Peak LOD Score Research Articles

Factor analysis of asthma and atopy traits shows 2 major components, one of which is linked to markers on chromosome 5q

Background: A variety of definitions of asthma and atopy traits have been used in genetic studies. The variables used may be correlated, increasing the likelihood of type I error. Objective: We sought to clarify and quantify phenotypes that may be characterized by related traits. Principal components and factor analysis were applied to the correlation matrix of asthma and atopy traits before linkage analysis. Methods: Factor analysis was performed on 468 Hispanic and non-Hispanic white children enrolled in the Tucson Children's Respiratory Study, with complete information on 24 items, including skin test response to 7 allergens, total serum IgE levels, presence or absence of asthma attacks, wheezing episodes, hay fever, and cough. Factor score coefficients were then applied to all siblings (n = 877), and quantitative factor scores were derived. Single-point and multipoint nonparametric sib-pair analyses were performed to assess linkage to markers on chromosome 5q31-33. Analyses were also performed for individual items. Results: Two main factors were identified: Factor I had high loadings on atopic items, including skin test responses, IgE, and hay fever, and Factor II had high loadings that included asthma diagnosis, wheezing, cough, and Alternaria species skin test response. Factors I and II were correlated at an r value of 0.19. For the quantitative factor scores, significant single-point linkage (P < .0001) was demonstrated only for atopic Factor I, and a peak multipoint LOD score of 2.7 was seen for marker D5S479. Multipoint LOD scores for individual items were 1.1 or less. Conclusion: These analyses suggest evidence for a locus or loci mapping to chromosome 5q31-33 associated with this composite atopic phenotype. (J Allergy Clin Immunol 2001;108:772-80.)

Evidence for a susceptibility locus on chromosome 6q influencing phonological coding dyslexia.

A linkage study of 96 dyslexia families containing at least two affected siblings (totaling 877 individuals) has found evidence for a dyslexia susceptibility gene on chromosome 6q11.2-q12 (assigned the name DYX4). Using a qualitative phonological coding dyslexia (PCD) phenotype (affected, unaffected, or uncertain diagnoses), two-point parametric analyses found highly suggestive evidence for linkage between PCD and markers D6S254, D6S965, D6S280, and D6S251 (LOD(max) scores = 2.4 to 2.8) across an 11 cM region. Multipoint parametric analysis supported linkage of PCD to this region (peak HLOD = 1.6), as did multipoint nonparametric linkage analysis (P = 0.012). Quantitative trait linkage analyses of four reading measures (phonological awareness, phonological coding, spelling, and rapid automatized naming speed) also provided evidence for a dyslexia susceptibility locus on chromosome 6q. Using a variance-component approach, analysis of phonological coding and spelling measures resulted in peak LOD scores at D6S965 of 2.1 and 3.3, respectively, under 2 degrees of freedom. Furthermore, multipoint nonparametric quantitative trait sibpair analyses suggested linkage between the 6q region and phonological awareness, phonological coding, and spelling (P = 0.018, 0.017, 0.0005, respectively, for unweighted sibpairs < 18 years of age). Although conventional significance thresholds were not reached in the linkage analyses, the chromosome 6q11.2-q12 region clearly warrants investigation in other dyslexia family samples to attempt replication and confirmation of a dyslexia susceptibility gene in this region.

A Genomewide Screen for Autism Susceptibility Loci

We report the analysis of 335 microsatellite markers genotyped in 110 multiplex families with autism. All families include at least two "affected" siblings, at least one of whom has autism; the remaining affected sibs carry diagnoses of either Asperger syndrome or pervasive developmental disorder. Affected sib-pair analysis yielded multipoint maximum LOD scores (MLS) that reach the accepted threshold for suggestive linkage on chromosomes 5, X, and 19. Nominal evidence for linkage (point-wise P<.05) was obtained on chromosomes 2, 3, 4, 8, 10, 11, 12, 15, 16, 18, and 20, and secondary loci were found on chromosomes 5 and 19. Analysis of families sharing alleles at the putative X chromosomal linked locus and one or more other putative linked loci produced an MLS of 3.56 for the DXS470-D19S174 marker combination. In an effort to increase power to detect linkage, scan statistics were used to evaluate the significance of peak LOD scores based on statistical evidence at adjacent marker loci. This analysis yielded impressive evidence for linkage to autism and autism-spectrum disorders with significant genomewide P values <.05 for markers on chromosomes 5 and 8 and with suggestive linkage evidence for a marker on chromosome 19.

