[Show abstract][Hide abstract] ABSTRACT: We present the findings of a large linkage study of bipolar affective disorder (BPAD) that involved genomewide analysis of 52 families (448 genotyped individuals) of Spanish, Romany, and Bulgarian descent and further fine mapping of the 1p34-p36, 4q28-q31, and 6q15-q24 regions. An additional sample of 56 German families (280 individuals) was included for this fine-mapping step. The highest nonparametric linkage scores obtained in the fine mapping were 5.49 for 4q31 and 4.87 for 6q24 in the Romany families and 3.97 for 1p35-p36 in the Spanish sample. MOD-score (LOD scores maximized over genetic model parameters) analysis provided significant evidence of linkage to 4q31 and at least borderline significance for the 1p and 6q regions. On the basis of these results and previous positive research findings, 4q31 and 6q24 should now be considered confirmed BPAD susceptibility loci, and 1p35-p36 is proposed as a new putative locus that requires confirmation in replication studies.
The American Journal of Human Genetics 01/2006; 77(6):1102-11. DOI:10.1086/498619 · 10.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alcohol dependence is a typical example of a complex trait that is governed by several genes and for which the mode of inheritance is unknown. We analyzed the microsatellite markers and the Affymetrix single-nucleotide polymorphisms (SNPs) for a subset of the Collaborative Study on the Genetics of Alcoholism family sample, 93 pedigrees of Caucasian ancestry comprising 919 persons, 390 of whom are affected according to DSM III-R and Feighner criteria. In particular, we performed parametric single-marker linkage analysis using MLINK of the LINKAGE package (for the microsatellite data), as well as multipoint MOD-score analysis with GENEHUNTER-MODSCORE (for the microsatellite and SNP data). By use of two liability classes, different penetrances were assigned to males and females. In order to investigate parent-of-origin effects, we calculated MOD scores under trait models with and without imprinting. In addition, for the microsatellite data, the MOD-score analysis was performed with sex-averaged as well as sex-specific maps. The highest linkage peaks were obtained on chromosomes 1, 2, 7, 10, 12, 13, 15, and 21. There was evidence for paternal imprinting at the loci on chromosomes 2, 10, 12, 13, 15, and 21. A tendency to maternal imprinting was observed at two loci on chromosome 7. Our findings underscore the fact that an adequate modeling of the genotype-phenotype relation is crucial for the genetic mapping of a complex trait.
[Show abstract][Hide abstract] ABSTRACT: TNF-related apoptosis-inducing ligand (TRAIL) is not only involved in cell death but also in other immunoregulatory mechanisms. So far, the regulation of the TRAIL pathway in physiologic and pathologic conditions remains unclear. Due to the implication in brain damage and the elevated expression in peripheral immune cells of patients with multiple sclerosis (MS), an autoimmune disease of the central nervous system, TRAIL might play a central role in the pathology of this disease. Here, we have identified a highly polymorphic region in the TRAIL promoter. Using single-strand conformation polymorphism analysis, we found four single nucleotide polymorphisms (SNPs) within 111 base pairs. One of these SNPs is located in a binding site for the transcription factor AP-1. However, the RNA and protein expression of TRAIL revealed no obvious differences in relation to the genotypes. Furthermore, investigating samples from both MS patients and healthy controls we could not detect any association of these newly described polymorphisms to the clinical disease pattern. Thus, the TRAIL promoter contains a highly polymorphic area which has, however, no impact on molecule expression, and is neither directly related to increased risk of developing MS nor associated with a certain course of this heterogeneous disease in our population.
Journal of Neuroimmunology 05/2004; 149(1-2):195-201. DOI:10.1016/j.jneuroim.2003.12.014 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The anti-inflammatory cytokine interleukin (IL)-10 is considered to play a major role in the pathophysiology of psoriasis, which is characterized by an IL-10 deficiency. Systemic administration of IL-10 has been shown to be an effective therapy for psoriasis. The IL-10 promoter region contains a highly polymorphic microsatellite (IL10.G) and in a recent case-control study the IL10.G13 (144 bp) allele was found to be associated with familial early onset psoriasis (type 1 psoriasis) having a susceptible effect.
As it is essential in multifactorial diseases to replicate findings before definite conclusions can be drawn, we decided to perform a follow-up study and to follow a genetic approach analysing allele transmission in families with a positive family history of psoriasis.
