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American Journal of Human Genetics Dec 2003We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134... (Comparative Study)
Comparative Study
We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.
Topics: Genetic Linkage; Genome, Human; Humans; Lod Score; Microsatellite Repeats; Pedigree; Schizophrenia; Siblings; Sweden; United Kingdom; United States
PubMed: 14628288
DOI: 10.1086/380206 -
The Journal of Investigative Dermatology Dec 2004Pili annulati (PA) is a rare hair shaft disorder characterized by discrete banding of hairs. We studied two families with PA in which the disorder segregated in an...
Pili annulati (PA) is a rare hair shaft disorder characterized by discrete banding of hairs. We studied two families with PA in which the disorder segregated in an autosomal dominant fashion. All family members were clinically examined and hair samples were examined under the light microscope. In family G, of 19 individuals examined, ten were affected, over three generations. In family B, there were three affected individuals of seven examined over three generations. A genome-wide scan of family G revealed a maximum logarithm of odds (LOD) of linkage score of 3.89 at marker D12S1723 at the telomeric region of chromosome 12q. From one critical recombinant in family G, the locus was narrowed down to a 9.2 cM region between D12S367 and the end of chromosome 12q. In family B linkage at the telomeric region of chromosome 12q also revealed a maximum LOD score of 0.89 at marker D12S1723. A combined LOD score, assuming no locus heterogeneity between the families was 4.78. Frizzled 10, which is located within the region, was sequenced but we were unable to detect a mutation causing PA. This study, for the first time, identifies a genetic locus for PA.
Topics: Chromosome Mapping; Chromosomes, Human, Pair 12; Female; Hair; Hair Color; Hair Diseases; Haplotypes; Humans; Lod Score; Male; Pedigree; Telomere
PubMed: 15610516
DOI: 10.1111/j.0022-202X.2004.23500.x -
American Journal of Human Genetics Jul 1999Cherubism is a rare familial disease of childhood characterized by proliferative lesions within the mandible and maxilla that lead to prominence of the lower face and an...
Cherubism is a rare familial disease of childhood characterized by proliferative lesions within the mandible and maxilla that lead to prominence of the lower face and an appearance reminiscent of the cherubs portrayed in Renaissance art. Resolution of these bony abnormalities is often observed after puberty. Many cases are inherited in an autosomal dominant fashion, although several cases without a family history have been reported. Using two families with clinically, radiologically, and/or histologically proved cherubism, we have performed a genomewide linkage search and have localized the gene to chromosome 4p16.3, with a maximum multipoint LOD score of 5. 64. Both families showed evidence of linkage to this locus. Critical meiotic recombinants place the gene in a 3-cM interval between D4S127 and 4p-telomere. Within this region a strong candidate is the gene for fibroblast growth factor receptor 3 (FGFR3); mutations in this gene have been implicated in a diverse set of disorders of bone development.
Topics: Adult; Cherubism; Chromosome Mapping; Chromosomes, Human, Pair 4; Female; Genetic Markers; Humans; Lod Score; Male; Pedigree
PubMed: 10364527
DOI: 10.1086/302454 -
American Journal of Human Genetics Apr 1995Cleidocranial dysplasia (CCD) is an autosomal dominant generalized bone dysplasia characterized by mild-to-moderate short stature, clavicular aplasia or hypoplasia,...
Cleidocranial dysplasia (CCD) is an autosomal dominant generalized bone dysplasia characterized by mild-to-moderate short stature, clavicular aplasia or hypoplasia, supernumerary and ectopic teeth, delayed eruption of secondary teeth, a characteristic craniofacial appearance, and a variety of other skeletal anomalies. We have performed linkage studies in five families with CCD, with 24 affected and 20 unaffected individuals, using microsatellite markers spanning two candidate regions on chromosomes 8q and 6. The strongest support for linkage was with chromosome 6p microsatellite marker D6S282 with a two-point lod score of 4.84 (theta = .03). Furthermore, the multipoint lod score was 5.70 in the interval between D6S282 and D6S291. These data show that the gene for autosomal dominant CCD is located within a 19-cM interval on the short arm of chromosome 6, between D6S282 and D6S291.
Topics: Chromosome Mapping; Chromosomes, Human, Pair 6; Cleidocranial Dysplasia; Female; Genetic Linkage; Humans; Lod Score; Male; Pedigree
PubMed: 7717404
DOI: No ID Found -
Clinical Orthopaedics and Related... Apr 2008Developmental dysplasia of the hip (DDH) is a spectrum of disorders affecting the proximal femur and/or acetabulum leading to an abnormal formation of the hip. Genetic...