A genomewide linkage study of age at onset in schizophrenia.

There is strong evidence for a genetic contribution to age at onset of schizophrenia, which probably involves both susceptibility loci for schizophrenia and modifying loci acting independent of disease risk. We sought evidence of linkage to loci that influence age at onset of schizophrenia in a sample of 94 affected sibling pairs with DSM-IV schizophrenia or schizoaffective disorder, and age at first psychiatric contact of 45 years or less. Individuals were genotyped for 229 microsatellite markers spaced at approximately 20 cM intervals throughout the genome. Loci contributing to age at onset were sought by a quantitative maximum-likelihood multipoint linkage analysis using MAPMAKER/SIBS. A nonparametric multipoint analysis was also performed. The genomewide significance of linkage results was assessed by simulation studies. There were six maximum-likelihood LOD score peaks of 1.5 or greater, the highest being on chromosome 17q (LOD = 2.54; genomewide P = 0.27). This fulfils Lander and Kruglyak's [1995: Nat Genet 11:241-247] criteria for suggestive linkage in that it would be expected to occur once or less (0.3 times) per genome scan. However, this finding should be treated with caution because the LOD score appeared to be almost solely accounted for by the pattern of ibd sharing at one marker (D17S787), with virtually no evidence of linkage over flanking markers. None of the linkage results achieved genomewide statistical significance, but the LOD score peak on chromosome 13q (LOD = 1.68) coincided with the region showing maximum evidence for linkage in the study by Blouin et al. [1998: Nat Genet 20:70-73] of categorical schizophrenia.

Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder

The first genome scan conducted in early-onset obsessive-compulsive disorder used a non-parametric analysis to identify a peak in a region of chromosome 9 containing the gene SLC1A1, which codes for the neuronal and epithelial glutamate transporter EAAC1. Interaction between the glutamatergic and serotonergic systems within the striatum suggests EAAC1 as a functional candidate in OCD as well. We determined the genomic organization of SLC1A1 primarily by using primers designed from cDNA sequence to amplify from adaptor-ligated genomic DNA restriction fragments. In order to confirm SLC1A1 as a positional candidate in early-onset OCD, common single nucleotide polymorphisms (SNPs) were identified that enabled mapping of SLC1A1 within the region of the lod score peak. Based on the linkage evidence, the coding region was sequenced in the probands of the seven families included in the genome scan. No evidence was found for a functional mutation, but several SNPs were identified. Capillary electrophoresis SSCP typing of a haplotype consisting of two common SNPs within EAAC1 revealed no significant linkage disequilibrium.

Submucosal gland distribution in the mouse has a genetic determination localized on Chromosome 9

Submucosal glands (SMG) are important secretory glands that are present in the major airways and bronchioles of humans. In mice the structure, cellular composition, and density of SMG are similar to those seen in humans, but the glands are present only in the trachea. Characterization of SMG is important as they secrete bacteriocidal products such as lactoferrin, lysozyme, and defensins believed to be of importance in the innate defense system. Serous cells in SMG are the primary site of cystic fibrosis transmembrane conductance regulator (CFTR) gene expression and the initial site of histological abnormality in cystic fibrosis (CF) individuals. In this study, we examined four inbred strains of mice (A/J, C57BL/6N, FVB/N, and BALB/CAnN) and revealed that the extent to which glands descend in the mouse trachea varied between inbred strains. In particular, the A/J and C57BL/6N strains exhibited few SMG extending further than the first or second intercartilaginous space (mean depth of 0.4+/-0.11 and 1.5+/-0.32 tracheal rings respectively) in the trachea, whereas the FVB/N and BALB/CAnN strains had SMG extending beyond the fourth space (mean depths of 3.3+/-0.46 and 5.6+/-0.45 rings respectively). We have previously shown that in congenic C57Bl/ 6N Cftr mutant mice (CF mice), the SMG are distributed more distally than in wild-type C57Bl/6N but are indistinguishable from BALB/CAnN wild-type or CF mice. The implication that SMG distribution is influenced by Cftr gene expression (or a gene closely linked to Cftr) led us to investigate the genetic difference between C57Bl6/N and BALB/CAnN mice. In recombinant inbred strain (RIS) analysis (with BALB/CJ and C57BL/6J progenitors), two loci were identified as being linked to the SMG phenotype (peak likelihood statistic levels of 8.8 and 9.9 on Chrs 9 and 10 respectively, indicating suggestive linkage). A subsequent segregation analysis of an F2 intercross between the C57BL/6N and BALB/CAnN mice indicated that there were at least two major genetic factors responsible for SMG distribution. The loci indicated in the RI analysis were included in a targeted genome scan involving 235 F2 intercross animals (C57BL/6N and BALB/CAnN strain intercross). The genome scan confirmed the locus on Chr 9 (between genetic markers D9Mit11 and D9Mit182), designated Smgdl, as significantly linked to the SMG distribution phenotype (peak LOD score 5.8) within a 95% confidence interval of 12 cM.