We studied 137 nuclear families (trio-design) comprising 456 individuals and genotyped the IL10.G marker. For comparison we also genotyped the microsatellite tn62 as a reference marker of the major psoriasis susceptibility locus on chromosome 6p21 (PSORS1). In the present study allele transmission was evaluated using the family-based association test (FBAT) and GENEHUNTER 2.0 based on the transmission/disequilibrium test.
The G13 allele (144 bp) had a frequency of 24%, was present in 88 families and clearly showed an even transmission (FBAT, P = 0.753). In contrast, allele 3 (IL10.G9) (136 bp) had a frequency of 39%, was present in 110 families and was transmitted in 43 trios and remained untransmitted in 67 trios (FBAT, P = 0.026), thus showing preferential nontransmission. For the HLA-linked tn62-marker we obtained a P-value of 0.00027 for allele 4 in the same study group.
In conclusion, we failed to confirm the susceptible effect of the G13 allele, but provide the first data for a protective effect of allele 3 (IL10.G9) for familial psoriasis. Our results suggest that the IL10.G polymorphism is not a major locus, but acts as a minor locus.
British Journal of Dermatology 09/2003; 149(2):381-5. DOI:10.1046/j.1365-2133.2003.05411.x · 4.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To follow up the novel psoriasis susceptibility region on chromosome 19 (PSORS6), we performed an association scan for psoriasis vulgaris using 45 evenly spaced DNA microsatellite markers. For this study, a new independent sample of 210 nuclear psoriasis families (trio design) from Northern Germany was recruited. We used the family based association test (FBAT) for an association scan over the chromosome 19 region encompassing 50.8 cM. We obtained a positive association for the markers D19S922 (allele 5, P = 0.008) and D19S916 (allele 13, P = 0.016), which correspond to the peak of the region identified in a previously performed scan. We identified two novel regions by a single marker, each showing negative association at D19S917 on 19p13.1 (allele 8, P = 0.0034) and at D19S425 (allele 9, P = 0.0005), compatible with the hypothesis of protective loci. These two novel regions were explored in more detail using novel microsatellite markers at an average distance of 100 kb. A separate analysis distinguishing between familial (n = 137) and sporadic (n = 73) psoriasis families showed that the familial trios contribute strongly in the region around D19S425 (P = 0.004), while the comparably small subset of 73 sporadic trios has a stronger effect at the locus around D19S917 (P = 0.026). These studies confirm the existence of a psoriasis susceptibility locus on chromosome 19 and give first evidence for the existence of both susceptible and protective loci in this region. Analysis of a dense marker set from these refined regions will eventually allow identification of the underlying susceptibility alleles.
[Show abstract][Hide abstract] ABSTRACT: Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.
The American Journal of Human Genetics 07/2003; 73(1):49-62. DOI:10.1086/376547 · 10.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A recent genome-wide scan revealed a major susceptibility locus for idiopathic generalized epilepsies (IGEs) in the chromosomal region 8p12 in 32 IGE families without members with juvenile myoclonic epilepsy (JME). This study explored the presence of an IGE locus in the chromosomal region 8p12.
Our study included 176 multiplex families of probands with common IGE syndromes. Parametric and nonparametric multipoint linkage analyses were carried out between the IGE trait and six microsatellite polymorphisms encompassing the putative susceptibility locus. To explore the associated phenotype-genotype relation, two distinct subgroups of families were selected by the presence (n = 64) or absence (n = 112) of a family member with JME. To adjust the phenotypic spectrum toward adolescent-onset IGEs, a third subgroup of 28 families without JME was chosen through an IGE proband with seizure onset at age 10-20 years.
Parametric and nonparametric multipoint linkage analyses provided no evidence for linkage between IGE and markers encompassing the putative IGE locus in the chromosomal region 8p12. Furthermore, we found no hint of linkage along the candidate region in any of the three family subgroups.
We failed to provide evidence for a major IGE locus in the chromosomal region 8p12. On the contrary, these parametric linkage results provide strong evidence against linkage across the candidate region under a broad range of genetic models. If there is a susceptibility locus for IGE in the chromosomal region 8p12, then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.
[Show abstract][Hide abstract] ABSTRACT: A recent genome-wide scan revealed suggestive evidence for two susceptibility loci for idiopathic generalized epilepsy (IGE) in the chromosomal regions 5p15 and 5q14-q22 in families with typical absence seizures. The present replication study tested the validity of the tentative IGE loci on chromosome 5. Our study included 99 multiplex families in which at least one family member had typical absence seizures. Parametric and non-parametric multipoint linkage analyses were carried out between the IGE trait and 23 microsatellite polymorphisms covering the entire region of chromosome 5. Multipoint parametric heterogeneity lod scores < -2 were obtained along chromosome 5 when a proportion of linked families greater than 50% was assumed under recessive inheritance and > 60% under dominant inheritance. Furthermore, non-parametric multipoint linkage analyses revealed no hint of linkage throughout the candidate region (P > 0.05). Accordingly, we failed to support previous evidence for common IGE loci on chromosome 5. If there is a susceptibility locus for IGE on chromosome 5 then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.
