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

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.

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

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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 5 in families with typical absence seizures.

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.

A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q.

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 approximately 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.

Comparative association analysis reveals that corneodesmosin is more closely associated with psoriasis than HLA-Cw*0602-B*5701 in German families.

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).

Peripheral blood cell bulk cultures are not suitable for the analysis of the genetic control of T-cell cytokine function.

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.

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, 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.

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.

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.

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.

Linkage analysis with adequate modeling of a parent-of-origin effect.

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.

Linkage analysis in alcohol dependence.

Alcohol dependence often is a familial disorder and has a genetic component. Research in causative factors of alcoholism is coordinated by a multi-center program, COGA [The Collaborative Study on the Genetics of Alcoholism, Begleiter et al., 1995]. We analyzed a subset of the COGA family sample, 84 pedigrees of Caucasian ancestry comprising 745 persons, 339 of whom are affected according to DSM-III-R and Feighner criteria. Using parametric and nonparametric methods, evidence for linkage was found on chromosome 1 (near markers D1S532, D1S1588, and D1S534), as well as on chromosome 15 (near marker D15S642). Other regions of the genome showed suggestive evidence for contributing loci. Related findings are discussed in recent publications investigating linkage in humans [Reich et al., 1998] and mice [Melo et al., 1996].

Fitting genetic mapping functions based on sperm typing: results for three chromosomal segments in cattle.

Genetic mapping functions translate the observed recombination rate between two loci into the corresponding map distance in Morgan units. Different mapping functions give different weights to multiple crossing over and therefore lead to different results. This points out that not every function is best suited to fit a data set. The data used in this study originated from 2214 sperm from 37 Norwegian bulls, which were genotyped for 11 markers. The optimal functions for the chromosomes 6, 23 and the sex chromosome of cattle were derived using the maximum likelihood method, the likelihood ratio test and empirical discriminant analysis. It became apparent that for each chromosome a different function fitted the data best. These were the function of Rao et al. (Human Heredity 1977, 27, 99-104) with p = 0.63 for chromosome 6, the function of Goldgar & Fain (American Journal of Human Genetics 1988, 43, 38-45) with C0 = 0.42, C1 = 0.47, C2 = 0.07 and C3 = 0.04 for chromosome 23 and the function of Felsenstein (Genetics 1979, 91, 769-75) with K = 0.23 for the sex chromosome. The well known functions of Haldane (Journal of Genetics 1919, 8, 299-309) and Kosambi (Annals of Eugenics 1944, 12, 172-5) were shown to be suboptimal in most cases. A function is said to be multilocus feasible if the evaluation of the probability of all possible recombination events does not lead to negative values. The optimal function for chromosome 23 turned out to be multilocus feasible, whereas the functions for chromosome 6 and the sex chromosome were not. The choice of the correct mapping function is shown to have a considerable impact in mapping studies, when double recombinations have to be taken into account. Since there is no unique best mapping function, it is argued that it might be useful to use a simple parametric mapping function (like the one of Felsenstein 1979) and to estimate the respective parameter specifically for a given data set.