Christine Windemuth

Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder

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.

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.

A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25-q26

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, θ = 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.

Genomewide scan and fine-mapping linkage studies in four European samples with bipolar affective disorder suggest a new susceptibility locus on chromosome 1p35-p36 and provides further evidence of loci on chromosome 4q31 and 6q24

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.

Association scan of the novel psoriasis susceptibility region on chromosome 19: evidence for both susceptible and protective loci.

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.

Identification and functional characterization of a highly polymorphic region in the human TRAIL promoter in multiple sclerosis

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.

Multiple sclerosis associated amino acids of polymorphic regions relevant for the HLA antigen binding are confined to HLA-DR2

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.

Interleukin-10 promoter polymorphism IL10.G and familial early onset psoriasis

Summary  Background 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.

Linkage analysis of alcohol dependence using MOD scores

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.

Exploration of a putative susceptibility locus for idiopathic generalized epilepsy on chromosome 8p12

Summary:  Purpose: 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.