots calculated after correction for LD followed the same general pattern as uncorrected ones. Since in our study almost half of the pedigree founders were genotyped, it is possible that LD had a minor impact on the LOD scores. Caution should probably be taken when using high density SNP maps when many non-genotyped founders are present in the study pedigrees.
Topics: Female; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Lod Score; Male; Oligonucleotide Array Sequence Analysis; Pedigree; Polymorphism, Single Nucleotide
PubMed: 16451701
DOI: 10.1186/1471-2156-6-S1-S86 -
Genetics May 2005Multiple sclerosis (MS) and its animal model, myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), share a complex genetic...
Multiple sclerosis (MS) and its animal model, myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), share a complex genetic predisposition with contributions from the major histocompatibility complex class II genes and many other genes. Linkage mapping in F(2) crosses between the susceptible DA rat strain and the resistant ACI or BN rat strains in various models of autoimmune neuroinflammation have repeatedly displayed suggestive linkage to a region on rat chromosome 15. A direct study of this region was undertaken in congenic strains by transferring resistant ACI alleles to the susceptible DA background. Phenotypic analysis demonstrated lower maximal and cumulative EAE scores in the DA.ACI-D15Rat6-D15Rat71 (C15), DA.ACI-D15Rat6-D15Rat48, D15Rat126-D15Rat71 (C15R3b), and DA.ACI-D15Rat23-D15rat71 (C15R4) strains compared to the parental DA rat strain. Linkage analysis was then performed in a (DA x PVG.AV1)F(7) advanced intercross line, resulting in a LOD score of 4.7 for the maximal EAE score phenotype at the peak marker D15Rat71 and a confidence interval of 13 Mb, overlapping with the congenic fragment defined by the C15R3b and the C15R4 strains. Thus, a new MOG-EAE locus with the designation Eae19 is identified on rat chromosome 15. There are 32 confirmed or predicted genes in the confidence interval, including immune-responsive gene 1 and neuronal ceroid lipofuscinose gene 5. Definition of loci such as Eae19 enables the characterization of genetically regulated, evolutionary conserved disease pathways in complex neuroinflammatory diseases.
Topics: Animals; Chromosome Mapping; Chromosomes, Mammalian; Encephalomyelitis, Autoimmune, Experimental; Genetic Linkage; Likelihood Functions; Lod Score; Rats; Time Factors
PubMed: 15716504
DOI: 10.1534/genetics.104.035261 -
Kidney International Oct 2001Autosomal-dominant medullary cystic kidney disease (MCKD) is an interstitial nephropathy characterized by structural renal tubular defects that result in salt wasting...
BACKGROUND
Autosomal-dominant medullary cystic kidney disease (MCKD) is an interstitial nephropathy characterized by structural renal tubular defects that result in salt wasting and a reduction in urinary concentration. The condition has clinical and morphological similarities to autosomal-recessive juvenile nephronophthisis. Two genes predisposing to MCKD have been localized. MCKD1 on chromosome 1q21 was localized in two Cypriot families, and MCKD2 on chromosome 16p12 was localized in a single Italian family. We have evaluated a large Welsh MCKD family for linkage at these two loci.
METHODS
Clinical data and DNA samples were collected from affected family members. Polymorphic microsatellite markers spanning the critical regions on chromosome 1 and chromosome 16 that encompass MCKD1 and MCKD2 were analyzed. Two-point and multipoint LOD scores were calculated.
RESULTS
The family fulfilled previously published criteria for the diagnosis of MCKD, but hyperuricemia and gout were not prominent features. Twenty-one affected individuals were identified. Mean age at death or end-stage renal disease was 47 years (37 to 60). Linkage and haplotype analysis generated strongly negative results at MCKD1 on chromosome 1q21 (two-point LOD score = -5.32). Strong evidence of linkage to MCKD2 was generated with a maximum multi-point LOD score of 3.75.
CONCLUSION
These results provide the first independent confirmation of a gene predisposing to MCKD on chromosome 16p12 and indicate that mutation of this gene is not restricted to a single family or population. The absence of hyperuricemia and gout in our family indicates that these are not obligatory features of MCKD2 mutations.
Topics: Adult; Chromosome Mapping; Chromosomes, Human, Pair 16; Female; Genetic Linkage; Genetic Predisposition to Disease; Humans; Kidney Medulla; Lod Score; Male; Middle Aged; Pedigree; Polycystic Kidney, Autosomal Dominant
PubMed: 11576337
DOI: 10.1046/j.1523-1755.2001.00932.x -
Genetic Epidemiology Jul 2006The ratio of male and female genetic map distances varies dramatically across the human genome. Despite these sex differences in genetic map distances, most multipoint...
