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ABSTRACT: To describe three Gypsy families with Marinesco-Sjögren syndrome (MSS), demyelinating neuropathy, and recurrent episodes of myoglobinuria in five of the six affected subjects. Because these families originated from the same genetically isolated founder population as did patients with congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome, and because the two syndromes have clinical manifestations in common, we hypothesized that the two related, albeit distinct, syndromes may represent clinical variants of a single genetic disorder.
Clinical studies were conducted and linkage and haplotype analyses were performed for the three families. A total of 16 individuals, including the 6 with MSS and 10 unaffected relatives, were genotyped for six polymorphic microsatellite markers from the CCFDN region on 18qter.
Linkage analysis of markers in the 18qter region, where we previously had located the CCFDN gene, produced a lod score of 3.55, demonstrating colocalization of the gene responsible for MSS with demyelinating neuropathy and myoglobinuria with the CCFDN gene. Moreover, the patients with MSS shared the conserved marker haplotype found in CCFDN chromosomes.
These data suggest that Marinesco-Sjögren syndrome with peripheral neuropathy and myoglobinuria, and congenital cataracts facial dysmorphism neuropathy syndrome are genetically identical and are caused by a single founder mutation.
Neurology 02/2002; 58(2):231-6. · 8.31 Impact Factor
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P Sklar,
S G Schwab,
N M Williams,
M Daly,
S Schaffner,
W Maier,
M Albus,
M Trixler,
P Eichhammer,
B Lerer, [......],
S Zammit,
A G Cardno,
S Jones,
G McCarthy,
V Milanova,
G Kirov,
M C O'Donovan,
E S Lander,
M J Owen,
D B Wildenauer
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ABSTRACT: A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.
Nature Genetics 07/2001; 28(2):126-8. · 35.53 Impact Factor
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S G Schwab, J Hallmayer,
M Albus,
B Lerer,
G N Eckstein,
M Borrmann,
R H Segman,
C Hanses,
J Freymann,
A Yakir,
M Trixler,
P Falkai,
M Rietschel,
W Maier,
D B Wildenauer
[show abstract]
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ABSTRACT: Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected sib-pairs with parental genotype information for statistical analysis strictly identity by descent. We genotyped 305 individuals with 463 markers at an average distance of approximately 10 cM genome-wide, and 1-2 cM in candidate regions (5q, 6p, q, 8p, 10p, 18p, 22q). The highest multipoint LOD scores (ASPEX) were obtained on 6p (D6S260, LOD = 2.0; D6S274, LOD = 2.2, MHC region, LOD = 2.15) and on 10p (D10S1714, LOD = 2.1), followed by 5q (D5S2066, LOD = 1.36), 6q (D6S271, LOD = 1.12; D6S1613, LOD = 1.11), 1q (D1S2675, LOD = 1.04), and 18p (broad disease model: D18S1116, LOD = 1.0). One hundred and thirty-three additional family members were available for some of the families (extended families) and were genotyped for these regions. GENEHUNTER produced a maximum NPL of 3.3 (P = 0.001) for the MHC region and NPL of 3.13 (P = 0.0015) for the region on 10p. There is support for these regions by independent groups. In genome-wide TDT analysis (sTDT, implemented in ASPEX), no marker passed the significance level of 0.0001 given by multiple testing, but nominal significance values for D10S211 (P = 0.03) and for GOLF (P = 0.0032) support further the linkage results on 10p and 18p. Our survey of 22 chromosomes identified candidate regions which should be useful to screen for schizophrenia susceptibility genes.
Molecular Psychiatry 12/2000; 5(6):638-49. · 13.67 Impact Factor
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J Hallmayer
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ABSTRACT: The low incidence of schizophrenia prohibits large scale prevention trials, and the question arises whether such studies become more feasible by taking into account genetic factors. The aim of the paper was to inform preventive endeavours with an account of the genetic background to schizophrenia.
The family, twin and adoptive studies of schizophrenia are reviewed and recent molecular genetic data presented.
Children of a parent diagnosed with schizophrenia have a ten-fold increased risk of developing the disorder. Twin and adoption studies strongly suggest the risk increase is mainly due to genetic factors. On an individual level, a positive family history is the strongest known risk factor for schizophrenia. For a prevention study, very large numbers of families have to be screened in order to reach a sufficient sample size.
One obvious way to increase the accuracy of predicting who is at high risk of developing schizophrenia would be to find specific mutations in the human genome. Attempts to isolate specific genes by means of linkage and association studies have been unsuccessful so far and, given the number of genes involved, it is extremely unlikely that the predictive value of individual genes will be high enough to warrant intervention. Genetic studies also suggest the genetic liability extends beyond the traditional clinical phenotypes. Prevention trials might become possible by adopting a broader approach.