Developmental dysplasia of the hip (DDH) is a spectrum of disorders affecting the proximal femur and/or acetabulum leading to an abnormal formation of the hip. Genetic factors are involved in the etiology of DDH. Early recognition of DDH affords the best results from treatment and a better knowledge of the genetics of DDH could enhance early diagnosis. Variants in the Type II collagen (COL2A1) and vitamin D receptor (VDR) genes have been associated with patients with osteoarthritis of the hip secondary to DDH, suggesting these genes could contribute to DDH. To see whether there was linkage between the COL2A1/VDR locus and nonsyndromic DDH, we conducted a linkage study on 11 families with multiple cases of DDH. We demonstrated no evidence of linkage between the COL2A1/VDR locus and nonsyndromic DDH (LOD score < -2), suggesting, although variants in these genes could play a role in osteoarthritis in patients with DDH, they do not contribute to nonsyndromic DDH. The search for causal gene variants should proceed with other candidates.
Topics: Collagen Type II; Female; Genetic Predisposition to Disease; Hip Dislocation, Congenital; Humans; Lod Score; Male; Pedigree; Receptors, Calcitriol; Risk Factors
PubMed: 18288556
DOI: 10.1007/s11999-008-0120-z -
Arthritis and Rheumatism Jun 2000Ankylosing spondylitis (AS) affects 0.25-1.0% of the population, and its etiology is incompletely understood. Susceptibility to this highly familial disease (lambda(s) =...
OBJECTIVE
Ankylosing spondylitis (AS) affects 0.25-1.0% of the population, and its etiology is incompletely understood. Susceptibility to this highly familial disease (lambda(s) = 58) is primarily genetically determined. There is a significant sex bias in AS, and there are differences in recurrence risk to the offspring of affected mothers and fathers, suggesting that there may be an X-linked recessive effect. We undertook an X-chromosome linkage study to determine any contribution of the X-chromosome to AS susceptibility.
METHODS
A linkage study of the X-chromosome using 234 affected sibling pairs was performed to investigate this hypothesis.
RESULTS
No linkage of the X-chromosome with susceptibility to AS was found. Model-free multipoint linkage analysis strongly excluded any significant genetic contribution (lambda > or = 1.5) to AS susceptibility encoded on the X-chromosome (logarithm of odds [LOD] <-2.0). Smaller genetic effects (lambda > or = 1.3) were also found to be unlikely (LOD <-1.0).
CONCLUSION
The sex bias in AS is not explained by X-chromosome-encoded genetic effects. The disease model best explaining the sex bias in occurrence and transmission of AS is a polygenic model with a higher susceptibility threshold in females.
Topics: Genetic Linkage; Genetic Predisposition to Disease; Humans; Lod Score; Spondylitis, Ankylosing; X Chromosome
PubMed: 10857794
DOI: 10.1002/1529-0131(200006)43:6<1353::AID-ANR19>3.0.CO;2-B -
American Journal of Human Genetics Sep 1990The original family with the Allan-Herndon type of X-linked mental retardation has been investigated for linkage by using DNA probes spanning the length of the X...
The original family with the Allan-Herndon type of X-linked mental retardation has been investigated for linkage by using DNA probes spanning the length of the X chromosome. Available for study, over 3 generations, were 13 affected males, three obligate carriers, and three normal sons of the obligate carriers. Initial disease-to-marker analysis suggested linkage to three markers (DXYS2 [7b], DXS250 [GMGX22], and DXS3 [p19-2]) located in Xq21. All three exhibited the same maximum lod score of 2.3 at a maximum theta of .05. Multipoint analysis using LINKMAP and a set of four DNA markers (DXYS1-DXYS2-DXS3-DXS94) gave a multipoint lod score of 3.58 for a location of the Allan-Herndon syndrome near locus DXYS1 (pDP34). Therefore, our data indicate that the gene for the Allan-Herndon syndrome is likely located in Xq21.
Topics: Abnormalities, Multiple; DNA Probes; Face; Female; Genetic Linkage; Genetic Markers; Humans; Intellectual Disability; Lod Score; Male; Muscular Diseases; Pedigree; Syndrome; X Chromosome
PubMed: 2393020
DOI: No ID Found -
American Journal of Human Genetics May 1992This paper investigates effects on lod scores when one individual in a data set changes diagnostic or recombinant status. First we examine the situation in which a...