The ratio of male and female genetic map distances varies dramatically across the human genome. Despite these sex differences in genetic map distances, most multipoint linkage analyses use sex-averaged genetic maps. We investigated the impact of using a sex-averaged genetic map instead of sex-specific maps for multipoint linkage analysis of affected sibling pairs when identity-by-descent states are incompletely known due to missing parental genotypes and incomplete marker heterozygosity. If either all or no parental genotypes were available, for intermarker distances of 10, 5, and 1 cM, we found no important differences in the expected maximum lod score (EMLOD) or location estimates of the disease locus between analyses that used the sex-averaged map and those that used the true sex-specific maps for female:male genetic map distance ratios 1:10 and 10:1. However, when genotypes for only one parent were available and the recombination rate was higher in females, the EMLOD using the sex-averaged map was inflated compared to the sex-specific map analysis if only mothers were genotyped and deflated if only fathers were genotyped. The inflation of the lod score when only mothers were genotyped led to markedly increased false-positive rates in some cases. The opposite was true when the recombination rate was higher in males; the EMLOD was inflated if only fathers were genotyped, and deflated if only mothers were genotyped. While the effects of missing parental genotypes were mitigated for less extreme cases of missingness, our results suggest that when possible, sex-specific maps should be used in linkage analyses.
Topics: Chromosome Mapping; Computer Simulation; Female; Gene Frequency; Genetic Diseases, Inborn; Humans; Lod Score; Male; Models, Genetic; Pedigree; Polymorphism, Single Nucleotide; Recombination, Genetic; Sex Factors
PubMed: 16685713
DOI: 10.1002/gepi.20151 -
Genetics Aug 2003Genome-wide scans for quantitative trait loci (QTL) have traditionally been summarized with plots of logarithm of odds (LOD) scores. A valuable modification is to...
Genome-wide scans for quantitative trait loci (QTL) have traditionally been summarized with plots of logarithm of odds (LOD) scores. A valuable modification is to supplement such plots with an additional vertical axis displaying quantiles of adjusted P values and labeling local maxima of the LOD scores with location-specific adjusted P values. This provides a visible gradation of genome-wide significance for the LOD score curve, instead of the stark dichotomy that a single threshold yields. Adjusted P values give genome-wide significance of individual LOD scores and are obtained through a straightforward modification of the familiar algorithm for generating permutation-based thresholds.
Topics: Algorithms; Animals; Chromosome Mapping; Chromosomes; Computer Simulation; Crosses, Genetic; Epistasis, Genetic; Genetic Markers; Genetic Variation; Genome; Lod Score; Probability; Quantitative Trait, Heritable; Rats
PubMed: 12930772
DOI: 10.1093/genetics/164.4.1683 -
American Journal of Human Genetics Apr 2005Stuttering is a common and sometimes severe communication disorder, of unknown primary etiology, that exists in populations worldwide. Many types of evidence suggest a...
Stuttering is a common and sometimes severe communication disorder, of unknown primary etiology, that exists in populations worldwide. Many types of evidence suggest a genetic contribution to stuttering; however, the complex inheritance of this disorder has hindered identification of these factors. We have employed highly inbred families to increase the power of linkage analysis of this disorder. Forty-four Pakistani families with documented or probable consanguinity, from the city of Lahore and surrounding areas, were included. Each family contained multiple cases of stuttering, which were diagnosed using the Stuttering Severity Instrument. Using the Marshfield Weber 9 marker panel, we performed a genomewide linkage scan focused on affected individuals and their parents. The analysis included 199 genotyped individuals, 144 affected and 55 unaffected. The Pedigree Relationship Statistical Test (PREST) was used to identify pedigrees that required additional specification of inbreeding. Initial nonparametric analysis gave evidence of linkage on chromosomes 1, 5, 7, and 12. Additional genotyping was performed on chromosome 12 to a 5-cM level of resolution, and 16 additional individuals were then included, bringing the number of families to 46. Analysis of the enlarged data set provided consistent evidence of linkage on chromosome 12: the S(homoz) scoring function gave a nonparametric LOD score of 4.61, and a LOD score of 3.51 was obtained using the S(all) scoring function. These results suggest that a locus on chromosome 12q may contain a gene with a large effect in this sample.
Topics: Chromosome Mapping; Chromosomes, Human, Pair 12; Consanguinity; Genetic Linkage; Humans; Lod Score; Stuttering
PubMed: 15714404
DOI: 10.1086/429226