Australian and New Zealand Journal of Psychiatry 12/2000; 34 Suppl:S47-55; discussion S56-7. · 2.93 Impact Factor
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American Journal of Medical Genetics 01/2000; 88(6):750-1.
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L Kalaydjieva,
A Perez-Lezaun,
D Angelicheva,
S Onengut,
D Dye,
N U Bosshard,
A Jordanova,
A Savov,
P Yanakiev,
I Kremensky,
B Radeva, J Hallmayer,
A Markov,
V Nedkova,
I Tournev,
L Aneva,
R Gitzelmann
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ABSTRACT: Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataracts in the first weeks of life. It has also been suggested that carriers of the deficiency are predisposed to presenile cataracts developing at age 20-50 years. Newborn screening data suggest that the gene frequency is very low worldwide but is higher among the Roma in Europe. Since the cloning of the galactokinase gene (GK1) in 1995, only two disease-causing mutations, both confined to single families, have been identified. Here we present the results of a study of six affected Romani families from Bulgaria, where index patients with galactokinase deficiency have been detected by the mass screening. Genetic linkage mapping placed the disease locus on 17q, and haplotype analysis revealed a small conserved region of homozygosity. Using radiation hybrid mapping, we have shown that GK1 is located in this region. The founder Romani mutation identified in this study is a single nucleotide substitution in GK1 resulting in the replacement of the conserved proline residue at amino acid position 28 with threonine (P28T). The P28T carrier rate in this endogamous population is approximately 5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.
The American Journal of Human Genetics 12/1999; 65(5):1299-307. · 10.60 Impact Factor
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B Salmon, J Hallmayer,
T Rogers,
L Kalaydjieva,
P B Petersen,
P Nicholas,
C Pingree,
W McMahon,
D Spiker,
L Lotspeich,
H Kraemer,
P McCague,
S Dimiceli,
N Nouri,
T Pitts,
J Yang,
D Hinds,
R M Myers,
N Risch
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ABSTRACT: Chromosomal region 15q11-q13 has been implicated to harbor a susceptibility gene or genes underlying autism. Evidence has been derived from the existence of cytogenetic anomalies in this region associated with autism, and the report of linkage in a modest collection of multiplex families. Most recently, linkage disequilibrium with the marker GABRB3-155CA2 in the candidate locus GABRB3, located in this region, has been reported. We searched for linkage using eight microsatellite markers located in this region of chromosome 15 in 147 affected sib-pairs from 139 multiplex autism families. We also tested for linkage disequilibrium in the same set of families with the same markers. We found no evidence for excess allele sharing (linkage) for the markers in this region. Also, we found no evidence of linkage disequilibrium, including for the locus GABRB3-155CA2. Thus, it appears that the role of this region of chromosome 15 is minor, at best, in the majority of individuals with autism.
American Journal of Medical Genetics 11/1999; 88(5):551-6.
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N Risch,
D Spiker,
L Lotspeich,
N Nouri,
D Hinds, J Hallmayer,
L Kalaydjieva,
P McCague,
S Dimiceli,
T Pitts, [......],
T Rogers,
B Salmon,
P Nicholas,
P B Petersen,
C Pingree,
W McMahon,
D L Wong,
L L Cavalli-Sforza,
H C Kraemer,
R M Myers
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ABSTRACT: We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying </=10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the replication family set, giving a maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may exist a gene of moderate effect in this region. We had only modestly positive or negative linkage evidence in candidate regions identified in other studies. Our results suggest that positional cloning of susceptibility loci by linkage analysis may be a formidable task and that other approaches may be necessary.
The American Journal of Human Genetics 08/1999; 65(2):493-507. · 10.60 Impact Factor
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J Hallmayer
American Journal of Medical Genetics 07/1999; 88(3):219-23.
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T Rogers,
L Kalaydjieva, J Hallmayer,
P B Petersen,
P Nicholas,
C Pingree,
W M McMahon,
D Spiker,
L Lotspeich,
H Kraemer,
P McCague,
S Dimiceli,
N Nouri,
T Peachy,
J Yang,
D Hinds,
N Risch,
R M Myers
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ABSTRACT: Several studies have suggested a role for the histocompatibility complex of loci (HLA) in the genetic susceptibility to autism. We have tested this hypothesis by linkage analysis using genetic marker loci in the HLA region on chromosome 6p in multiplex families with autism. We have examined sharing of alleles identical by descent in 97 affected sib pairs from 90 families. Results demonstrate no deviation from the null expectation of 50% sharing of alleles in this region; in fact, for most marker loci, the observed sharing was less than 50%. Thus, it is unlikely that loci in this region contribute to the genetic etiology of autism to any significant extent in our families.