A Duplication in Chromosome 4q35 Is Associated with Hereditary Benign Intraepithelial Dyskeratosis

Hereditary benign intraepithelial dyskeratosis (HBID) is an autosomal dominant disorder characterized by elevated epithelial plaques on the ocular and oral mucous membranes. It has been reported primarily, but not exclusively, in individuals of American Indian heritage in North Carolina. We have examined and obtained DNA on two large families affected by HBID. Using genetic linkage analysis we have localized the HBID gene to chromosome 4 (4q35) with a peak LOD score of 8.97. Molecular analysis of these data reveals that all individuals affected with HBID in both families demonstrate the presence of three alleles for two tightly linked markers, D4S1652 and D4S2390, which map to the telomeric region of 4q35. This suggests the presence of a duplication segregating with the disease phenotype that is most likely involved in its causation.

Fine mapping and genetic heterogeneity in the pure form of autosomal dominant familial spastic paraplegia.

We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family 3) showed significant evidence for linkage to chromosome 12q, peaking at D12S1691 (maximum lod = 3.22). Haplotype analysis of family 3 did not identify any recombinants among affected individuals in the 12q candidate region. Family 5 yielded a peak lod score of 2.02 at marker D19S868 and excluded linkage to other known SPG loci. Haplotype analysis of family 5 revealed several cross-overs in affected individuals, thereby potentially narrowing the SPG12 candidate region to a 5-cM region between markers D19S868 and D19S220. Three of the families definitively excluded all four loci examined, providing evidence for further genetic heterogeneity of pure, autosomal dominant SPG. In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus.

Influence of marker heterozygosity and genetic heterogeneity on fine mapping.

The purpose of the current study was to utilize the Genetic Analysis Workshop 12 simulated data to evaluate fine-mapping strategies for quantitative traits. We approached the analysis as if it was a follow-up to a genome scan that had identified two regions of interest and used the provided 1-cM density microsatellite typing data to mimic fine mapping of these regions. As these investigators knew the true locations of the putative genes under study, we explored the effects of the informativeness of microsatellite markers (marker heterozygosity) and the effects of genetic heterogeneity across families for ten replicates of the data. These results shed a cautionary light on the reliability of fine-mapping efforts on refining mapping locations as the position and the strength of the lod score can be markedly affected by the sampling of the population, the amount of variation accounted for by the gene, and the informativeness of the marker. Our studies did not reveal a large effect of unlinked families on the shape of the lod score peak.

Replication of linkage to quantitative trait loci: variation in location and magnitude of the lod score.

Replication of linkage signals from independent samples is considered an important step toward verifying the significance of linkage signals in studies of complex traits. The purpose of this empirical investigation was to examine the variability in the precision of localizing a quantitative trait locus (QTL) by analyzing multiple replicates of a simulated data set with the use of variance components-based methods. Specifically, we evaluated across replicates the variation in both the magnitude and the location of the peak lod scores. We analyzed QTLs whose effects accounted for 10-37% of the phenotypic variance in the quantitative traits. Our analyses revealed that the precision of QTL localization was directly related to the magnitude of the QTL effect. For a QTL with effect accounting for > 20% of total phenotypic variation, > 90% of the linkage peaks fall within 10 cM from the true gene location. We found no evidence that, for a given magnitude of the lod score, the presence of interaction influenced the precision of QTL localization.