This paper investigates effects on lod scores when one individual in a data set changes diagnostic or recombinant status. First we examine the situation in which a single offspring in a nuclear family changes status. The nuclear-family situation, in addition to being of interest in its own right, also has general theoretical importance, since nuclear families are "transparent"; that is, one can track genetic events more precisely in nuclear families than in complex pedigrees. We demonstrate that in nuclear families log10 [(1-theta)/theta] gives an upper limit on the impact that a single offspring's change in status can have on the lod score at that recombination fraction (theta). These limits hold for a fully penetrant dominant condition and fully informative marker, in either phase-known or phase-unknown matings. Moreover, log10 [(1-theta)/theta] (where theta denotes the value of theta at which Zmax occurs) gives an upper limit on the impact of a single offspring's status change on the maximum lod score (Zmax). In extended pedigrees, in contrast to nuclear families, no comparable limit can be set on the impact of a single individual on the lod score. Complex pedigrees are subject to both stabilizing and destabilizing influences, and these are described. Finally, we describe a "sensitivity analysis," in which, after all linkage analysis is completed, every informative individual in the data set is changed, one at a time, to see the effect which each separate change has on the lod scores. The procedure includes identifying "critical individuals," i.e., those who would have the greatest impact on the lod scores, should their diagnostic status in fact change. To illustrate use of the sensitivity analysis, we apply it to the large bipolar pedigree reported by Egeland et al. and Kelsoe et al. We show that the changes in lod scores observed there, on the order of 1.1-1.2 per person, are not unusual. We recommend that investigators include a sensitivity analysis as a standard part of reporting the results of a linkage analysis.
Topics: Female; Genes, Dominant; Genetic Linkage; Humans; Lod Score; Male; Mathematics; Pedigree; Sensitivity and Specificity; Software
PubMed: 1570835
DOI: No ID Found -
Molecular Vision 2009A linkage study on autosomal recessive high myopia (arHM) has not been reported, although several loci for autosomal dominant high myopia (adHM) have been mapped. Data...
PURPOSE
A linkage study on autosomal recessive high myopia (arHM) has not been reported, although several loci for autosomal dominant high myopia (adHM) have been mapped. Data from a consanguineous Chinese family with arHM were collected to map the genetic locus associated with this condition.
METHODS
Phenotypic information and DNA samples were collected from family members. A genome-wide linkage scan combined with homozygosity mapping was performed by using 382 microsatellite DNA markers from the entire genome spaced at intervals of about 10 cM.
RESULTS
The pedigree and clinical data of the family indicate that the high myopia is autosomal recessive. A genome-wide scan of chromosomes 1-22 gave a LOD score greater than 1.0 for 22 markers. Linkage to most of these markers was not supported by closely flanking markers except for three possible loci on chromosomes 11, 14, and 17. Fine mapping and haplotype analysis provide evidence for a locus at 14q22.1-q24.2 in a 25.23 Mb region between markers D14S984 and D14S999 with a maximum LOD score of 2.19. All 11 microsatellite markers inside the linkage interval as well as haplotype construction point to a gene at this locus. Linkage elsewhere on chromosome 11 and chromosome 17 could not be excluded due to the small size of the family.
CONCLUSIONS
Pedigree and clinical data suggest that an autosomal recessive gene is responsible for high myopia in a consanguineous Chinese family. Genome-wide linkage analysis was used to map the gene for high myopia to a few limited loci. The resultant information should help future studies identify the gene for arHM. To our knowledge, this report is the first clinical and linkage study on a consanguineous family with arHM.
Topics: Adolescent; Adult; China; Chromosomes, Human, Pair 14; Family; Female; Genes, Recessive; Genetic Linkage; Humans; Lod Score; Male; Microsatellite Repeats; Middle Aged; Myopia; Pedigree
PubMed: 19204786
DOI: No ID Found -
Genetic Epidemiology May 2004Combined association and linkage analysis is a powerful tool for pinpointing functional quantitative traits (QTLs) responsible for regions of significant linkage...
Combined association and linkage analysis is a powerful tool for pinpointing functional quantitative traits (QTLs) responsible for regions of significant linkage identified in genome-wide scans. We applied this technique to apoE plasma levels and the APOEepsilon2/epsilon3/epsilon4 polymorphism in two Dutch twin cohorts of different age ranges. Across chromosome 19, short tandem repeats and the APOEepsilon2/epsilon3/epsilon4 polymorphism were genotyped in adolescent (aged 13-22 years) and adult (aged 34-62 years) Dutch twins. In both samples, evidence for indicative linkage with plasma apoE levels was found (maximum LOD score (MLS)=0.8, MLS=2.5, respectively) at 19q13.32. These linkage regions included the APOE locus. As expected, the APOEepsilon2/epsilon3/epsilon4 polymorphism was strongly associated with apoE plasma levels in both samples. An extension of the between/within families association test developed by Fulker et al. ([1999] Am. J. Hum. Genet. 64:259-267) showed that these associations were not due to population stratification. The combined association and linkage analyses revealed that the association of the APOEepsilon2/epsilon3/epsilon4 polymorphism with apoE plasma levels completely explained the linkage in the adolescent twins and partly in the adult twins.
Topics: Adolescent; Adult; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Chromosomes, Human, Pair 19; Cohort Studies; Female; Genetic Linkage; Genotype; Humans; Lod Score; Male; Netherlands; Polymorphism, Genetic; Quantitative Trait, Heritable
PubMed: 15095392
DOI: 10.1002/gepi.10318