Journal of Autism and Developmental Disorders 07/1999; 29(3):195-201. · 3.34 Impact Factor
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O Wittekindt,
S G Schwab,
E Burgert,
M Knapp,
M Albus,
B Lerer, J Hallmayer,
M Rietschel,
R Segman,
M Borrmann,
D Lichtermann,
M A Crocq,
W Maier,
D J Morris-Rosendahl,
D B Wildenauer
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ABSTRACT: A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.
Molecular Psychiatry 06/1999; 4(3):267-70. · 13.67 Impact Factor
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P Franke,
S G Schwab,
M Knapp,
M Gänsicke,
C Delmo,
P Zill,
M Trixler,
D Lichtermann, J Hallmayer,
D B Wildenauer,
W Maier
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ABSTRACT: The present study tests the hypothesis that the 9-repeat allele of the dopamine transporter gene (DAT1; SLC6A3) is more frequent in alcohol-dependent probands--and in particular those with severe withdrawal symptoms (seizures and/or delirium)--compared to nonalcoholics.
To avoid stratification effects, the family-based association approach of Falk and Rubinstein was used in our sample of 87 alcohol-dependent probands and their biological parents.
By applying a family-based association approach, we were not able to detect significant association between allele 9 at DAT1 (SLC6A3) and alcoholism as well as between patients with or without severe withdrawal symptoms.
Based on our data, the impact of the 9-repeat allele of the dopamine transporter gene in alcoholism and the severity of alcohol withdrawal symptoms is putatively not substantial.
Biological Psychiatry 04/1999; 45(5):652-4. · 8.28 Impact Factor
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S G Schwab, J Hallmayer,
B Lerer,
M Albus,
M Borrmann,
S Hönig,
M Strauss,
R Segman,
D Lichtermann,
M Knapp,
M Trixler,
W Maier,
D B Wildenauer
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ABSTRACT: The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the intronic CA-repeat marker G-olfalpha on chromosome 18p. The value decreased to .000088 (.0007) when nine sibs with recurrent unipolar depressive disorder were included. Linkage analysis using SSLP markers densely spaced around G-olfalpha yielded a maximum two-point LOD score of 3.1 for a marker 0.5 cM distal to G-olfalpha. Multipoint analysis under the assumption of heterogeneity supported this linkage-whether the affected pheotype was defined narrowly or broadly-as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In order to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olfalpha was transmitted 47 times and was not transmitted 21 times (P=.009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psychoses.
The American Journal of Human Genetics 11/1998; 63(4):1139-52. · 10.60 Impact Factor
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S G Schwab, J Hallmayer,
M Albus,
B Lerer,
C Hanses,
K Kanyas,
R Segman,
M Borrman,
B Dreikorn,
D Lichtermann,
M Rietschel,
M Trixler,
W Maier,
D B Wildenauer
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ABSTRACT: Recent reports on potential linkage by Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557], and by Straub et al. [1997: Am J Med Genet 74:558], prompted us to study chromosome 10 in a sample of 72 families containing 2 or more affected sibs with schizophrenia for additional evidence of linkage. We obtained highest allele sharing for the two markers D10S582 (61.5% allele sharing, chi2 = 7.6, P = 0.0058) and D10S1423 (59% allele sharing, chi2 = 4.76, P = 0.029). D10S1423 is one of the markers with the highest lod scores in the study of Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557]. GENEHUNTER analysis revealed a nonparametric lod score (NPL) of 3.2 (P = 0.0007) for the marker D10S1714, which lies in the same region. Multipoint affected sib-pair lod score analysis (identity by descent) calculated by ASPEX revealed a lod score of 1.72 for all possible sib-pair combinations (107) and of 2.13, when only independent sib-pairs (87) were counted. Our study provides further evidence for a potential susceptibility locus for schizophrenia on chromosome 10p.
American Journal of Medical Genetics 08/1998; 81(4):302-7.