Genetic Heterogeneity of Usher Syndrome: Analysis of 151 Families with Usher Type I

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

Chromosomal Duplication Involving the Forkhead Transcription Factor Gene FOXC1 Causes Iris Hypoplasia and Glaucoma

The forkhead transcription factor gene FOXC1 (formerly FKHL7) is responsible for a number of glaucoma phenotypes in families in which the disease maps to 6p25, although mutations have not been found in all families in which the disease maps to this region. In a large pedigree with iris hypoplasia and glaucoma mapping to 6p25 (peak LOD score 6.20 [recombination fraction 0] at D6S967), no FOXC1 mutations were detected by direct sequencing. However, genotyping with microsatellite repeat markers suggested the presence of a chromosomal duplication that segregated with the disease phenotype. The duplication was confirmed in affected individuals by FISH with markers encompassing FOXC1. These results provide evidence of gene duplication causing developmental disease in humans, with increased gene dosage of either FOXC1 or other, as yet unknown genes within the duplicated segment being the probable mechanism responsible for the phenotype.

A quantitative-trait locus controlling peripheral B-cell deficiency maps to mouse Chromosome 15.

Peripheral B-lymphocyte homeostasis is determined through incompletely defined positive and negative regulatory processes. The A/WySnJ mouse, but not the related A/J strain, has disturbed homeostasis leading to peripheral B-lymphocyte deficiency. B lymphopoeisis is normal in A/WySnJ mice, but the B cells apoptose rapidly in the periphery. This B cell-intrinsic defect segregated as a single locus, Bcmd, in (A/WySnJxA/J)F2 mice. Here we mapped a quantitative-trait locus (QTL) that contributes to the A/WySnJ B-cell deficiency by examining the F2 progeny of a cross between strains A/WySnJ and CAST/Ei. In this cross, minimally 1.9 QTLs controlling peripheral B lymphocyte deficiency segregated. The (A/WySnJxCAST/Ei)F2 mice were phenotyped for splenic B-cell percentage and the DNA from progeny with extreme phenotypes was used to map the QTL by the simple-sequence length polymorphism method. A genome scan showed linkage between peripheral B-cell deficiency and Chromosome (Chr) 15 markers. When closely spaced Chr 15 markers were analyzed, the 99% confidence interval for the QTL map position extended along the entire chromosome length. The peak lod scores >17 occurred between 30 and 45 cM. We conclude that a significant QTL segregating in (A/WySnJxCAST/Ei)F2 mice resides in this middle region of Chr 15.

Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping.

HED is an autosomal dominant skin disorder that is particularly common in the French Canadian population of south-west Quebec. We previously mapped the HED gene to the pericentromeric region of chromosome 13q using linkage analysis in eight French Canadian families. In this study, we extend our genetic analysis to include a multiethnic group of 29 families with 10 polymorphic markers spanning 5.1 cM in the candidate region. Two-point linkage analysis strongly suggests absence of genetic heterogeneity in HED in four families of French, Spanish, African and Malaysian origins. Multipoint linkage analysis in all 29 families generated a peak lod score of 53.5 at D13S1835 with a 1 lod unit support interval spanning 1.8 cM. Recombination mapping placed the HED gene in a 2.4 cM region flanked by D13S1828 proximally and D13S1830 distally. We next show evidence for a strong founder effect in families of French Canadian origin thereby representing the first example of a founder disease in the south-west part of the province of Quebec. Significant association was found between HED in these families and all markers analysed (Fisher's exact test, P < 0.001). Complete allelic association was detected at D13S1828, D13S1827, D13S1835, D13S141 and D13S175 (P(excess) = 1) spanning 1.3 cM. A major haplotype including all 10 associated alleles was present on 65% of affected chromosomes. This haplotype most likely represents the founder haplotype that introduced the HED mutation into the French Canadian population. Luria-Delbrück equations and multipoint likelihood linkage disequilibrium analysis positioned the gene at the D13S1828 locus (likely range estimate: 1.75 cM) and 0.58 cM telomeric to this marker (support interval: 3.27 cM) respectively.

