Autosomal dominant ataxia: Genetic evidence for locus heterogeneity from a cuban founder-effect population

The locus for autosomal dominant ataxia with a diagnosis of olivo-ponto-cerebellar atrophy at autopsy has been previously assigned to chromosome 6p. However, evidence for two alternative locations has been reported. We have recently described a large potential founder-effect population of such patients in the Holguin province of Cuba. With an estimated 1,000 patients available for analysis, this extensive cluster of families provides a unique opportunity for the definitive localization of the genetic mutation. Linkage analysis between the disease locus in this population and markers within and flanking the HLA region on chromosome 6 were undertaken in 12 families comprising over 100 affected individuals. Despite similarity in the clinical phenotype between those families where the disease locus has been reported to be linked to the HLA locus and the Cuban patients, no evidence of linkage to this region could be demonstrated in the latter. The disease locus was excluded from a 96-cM genetic interval of the short arm of chromosome 6, encompassing the F13A1-HLA-GLO1-MUT/D6S4 loci. These data strongly support the existence of genetic heterogeneity for the disease.     

Use of a Quantitative Trait to Map a Locus Associated with Severity of Positive Symptoms in Familial Schizophrenia to Chromosome 6p

A number of recent linkage studies have suggested the presence of a schizophrenia susceptibility locus on chromosome 6p. We evaluated 28 genetic markers, spanning chromosome 6, for linkage to schizophrenia in 10 moderately large Canadian families of Celtic ancestry. Parametric analyses of these families under autosomal dominant and recessive models, using broad and narrow definitions of schizophrenia, produced no significant evidence for linkage. A sib-pair analysis using categorical disease definitions also failed to produce significant evidence for linkage. We then conducted a separate sibpair analysis using scores on positive-symptom (psychotic), negative-symptom (deficit), and general psychopathology-symptom scales as quantitative traits. With the positive symptom-scale scores, the marker D6S1960 produced P = 1.2 x 10(-5) under two-point and P = 5.4 x 10(-6) under multipoint analyses. Using simulation studies, we determined that these nominal P values correspond to empirical P values of .034 and .0085, respectively. These results suggest that a schizophrenia susceptibility locus on chromosome 6p may be related to the severity of psychotic symptoms. Assessment of behavioral quantitative traits may provide increased power over categorical phenotype assignment for detection of linkage in complex psychiatric disorders.     

Migraine with Aura Susceptibility Locus on Chromosome 19p13 Is Distinct from the Familial Hemiplegic Migraine Locus

Migraine is a common neurological disease with a major genetic component. Recently, it has been proposed that a single locus on chromosome 19p13 contributes to the genetic susceptibility of both rare familial hemiplegic migraine (FHM) and more common types of migraine, migraine with aura and migraine without aura. We analyzed 16 families for co-segregation of migraine with aura and chromosome 19p13 markers. Using multipoint model-free linkage analysis, we obtained a lod score of 4.28 near D19S592. Using an affecteds-only model of linkage, we observed a lod score of 4.79 near D19S592. We were able to provide statistical evidence that this locus on chromosome 19p13 is most likely not the gene CACNA1A, mutations in which cause FHM. These data indicate that chromosome 19p13 contains a locus which contributes to the genetic susceptibility of migraine with aura that is distinct from the FHM locus.     

Tight linkage of the gene for spinocerebellar ataxia to D6S89 on the short arm of chromosome 6 in a kindred for which close linkage to both HLA and F13A1 is excluded.

A locus for an autosomal dominant form of spinocerebellar ataxia (SCA1) has been assigned to the short arm of chromosome 6 on the basis of linkage to the major histocompatibility system (HLA). In this study of a five-generation American black family, close linkage between the disease locus and both HLA and the coagulation factor XIIIA (F13A1) locus was excluded, and lod scores for all locations of the disease locus between HLA and F13A1 were less than -1.4. These results suggest that the locus causing spinocerebellar ataxia in this family is not in this region. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is between HLA and F13A1. The maximum lod score for SCA1 and D6S89 is 4.90 at a recombination fraction of 0, both in males and in females. These data show that exclusion of close linkage to the HLA complex and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus in that family is on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89, to determine whether the locus causing the disease is SCA1.     

Genomewide scan in german families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13

Psoriasis is a common chronic inflammatory skin disease with a strong genetic component. Few psoriasis-susceptibility loci have been reported, and only two have been confirmed in independent data sets. This article reports results of a genomewide scan that was performed, using 370 microsatellite markers, for psoriasis-susceptibility loci in 32 German extended families, comprising 162 affected and 195 unaffected individuals. Nonparametric linkage analysis of all families provided strong evidence for a novel psoriasis-susceptibility locus on chromosome 19p (Zlr=3.50; P=.0002). Parametric analysis revealed a heterogeneity LOD score of 4.06, corresponding to a genomewide significance level of.037, under the assumption of a recessive model with high disease-allele frequency and 66% as the proportion of linked families. This study confirms linkage of psoriasis to the HLA region on chromosome 6p and suggests additional regions on chromosomes 8q and 21q for further investigations.     

Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families

Childhood-onset asthma is frequently found in association with atopy. Although asthmatic children may develop IgE antibodies against variety of allergens, asthma is associated primarily with allergy to house-dust mites, molds, or other allergens. In this study, we conducted a genome-wide linkage search in 47 Japanese families (197 members) with more than two mite-sensitive atopic asthmatics (65 affected sib-pairs) using 398 markers. Multipoint linkage analysis was carried out for atopic asthma as a qualitative trait using the MAPMAKER/SIB program. We observed significant evidence for linkage with maximum lod scores (MLS) of 4.8 near the interleukin 12 B gene locus on chromosome 5q31-q33. In addition, suggestive evidence on 4q35 with MLS = 2.7 and on 13q11 with MLS = 2.4 was obtained. The other possible linkage regions included 6p22-p21.3 (MLS = 2.1), 12q21-q23 (MLS = 1.9), and 13q14.1-q14.3 (MLS = 2.0). Many of the linkage loci suggested in this study were at or close to those suggested by genome-wide studies for asthma in Caucasian populations. The present study suggests the contribution of the interleukin 12 B gene or nearby gene(s) to mite-sensitive atopic asthma and a considerable number of genetic variants common across Caucasians and Japanese populations contributing to asthma, although the relative importance of various variants may differ between the groups.     

Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11

Rupture of intracranial aneurysms (IAs) causes subarachnoid hemorrhage, a devastating condition with high morbidity and mortality. Angiographic and autopsy studies show that IA is a common disorder, with a prevalence of 3%-6%. Although IA has a substantial genetic component, little attention has been given to the genetic determinants. We report here a genomewide linkage study of IA in 104 Japanese affected sib pairs in which positive evidence of linkage on chromosomes 5q22-31 (maximum LOD score [MLS] 2.24), 7q11 (MLS 3.22), and 14q22 (MLS 2.31) were found. The best evidence of linkage is detected at D7S2472, in the vicinity of the elastin gene (ELN), a candidate gene for IA. Fourteen distinct single-nucleotide polymorphisms (SNPs) were identified in ELN, and no obvious allelic association between IA and each SNP was observed. The haplotype between the intron-20/intron-23 polymorphism of ELN is strongly associated with IA (P=3.81x10-6), and homozygous patients are at high risk (P=.002), with an odds ratio of 4.39. These findings suggest that a genetic locus for IA lies within or close to the ELN locus on chromosome 7.     

Linkage of human narcolepsy with HLA association to chromosome 4p13-q21

Although narcolepsy is highly associated with human leukocyte antigen (HLA) DQ6/DQB1*0602 and/or DR2/DRB1*1501, most individuals with the HLA haplotype are free of narcolepsy. This indicates that HLA alone makes a relatively small contribution to the development of narcolepsy and that a non-HLA gene(s) can contribute to the genetic predisposition even in narcoleptic cases with HLA association. We conducted a genome-wide linkage search for narcolepsy in eight Japanese families with 21 DR2-positive patients (14 narcoleptic cases with cataplexy and 7 cases with an incomplete form of narcolepsy). A lod score of 3.09 suggested linkage to chromosome 4p13-q21. A lod score of 1.53 was obtained at the HLA-DRB1 locus, though this lod score may be biased since all the affected patients and many of the family members were DR2-positive. No other loci including hypocretin, hypocretin receptor 1, and hypocretin receptor 2 had lod scores greater than 1.0. The present study suggests that chromosome 4p13-q21 contains a second locus for HLA-associated human narcolepsy.     

Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy: no evidence for an epilepsy locus in the HLA region.

Evidence for a locus (EJM1) in the HLA region of chromosome 6p predisposing to idiopathic generalized epilepsy (IGE) in the families of patients with juvenile myoclonic epilepsy (JME) has been obtained in two previous studies of separately ascertained groups of kindreds. Linkage analysis has been undertaken in a third set of 25 families including a patient with JME and at least one first-degree relative with IGE. Family members were typed for eight polymorphic loci on chromosome 6p: F13A, D6S89, D6S109, D6S105, D6S10, C4B, DQA1/A2, and TCTE1. Pairwise and multipoint linkage analysis was carried out assuming autosomal dominant and autosomal recessive inheritance and age-dependent high or low penetrance. No significant evidence in favor of linkage was obtained at any locus. Multipoint linkage analysis generated significant exclusion data (lod score < -2.0) at HLA and for a region 10-30 cM telomeric to HLA, the extent of which varied with the level of penetrance assumed. These observations indicate that genetic heterogeneity exists within this epilepsy phenotype.     

Mapping the locus for familial hypertrophic cardiomyopathy to chromosome 11 in a family with a case of apical hypertrophic cardiomyopathy of the Japanese type

To identify the disease locus of familial hypertrophic cardiomyopathy (FHC) in a Chinese family, a genetic linkage study was performed using polymorphisms from various chromosomal regions. This family has eight affected members, including a case with typical features of apical hypertrophic cardiomyopathy of the Japanese type. The results revealed significant evidence of linkage of polymorphisms on chromosome 11p13–q13 and FHC in this family with a maximal lod score of 3.38 at θ = 0.00. Our data suggest that the locus responsible for FHC in this family maps to chromosome 11 and that the molecular basis of FHC in the case of apical hypertrophic cardiomyopathy of the Japanese type might be similar to that of other affected members in the same family. Further studies are needed to elucidate the whole spectrum of the genetic basis of apical hypertrophic cardiomyopathy of the Japanese type. Received: 15 June 1995 / Revised: 22 August 1995