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R Kaneva,
V Milanova,
G Onchev,
V Stoyanova,
C H Chakarova,
A Nikolova, J Hallmayer,
M Belemezova,
T Milenska,
G Kirov,
I Kremensky,
L Kalaydjieva,
A Jablensky
Psychiatric Genetics 02/1998; 8(4):245-9. · 2.58 Impact Factor
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ABSTRACT: DQCAR is a (CA)n microsatellite located in the HLA class II region and tightly linked to HLA-DQB1. Previous studies showed a strikingly low level of size variation in DQCAR alleles within an extensive subfamily of HLA-DQ subtypes (DQ1). DQCAR alleles in non-DQ1 subtypes showed a higher degree of size polymorphism. In this study sequence analysis demonstrates that DQ1-associated DQCAR alleles have a single C-->A nucleotide substitution interrupting the CA repeat array. Frequent CA-->GA mutations are also observed in DQ1-associated microsatellites with identical allele sizes. In contrast, DQCAR alleles associated with non-DQ1 haplotypes display a perfect CA repeat sequence and the variation in allele size is attributable only to differences in the number of CA repeats. Our results imply that several mutational mechanisms are involved in the generation of allelic diversity within the same microsatellite locus. The possibility of different mutation rates in the same locus should to be taken into account when using these markers in evolutionary and disease studies.
Genome Research 06/1997; 7(6):635-41. · 13.61 Impact Factor
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ABSTRACT: Suggestive evidence for a potential susceptibility locus for schizophrenia at 5q31 was obtained in two family samples. Sample I consisted of 14 families with schizophrenia and revealed for the marker IL9 a lod score of 1.8 by two point lod score analysis. Sample II comprised 44 families including four from sample I and was ascertained in order to employ affected sib-pair analysis by identity by descent. A lod score of 1.8 around the marker D5S399 was obtained by multipoint analysis. The lod score remained positive, but decreased to 1.27 when the four families from sample I were excluded in order to use sample II as a statistically independent replication sample. We propose a susceptibility locus for schizophrenia with probably minor contribution in the pedigrees under investigation.
Molecular Psychiatry 04/1997; 2(2):156-60. · 13.67 Impact Factor
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ABSTRACT: The understanding of the mutational mechanism that generates high levels of variation at microsatellite loci lags far behind the application of these genetic markers. A phylogenetic approach was developed to study the pattern and rate of mutations at a dinucleotide microsatellite locus tightly linked to HLA-DQB1 (DQCAR). A random Japanese population (n = 129) and a collection of multiethnic samples (n = 941) were typed at the DQB1 and DQCAR loci. The phylogeny of DQB1 alleles was then reconstructed and DQCAR alleles were superimposed onto the phylogeny. This approach allowed us to group DQCAR alleles that share a common ancestor. The results indicated that the DQCAR mutation rate varies drastically among alleles within this single microsatellite locus. Some DQCAR alleles never mutated during a long period of evolutionary time. Sequencing of representative DQCAR alleles showed that these alleles lost their ability to mutate because of nucleotide substitutions that shorten the length of uninterrupted CA repeat arrays; in contrast, all mutating alleles had relatively longer perfect CA repeat sequences.
Proceedings of the National Academy of Sciences 01/1997; 93(26):15285-8. · 9.68 Impact Factor
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J Hallmayer,
J M Hebert,
D Spiker,
L Lotspeich,
W M McMahon,
P B Petersen,
P Nicholas,
C Pingree,
A A Lin,
L L Cavalli-Sforza,
N Risch,
R D Ciaranello
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ABSTRACT: Genetic factors undoubtedly play a major etiologic role in autism, but how it is inherited remains unanswered. The increased incidence in males suggests possible involvement of the X chromosome.
Using data from 38 multiplex families with autism (2 or more autistic siblings), we performed a multipoint sib-pair linkage analysis between autism and 35 microsatellite markers located on the X chromosome. The model included a single parameter, the risk ratio lambda xs (i.e., ratio of risk to siblings compared with the population prevalence), owing to an X-linked gene. Different lambda xs values were assumed and regions of exclusion were established.
The entire X chromosome could be excluded for a lambda xs value of 4. The ability to exclude an X-linked gene decreased with smaller lambda xs values, and some positive evidence was obtained with smaller values. A maximum lod score of 1.24 was obtained at locus DXS424 with a lambda xs value of 1.5.
We were able to exclude any moderate to strong gene effect causing autism on the X chromosome. Smaller gene effects (lambda xs < 4) could not be excluded, in particular, a gene of small effect located between DXS453 and DXS1001.
Archives of General Psychiatry 12/1996; 53(11):985-9. · 12.02 Impact Factor
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L Kalaydjieva, J Hallmayer,
D Chandler,
A Savov,
A Nikolova,
D Angelicheva,
R H King,
B Ishpekova,
K Honeyman,
F Calafell, [......],
J Petrova,
I Turnev,
A Hristova,
M Moskov,
S Stancheva,
I Petkova,
A H Bittles,
V Georgieva,
L Middleton,
P K Thomas
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ABSTRACT: Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.
Nature Genetics 11/1996; 14(2):214-7. · 35.53 Impact Factor