Glycerol as a Correlate of Impaired Glucose Tolerance: Dissection of a Complex System by Use of a Simple Genetic Trait

Glycerol kinase (GK) represents the primary entry of glycerol into glucose and triglyceride metabolism. Impaired glucose tolerance (IGT) and hypertriglyceridemia are associated with an increased risk of diabetes mellitus and cardiovascular disease. The relationship between glycerol and the risk of IGT, however, is poorly understood. We therefore undertook the study of fasting plasma glycerol levels in a cohort of 1,056 unrelated men and women of French-Canadian descent. Family screening in the initial cohort identified 18 men from five families with severe hyperglycerolemia (values above 2.0 mmol/liter) and demonstrated an X-linked pattern of inheritance. Linkage analysis of the data from 12 microsatellite markers surrounding the Xp21.3 GK gene resulted in a peak LOD score of 3.46, centered around marker DXS8039. In addition, since all of the families originated in a population with a proven founder effect-the Saguenay Lac-St.-Jean region of Quebec-a common disease haplotype was sought. Indeed, a six-marker haplotype extending over a region of 5.5 cM was observed in all families. Resequencing of the GK gene in family members led to the discovery of a N288D missense mutation in exon 10, which resulted in the substitution of a highly conserved asparagine residue by a negatively charged aspartic acid. Although patients with the N288D mutation suffered from severe hyperglycerolemia, they were apparently otherwise healthy. The phenotypic analysis of the family members, however, showed that glycerol levels correlated with impaired glucose metabolism and body-fat distribution. We subsequently noted a substantial variation in glycerolemia in subjects of the initial cohort with normal plasma glycerol levels and demonstrated that this variance showed significant family resemblance. These results suggest a potentially important genetic connection between fasting glycerolemia and glucose homeostasis, not only in this X-linked deficiency but, potentially, in individuals within the "normal" range of plasma glycerol concentrations.

Fine Mapping of the Chromosome 12 Late-Onset Alzheimer Disease Locus: Potential Genetic and Phenotypic Heterogeneity

Apolipoprotein E (APOE) is the only confirmed susceptibility gene for late-onset Alzheimer disease (AD). In a recent genomic screen of 54 families with late-onset AD, we detected significant evidence for a second late-onset AD locus located on chromosome 12 between D12S373 and D12S390. Linkage to this region was strongest in 27 large families with at least one affected individual without an APOE-4 allele, suggesting that APOE and the chromosome 12 locus might have independent effects. We have since genotyped several additional markers across the region, to refine the linkage results. In analyzing these additional data, we have addressed the issue of heterogeneity in the data set by weighting results by clinical and neuropathologic features, sibship size, and APOE genotype. When considering all possible affected sib pairs (ASPs) per nuclear family, we obtained a peak maximum LOD score between D12S1057 and D12S1042. The magnitude and location of the maximum LOD score changed when different weighting schemes were used to control for the number of ASPs contributed by each nuclear family. Using the affected-relative-pair method implemented in GENEHUNTER-PLUS, we obtained a maximum LOD score between D12S398 and D12S1632, 25 cM from the original maximum LOD score. These results indicate that family size influences the location estimate for the chromosome 12 AD gene. The results of conditional linkage analysis by use of GENEHUNTER-PLUS indicated that evidence for linkage to chromosome 12 was stronger in families with affected individuals lacking an APOE-4 allele; much of this evidence came from families with affected individuals with neuropathologic diagnosis of dementia with Lewy bodies (DLB). Taken together, these results indicate that the chromosome 12 locus acts independently of APOE to increase the risk of late-onset familial AD and that it may be associated with the DLB variant of AD.

