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M Rietschel

Publications and source records attributed to M Rietschel.

At least 19 recordsLinked to original sources
PubMed2006

Variation of the serotonin transporter gene SLC6A4 in the susceptibility to migraine with aura.

To replicate a reported association between migraine with aura (MA) and a promoter polymorphism in the serotonin transporter gene (SLC6A4), we performed a case-control study in a large German sample comprising 472 patients with MA and 506 controls. Neither this polymorphism nor a systematic analysis with single nucleotide polymorphisms capturing the main haplotype diversity of the SLC6A4 locus provided evidence for a contribution of SLC6A4 to the predisposition of complex inherited MA.

Adult↗
PubMed2006

Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14.

Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non-parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (AAO of 21 years or below). Non-parametric multipoint analysis suggested eight regions of linkage with P-values<0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12). The 3p14 region showed the most significant linkage (genome-wide P-value estimated over 10 000 simulated replicates of 0.015 [0.01-0.02]). After genome-wide search analysis, we performed additional linkage analyses with increased marker density using markers in four regions suggestive for linkage and having an information contents lower than 75% (3p14, 10q23, 16q23 and 20p12). For these regions, the information content improved by about 10%. In chromosome 3, the non-parametric linkage score increased from 3.51 to 3.83. This study is the first to use early-onset bipolar type I probands in an attempt to increase sample homogeneity. These preliminary findings require confirmation in independent panels of families.

Adolescent↗
PubMed2006

Transmission disequilibrium and haplotype analyses of the G72/G30 locus: suggestive linkage to schizophrenia in Palestinian Arabs living in the North of Israel.

Association of the G72/G30 locus with schizophrenia was recently reported in French Canadian, Russian, and Ashkenazi populations using case-control studies. In the present study we hypothesize the existence of a G72/G30 risk allele over-transmitted to affected sibs in Palestinian Arab families. A total of 223 Palestinian Arab families that included an affected offspring and parents were genotyped with 11 SNPs encompassing the G72/G30 genes. The families were recruited from three regions of Israel: 56 from the North (Afula), 136 from the central hill region (Bethlehem, Palestinian Authority), and 31 from the South (Beersheva). Individual SNP analyses disclosed a risk allele in SNP rs3916970 by both haplotype relative risk (HRR: chi(2) = 5.59, P = 0.018) and transmission disequilibrium test (TDT: chi(2) = 6.03, P = 0.014) in the Afula families. Follow-up multilocus analysis using family-based association tests (FBAT: z = 2.197, P = 0.028) exposed the adjacent haplotype. SNP rs3916970 is located about 8 kb from the linkage disequilibrium block that was reported to be associated with schizophrenia in Ashkenazi Jews. Excess of similar haplotypes of this region was observed in the Palestinian Arabs and the Ashkenazi patients. These data suggest a common risk factor for schizophrenia susceptibility in the G72/G30 locus among Ashkenazi Jews and Palestinian Arabs. The results strengthen previous reports on the role of this locus in the etiology of schizophrenia.

Alleles↗
PubMed2006

[Attitudes towards predictive genetic testing for Alzheimer's disease].