Epilepsy Research 10/2002; 51(1-2):23-9. DOI:10.1016/S0920-1211(02)00097-9 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Irregularities of dopaminergic and serotonergic neurotransmission have been implicated in a variety of neuropsychiatric disorders. DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase, is an enzyme involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. Therefore, the DDC gene can be considered as a candidate gene for affective disorders. Recently, two novel variants were reported in the DDC gene: a 1-bp deletion in the promoter and a 4-bp deletion in the untranslated exon 1. Subsequently, an association case-control study including 112 English patients and 80 Danish patients with bipolar affective disorder (BPAD) revealed a significant association with the 1-bp deletion. This finding prompted us to analyze whether this effect was also present in a larger and ethnically homogeneous sample of 228 unrelated German patients with BPAD (208 patients with BP I disorder, 20 patients with BP II disorder), 183 unrelated patients with unipolar affective disorder (UPAD), and 234 healthy control subjects. For both BPAD and UPAD we could not detect a genetic association with either variant. Thus, our results do not support an involvement of the 1-bp or 4-bp deletion within the DDC gene in the etiology of affective disorders.
American Journal of Medical Genetics 08/2002; 114(5):519-22. DOI:10.1002/ajmg.10308 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A recent genome-wide scan showed strong evidence for a major locus for common syndromes of idiopathic generalized epilepsy (IGE) at the marker D18S474 on chromosome 18q21.1 (LOD score 4.5/5.2 multipoint/two-point). The present replication study tested the presence of an IGE locus in the chromosomal region 18q21.1. Our linkage study included 130 multiplex families of probands with common IGE syndromes. Eleven microsatellite polymorphisms encompassing a candidate region of 30 cM on either side of the marker D18S474 were genotyped. The two-point homogeneity LOD score for D18S474 showed strong evidence against linkage at the original linkage peak (Z = -18.86 at theta(m = f) = 0.05), assuming a recessive mode of inheritance with 50% penetrance. Multipoint parametric heterogeneity LOD scores < -2 were obtained along the candidate region when proportions of linked families greater than 35% were assumed under recessive inheritance. Furthermore, non-parametric multipoint linkage analyses showed no hint of linkage throughout the candidate region (P > 0.19). Accordingly, we failed to support evidence for a major IGE locus in the chromosomal region 18p11-18q23. If there is a susceptibility locus for IGE in this region then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.
American Journal of Medical Genetics 08/2002; 114(6):673-8. DOI:10.1002/ajmg.10645 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of ∼1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25–q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing ‘suggestive’ evidence for linkage localized to 1p33–p36, 2q21–q33, 3p14, 3q26–q27, 6q21–q22, 8p21, 13q11 and 14q12–q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24–p21 and 2q31–q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21–q23.
Human Molecular Genetics 01/2002; 10(25). DOI:10.1093/hmg/10.25.2933 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently evidence has been provided for a genetic control of T-cell dependent cytokine production by HLA-class II. Candidate genes in multiple sclerosis, a T-cell mediated autoimmune disease, are the disease-associated DR2, DQ6, Dw2 haplotype. Previous observations by us and others imply a HLA-DR2 dependent propensity of antigen-specific T-cell lines to produce increased amounts of TNF-alpha/beta. Here, we tested a possible association between HLA or disease status with cytokine production employing the simple and widely used method of bulk cultures. Peripheral blood cells of 48 patients and 68 healthy individuals were analyzed. We observed no significant differences of the cytokine production in relation to disease status or any HLA polymorphism. Our data indicate that, in contrast to monoclonal T-cell cultures, bulk cultures are not suitable to detect immunogenetic control of T-cell function.