Polygenetic susceptibility and resistance to 4-nitroquinoline 1-oxide-induced tongue carcinomas in the rat

Summary Oral administration of 4-nitroquinoline 1-oxide (4NQO) to rats induced a high incidence of tongue carcinomas (TCs). The inbred Dark-Agouti (DA) strain of rats showed much higher susceptibility to 4NQO-induced TCs than the Wistar-Furth (WF) strain. Our previous study on crosses between the two strains postulated a semidominant susceptibility gene in DA and a semidominant resistance gene in WF rats. This hypothesis was confirmed by the genetic analysis of the back-crosses to either parent with PCR-based microsatellite assay. Using the number of TCS with >5 mm diameter as a quantitative parameter, we mapped a quantitative trait locus Stc1 (Susceptibility to TC) favouring TC development near the locus D19Mit9 on Chr. 19 with a peak LOD score of 6.08. Two other regions in Chr. 3 and Chr. 14 showed weak linkage for susceptibility, but were not statistically significant. On the other hand, another quantitative trait locus Rtc1 (Resistance to TC) providing resistance to TCs was mapped on Chr. 1 between the loci of D1Mit1 and D1Mit3 with a peak LOD score of 3.30. Quantitative parameters such as the number of tumours in the tongue or upper alimentary tract, the frequency of larger tumours and their maximum size were closely correlated and principally determined by Stc1 and Rtc1 . Therefore the susceptibility to 4NQO-induced TCs in crosses between DA and WF is explained by the combinations of genotypes at these two loci. Possible candidate genes for Stc1 and Rtc1 are discussed.

Evaluation of linkage of markers on chromosome 6p with schizophrenia in Taiwanese families

Previous studies have indicated possible linkage of schizophrenia with chromosome 6p21-24. In an attempt to replicate these findings, we studied the linkage of schizophrenia with nine markers on chromosome 6p21-24 in 39 Taiwanese schizophrenic nuclear families with at least two affected siblings. Two diagnostic models (narrow: Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other nonaffective psychotic disorders) were used to define the disease phenotypes. With the broad and narrow diagnostic models, the marker D6S296 produced maximum two-point lod scores of 1.46 (straight theta = 0.2) and 1.35 (straight theta = 0. 2), respectively, in the recessive inheritance model. Assuming locus heterogeneity, a multipoint lod score of 0.85 was obtained between markers D6S296 and D6S277 under the narrow/recessive model. Maximum nonparametric lod scores of 1.25 ( p= 0.09) and 1.36 (p = 0.08) were observed, but still not statistically significant, at D6S296 in the narrow and broad diagnostic models, respectively. Both two-point analysis of the dominant model (lod score 0.85) and nonparametric analysis (lod score 1.25) showed a mild peak lod score appeared at marker D6S 285 as well. The results add some support to the suggestive linkage of schizophrenia with markers in the regions of chromosome 6p22 and 6p24 in an ethnically distinct Taiwanese sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:74-78, 2000.

A Locus for Autosomal Dominant “Pure” Hereditary Spastic Paraplegia Maps to Chromosome 19q13

Genetic loci for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) have been mapped to chromosomes 2p, 8q, 12q, 14q, and 15q. We undertook a genomewide linkage screen of a large family with ADPHSP, for which linkage at all previously identified ADPHSP loci was excluded. Analysis of markers on chromosome 19q gave a peak pairwise LOD score of 3.72 at D19S420, allowing assignment of a novel ADPHSP locus (which we have termed "SPG12") to this region. Haplotype construction and analysis of recombination events narrowed the SPG12 locus to a 16.1-cM region between markers D19S868 and D19S902.

Fine-mapping of the type 1 diabetes locus ( IDDM4 ) on chromosome 11q and evaluation of two candidate genes ( FADD and GALN ) by affected sibpair and linkage-disequilibrium analyses

Previous studies have identified a susceptibility region for insulin-dependent (type 1) diabetes mellitus on chromosome 11q13 (IDDM4). In this study, 15 polymorphic markers were analyzed for 382 affected sibpair (ASP) families with type 1 diabetes. Our analyses provided additional evidence for linkage for IDDM4 (a peak LOD score of 3.4 at D11S913). The markers with strong linkage evidence are located within an interval of approximately 6 cM between D11S4205 and GALN. We also identified polymorphisms in two candidate genes, Fas-associated death domain protein (FADD) and galanin (GALN). Analyses of the data by transmission/disequilibrium test (TDT) and extended TDT (ETDT) did not provide any evidence for association/linkage with these candidate genes. However, ETDT did reveal significant association/linkage with the marker D11S987 (P=0.0004) within the IDDM4 interval defined by ASP analyses, suggesting that IDDM4 may be in the close proximity of D11S987.