Most neuropsychiatric disorders have a complex aetiology. Discovery of the underlying genetics will provide insights into the disorders and allow the subsequent development of therapeutic interventions based upon an understanding of causality. The first vulnerability genes in Alzheimer's disease (AD) have been identified. The contribution of each vulnerability gene to the disorder is limited and does not enable prediction of course and onset in individual cases, only modification of the a priori risk. However, people may wish to be informed about this modification. Professionals have not favoured this form of predictive testing due to an awareness of its limitations and its potential for harm. However, little is known about public attitudes and understanding of such genetic testing in neuropsychiatric disorders. The aim of our study was to assess the attitudes of the general population and to explore the influence on these attitudes of knowledge about the illness and the understanding of risk information. In our study, a representative sample of the German general population (n=2001), relatives of patients with Alzheimer's disease (n=101) and physicians (n=43) were interviewed about their attitudes towards genetic tests for Alzheimer's disease and their perception and interpretation of risk information. To assess the influence of genetic counselling on these factors, 234 people were questioned before, and four weeks after, they were provided with detailed relevant information. Our results indicate that a substantial proportion of the German population (57%) is in favour of psychiatric genetic testing for AD in general. Even when the explanatory power of a genetic test is limited, a substantial proportion of the population (47%) expressed an interest in genetic testing. Counselling slightly decreased the interest in having a genetic test for oneself (from 47% to 38%). Physicians were more hesitant than both relatives and the general population concerning predictive genetic testing. Only a minority (11%) favoured prenatal genetic testing. Our results also show that both knowledge about AD and the capacity to interpret risk estimates are limited. While physicians' estimation of their personal risk for developing AD approximated to the actual average risk for the population, people in the general population and the relatives of AD patients tended to overestimate their personal risk. However, most of the general population still perceived this risk as average or low. While most physicians could correctly interpret information regarding the probability of risk, only one third of AD patients' relatives or members of the general population could. As the decision of an individual to undergo predictive testing relies mainly on his understanding of risk, the ability to correctly interpret risk information will be of crucial importance in the future. From a medical perspective, the prevailing approach of professional associations to genetic testing appears reasonable and therefore should not be changed at present.

Adult↗
PubMed2006

Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples.

To investigate the role of the corticotropin releasing hormone receptor 1 (CRHR1) in patterns of human alcohol drinking and its potential contribution to alcohol dependence, we analysed two independent samples: a sample of adolescents, which consisted of individuals from the 'Mannheim Study of Risk Children' (MARC), who had little previous exposure to alcohol, and a sample of alcohol-dependent adults, who met DSM-IV criteria of alcohol dependence. Following determination of allelic frequencies of 14 polymorphisms of the CRHR1 gene, two haplotype tagging (ht)SNPs discriminating between haplotypes with a frequency of > or =0.7% were identified. Both samples were genotyped and systematically examined for association with the htSNPs of CRHR1. In the adolescent sample, significant group differences between genotypes were observed in binge drinking, lifetime prevalence of alcohol intake and lifetime prevalence of drunkenness. The sample of adult alcohol-dependent patients showed association of CRHR1 with high amount of drinking. This is the first time that an association of CRHR1 with specific patterns of alcohol consumption has been reported. Our findings support results from animal models, suggesting an importance of CRHR1 in integrating gene-environment effects in alcohol use disorders.

Adolescent↗
PubMed2005

Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study.

The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.

Age Factors↗
PubMed2005

A dopamine transporter mutation associated with bipolar affective disorder causes inhibition of transporter cell surface expression.

The dopamine transporter (DAT) plays a crucial role in dopaminergic neurotransmission as it clears the extracellular space of dopamine (DA) and thus controls the concentration of active neurotransmitter. Genetic association studies have reported a variable number of tandem repeat polymorphisms in the 3'-noncoding region of the DAT gene implicating this protein in the development of various psychiatric disorders. In a sample of bipolar patients, two rare missense substitutions (A559V and E602G) have been identified, one of which (E602G) was inherited by the patient from her affected father. None of these mutations had been identified in any control subjects of this survey. Using a heterologous cellular expression system, we have analysed possible consequences of these mutations on functional properties of the encoded DAT protein. DA transport measurements and antagonist binding revealed that the A559V mutant protein is fully functional, whereas the E602G mutant is not. Further analyses by confocal microscopy showed that the E602G protein is transcribed and translated but not delivered to the cell surface. Taken together, our results suggest that this missense mutation has functional consequences thus supporting the need to screen larger samples of patients and their relatives for this rare but bipolar disorder-associated mutation in the DAT gene.

Adult↗
PubMed2004

Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia.