[Show abstract][Hide abstract] ABSTRACT: HLA antigens are associated with psoriasis vulgaris across populations with different ethnic background. We have previously shown that in Caucasians this association is primarily based on the class I alleles of the extended HLA haplotype 57.1 (EH57.1/I), HLA-Cw6-HLA-B57. However, it remained unclear whether HLA-Cw6 itself or a closely linked locus predisposes to the disease. An interesting candidate for this presumed locus is corneodesmosin, which is exclusively synthesized in keratinocytes. The corneodesmosin gene locus (CDSN) is only 160 kb telomeric to HLA-C and tightly associated with psoriasis. In order to find out whether EH57.1/I or a corneodesmosin variant are the susceptibility determinants on 6p, HLA class I alleles and single-nucleotide polymorphisms (SNPs) of corneodesmosin were investigated at the sequence level and analyzed by comparative association tests. Transmission disequilibrium tests (TDT) were performed in 52 nuclear families, of which 36 were fully informative for a joint comparison of HLA and CDSN with regard to association to psoriasis. The extended TDT according to Wilson was employed to test for locus interaction. Using the HLA haplotype EH57.1/I and the CDSN haplotype formed by three intragenic variant sites at nt=619 (T), 1236 (T), and 1243 (C), we obtained the best resolution of parental transmission to index cases in the trio families. On direct comparison of the contributions of the HLA and the CDSN haplotypes, there was a markedly stronger association of the corneodesmosin TTC haplotype, which is not apparent in single locus analysis. We show furthermore that there is no higher order interaction between psoriasis, HLA, and CDSN. This lack of three-locus interaction is suggestive of two independent genetic contributions to psoriasis within the major histocompatibility complex (MHC).
[Show abstract][Hide abstract] ABSTRACT: In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.
[Show abstract][Hide abstract] ABSTRACT: Various polymorphisms of the X-chromosomal monoamine oxidase A (MAO-A) gene were investigated for association with affective disorders. However, none of the studied variants could consistently be associated with either major depressive or bipolar affective disorder. Recently, a positive association between panic disorder and a novel functional repeat polymorphism in the MAO-A gene promoter, with the longer alleles being more active, was reported. Since monoaminergic neurotransmission is supposed to play an important role in affective disorders, we investigated a potential association of this polymorphism with major depressive illness in a sample of 146 unrelated patients of German descent and a control group of 101 individuals with a negative life history for affective disorders. Similarly to the recent findings in panic disorder, we observed a significantly increased frequency of genotypes containing only long alleles in female patients with recurrent major depression in comparison with age- and sex-matched controls. Thus, our data suggest that an excess of high-activity MAO-A gene promoter alleles resulting in an elevated MAO-A activity is a risk factor for major depressive disorder in females. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:801-803, 2000.
American Journal of Medical Genetics 01/2001; 96(6):801-3. DOI:10.1002/1096-8628(20001204)96:6<801::AID-AJMG21>3.3.CO;2-W · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
The American Journal of Human Genetics 11/2000; 67(4):1020-4. DOI:10.1086/303075 · 10.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Among the candidate genes for multiple sclerosis (MS), the strongest influence is conferred by human leucocyte antigen (HLA) class II genes, in particular the DR2, DQ6, Dw2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602). Similar to other autoimmune diseases, it is not clear yet how the presence of a specific HLA-DR or -DQ molecule translates into an increased disease susceptibility. Previous observations by us and others imply a HLA-DR2 dependent propensity of antigen-specific T-cell lines to produce increased amounts of TNF-alpha/beta as one mechanism how DR2 could contribute to susceptibility. In this article, we investigated the distribution of polymorphic stretches of the DRB1, DQA1, and DQB1 chains known to be relevant for antigen binding, in 66 unrelated patients with relapsing remitting MS and 210 unrelated controls. We found a significant association with disease for the appearance of proline at position 11, arginine at position 13, and alanine at position 71 of HLA-DRbeta1. Surprisingly, we identified only residues preferentially expressed in the MS group that were related to HLA-DR2. Thus, the contribution of HLA class II to the pathogenesis of MS is not mediated by allele-overlapping antigen binding sites, but is confined to the disease associated HLA allele.
Human Immunology 11/2000; 61(10):1021-30. DOI:10.1016/S0198-8859(00)00173-7 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present an extension to parametric linkage analysis that allows modeling diseases with a parent-of-origin effect (i.e., imprinting). Different penetrances are assumed for individuals being heterozygous at the disease locus, depending on their having inherited the disease allele from the father or mother. Motivated by the finding of a maternally expressed locus influencing alcohol consumption in mice (Alcp2), the analysis method has been included into the program GENEHUNTER for application to Problem 1, Collaborative Study on the Genetics of Alcoholism of Genetic Analysis Workshop 11. By this extension, a powerful tool is provided for adequately modeling an inherited disease in linkage analysis that supposedly has imprinting effects. The program has been used to analyze the data set on alcohol dependence in humans and can be applied to other genetically determined traits as well.