Schizophrenia is characterized by thought disorders, hallucinations and delusions. Genetic studies have shown a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GRIK2 was evaluated in 356 schizophrenic patients from three different clinical centers. Whereas paternal transmission shows equilibrium, we observed maternal transmission disequilibrium of GRIK2 in the largest population (p=0.03), which was still significant when all populations were added (p=0.05). These results are similar to the maternal GRIK2 transmission disequilibrium previously reported for autism, and support the presence of a susceptibility gene for schizophrenia at 6q16.

Alleles↗
PubMed2004

Cholecystokinin- and cholecystokinin-B-receptor gene polymorphisms in panic disorder.

Panic disorder like other neuropsychiatric disorders is believed to be caused by multiple psychosocial and biological factors. Several lines of evidence point to a role for the peptide neurotransmitter cholecystokinin in the pathogenesis of panic disorder. We therefore determined the allele and genotype frequencies of a single nucleotide polymorphism in the CCK gene (-36C>T) and one CT repeat polymorphism in the CCK-B-receptor gene in a German panic disorder sample (n = 115 for CCK gene polymorphism, n = 111 for CCK-B-receptor polymorphism) and compared them with gender and age matched controls. The length of the polymorphic CT repeat alleles varies between 146 bp and 180 bp. We first analysed the results by a permutation test which provided evidence for heterogeneity between patients and controls (p=0.002). We then analysed the data as a di-allelic polymorphism with a short (146-162bp) and a long (164-180bp) allele and as a tetra-allelic polymorphism with 4 alleles (146-154bp, 156-162bp, 164-170bp, 172-180bp). In the di-allelic analysis as well as in the tetra-allelic analysis there was an excess of the longer allele (p = 0.001) or the two longer alleles (p = 0.041) respectively in patients with panic disorder. No difference between groups was observed for the -36C > T polymorphism. Our findings are consistent with the notion that genetic variation in the CCK neurotransmitter system contributes to the pathogenesis of panic disorder.

Adult↗
PubMed2004

Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder.

A recent study has suggested that the brain-expressed genes for G72 and D-amino-acid oxidase (DAAO) exert an influence on susceptibility to schizophrenia. Our aim was to replicate this finding in German schizophrenic patients and to assess whether G72 and DAAO might also contribute to the development of bipolar affective disorder. We genotyped seven single-nucleotide polymorphisms (SNPs) in the G72 gene and three in the DAAO gene in 599 patients (299 schizophrenic, 300 bipolar) and 300 controls. At G72, individual SNPs and a four-marker haplotype were associated with schizophrenia. The most significant SNP as well as the haplotype were also associated with bipolar affective disorder (BPAD). DAAO was associated with schizophrenia, but not with BPAD. The association of variation at G72 with schizophrenia as well as BPAD provides molecular support for the hypothesis that these two major psychiatric disorders share some of their etiologic background.

Adult↗
PubMed2004

Etiopathogenetic mechanisms in long-term course of schizophrenia.

Schizophrenia is a severe mental disorder with a relapsing long-term course in 80 % of the sufferers. The underlying neurobiological principles of the long-term course are widely unknown. Therefore an attempt is made to evaluate data from structural imaging and neuropsychology to shed some light on these mechanisms. Interestingly there was a significant correlation between length of illness and volume reduction in the prefrontal grey matter in schizophrenia. There was a lack of such a correlation for the whole brain volume, white matter volume or the grey matter volume outside the prefrontal lobe. Furthermore none of the neuropsychological measures correlated with length of illness. Both findings are supported by data from prospective studies up to five years demonstrating a significant loss of frontal grey matter volume, but no change of cognitive dysfunction in the course of time. The attempt is made to connect prefrontal grey matter loss with post-mortem findings of reduced neuropil but preserved cytoarchitecture leading to recently described candidate genes and their function.

Brain↗
PubMed2003

Family-based and case-control study of catechol-O-methyltransferase in schizophrenia among Palestinian Arabs.

COMT is a ubiquitous enzyme crucial to catechol metabolism. The molecular basis of COMT thermolability, that leads to three to fourfold differences in enzyme activity, is due to a substitution of valine with methionine in the Val158/108Met polymorphism. Of special interest is the role of this gene in major psychoses especially since a microdeletion (22q11) containing the COMT gene (velo-cardio-facial syndrome) also carries with it several types of behavioral disorders, including an increased prevalence of schizophrenia. Almost 20 genetic studies have examined the role of COMT in schizophrenia with ambiguous results. Towards clarifying the role of this polymorphism in conferring risk for psychosis, we examined a large group of culturally and ethnically akin Palestinian Arab schizophrenic triads (N = 276) using both a case-control and family-based study. In 194 informative triads with at least one heterozygote parent, no preferential transmission of either COMT allele was observed in this sample (TDT statistic chi-square = 0.14 NS; 131 COMT valine alleles were transmitted and 125 alleles not transmitted). However, using a case-control design a significant increase (Likelihood ratio = 3.935, P = 0.047) in the valine allele was observed in the group of schizophrenic patients (N = 276) compared to an ethnically matched control group (N = 77). The association was stronger in female patients (P = 0.012) similar to other studies showing that some COMT behavioral effects are gender sensitive. In summary, by case-control design but not by a family-based study, there is a weak effect in female patients of the high activity COMT allele in conferring risk for schizophrenia.

Amino Acid Substitution↗
PubMed2003

Genetics of schizophrenia and affective disorders.

The molecular-genetic basis of non-mendelian, genetically influenced disorders (complex disorders) is beginning to be uncovered. Recently, major progress in localization and detection of disposition genes of schizophrenia and bipolar disorder was achieved. We provide a comprehensive overview of recent results of linkage and association studies in schizophrenia and bipolar disorder. Several disposition genes for schizophrenia (DTNBP1, NRG1, G72) were identified, whereas evidence for specific disposition genes in bipolar disorder is more limited. Multiple limitations of current research strategies in the search of disposition genes of complex disorders have to be considered; alternative phenotype definitions, genome-wide association studies and parallel investigation of epigenetic misregulations might overcome these limitations.

Animals↗
PubMed2002

[Genetics of bipolar affective disorders. Current status of research for identification of susceptibility genes].

Bipolar affective disorder is a highly heritable condition, as evidenced by twin, family, and adoption studies. However, the mode of inheritance is complex and linkage findings have been difficult to replicate. Despite these limitations, consistent linkage findings have emerged for several chromosomes, notably 3p12-p14, 4p16, 10q25-q26, and 12q23-q24. Three additional areas, 13q32-q33, 18p11-q11, and 22q12-q13, have shown linkage in regions that appear to overlap with linkage findings in schizophrenia. These chromosomal regions might harbour genes that contribute to the development of bipolar affective disorder. Recent candidate gene studies include some positive results for the serotonin transporter gene (5-HTT) on 17q11-q12 and the catechol-O-methyltransferase gene (COMT) on 22q11. New methods are being developed for linkage disequilibrium mapping and candidate gene approaches. One can be optimistic that over the next few years bipolar susceptibility genes will be identified.

Bipolar Disorder↗
PubMed2002

Excess of allele1 for alpha3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study.

The available data from preclinical and pharmacological studies on the role of gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in brain GABAergic system activity contributes to the vulnerability to bipolar affective disorders (BPAD). Moreover, the localization of the alpha3 subunit GABA receptor GABRA3 gene on the Xq28, a region of interest in certain forms of bipolar illness, suggests that GABRA3 may be a candidate gene in BPAD. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentric case-control sample, matched for sex and ethnogeographical origin. Allele and genotype (in females) frequencies were compared in 185 BPAD patients and 370 controls. A significant increase of genotype 1-1 was observed in BPAD females compared to controls (P=0.0004). Furthermore, when considering recessivity of allele 1 (females with genotype 1-1 and males carrying allele 1), results were even more significant (P= 0.00002). Our findings suggest that the GABRA3 polymorphism may confer susceptibility to or may be in linkage disequilibrium with another gene involved in the genetic etiology of BPAD.

Alleles↗