Biomedical subjects

T Sander

Publications and source records attributed to T Sander.

At least 37 records · Page 2Linked to original sources

PubMed2000

Genetics of alcohol withdrawal.

Alcohol withdrawal is a clinically and etiologically heterogeneous syndrome caused by a complex interaction of environmental (e.g., amount of ethanol) and genetic factors. Multiple genes are considered to be involved in various components of the syndrome, each of them contributing only modestly to withdrawal vulnerability. Association studies using candidate genes of the dopamine, serotonin, gabaergic and opioidergic systems are reviewed and methodological limitations are discussed.

Adult↗

PubMed2000

DRD4 exon III VNTR polymorphism-susceptibility factor for heroin dependence? Results of a case-control and a family-based association approach.

Dopaminergic abnormalities are implicated in the pathogenesis of substance abuse.1 Recently, two reports have been published suggesting an association between opioid dependence and presence of long alleles of the dopamine D4 receptor (DRD4) gene exon III VNTR.2, 3 We have attempted to replicate this finding using a two-tiered strategy employing independent case-control and family-based association samples. Our study was possibly the largest candidate gene association study to date on opioid dependence in a sample of 815 subjects, 396 of whom were patients. We found long alleles of the DRD4 exon III VNTR in similar frequency among 285 heroin addicts and 197 controls. Furthermore, no preferential transmission of long alleles to affected offspring was observed in a sample of 111 patients and their parents. Our results, therefore, do not support the hypothesis that alleles of the DRD4 exon III VNTR are susceptibility factors for opioid dependence in man. Molecular Psychiatry(2000) 5, 101-104.

Adult↗

PubMed2000

Genetic variation of European beech (Fagus sylvatica L.) along an altitudinal transect at Mount Vogelsberg in Hesse, Germany.

Allelic and genotypic variation at 13 different enzyme loci of autochthonous European beech (Fagus sylvatica L.) was investigated in six 110-160-year-old stands growing at elevations between 150 and 660 m above sea level on the western slope of mount Vogelsberg in central Germany. The highest elevated population showed the highest number of effective alleles (Ne), the highest total heterozygosity (He) and the highest population differentiation deltaT. Also, the genotype SKD-A2A3 of shikimate dehydrogenase was significantly more frequent at the two highest elevated stands (P = 11%) than at the three lowest elevated stands (P = 1%). Further differences in genotype frequencies between 11 of 15 stand pairs were elevation independent.

Alcohol Oxidoreductases↗

PubMed2000

Genetic variation of the glutamate transporter EAAT2 gene and vulnerability to alcohol dependence.

Glutamate-mediated excitatory pathways play an important role in the pathogenesis of alcohol dependence. The present association study tested the candidate gene hypothesis that variation of the gene encoding the astroglial glutamate transporter EAAT2 confers vulnerability to alcohol dependence. Genotypes of a silent G603A nucleotide exchange in exon 5 of the EAAT2 gene were assessed in 565 subjects of German descent, comprising 342 alcohol-dependent subjects and 223 control subjects. Two more homogeneous subgroups of alcoholics were selected: (1) 112 alcoholics with a history of alcohol withdrawal seizure or delirium; and (2) 54 alcoholics with an antisocial personality disorder. The Tridimensional Personality Questionnaire was applied to assess personality dimensions in 106 alcohol-dependent males. The allele frequencies of the G603A polymorphism did not differ significantly between the control subjects and either the entire sample of alcoholics or the alcoholics with severe physiological withdrawal symptoms. Without correction for multiple testing, there was a significant increase of the frequency of the A603 allele in the antisocial alcoholics compared with either the control subjects [chi2 = 4.587, 1 degree of freedom (df), P = 0.032] or the alcoholics without ASPD (chi2 = 4.968, 1 df, P = 0.026). The personality trait of Harm Avoidance was significantly lower in alcoholics carrying the A603 allele compared with those lacking it (U-test; P = 0.009). These two consistent lines of evidence suggest that genetic variation of the EAAT2 gene confers vulnerability to risk-taking behavior in alcoholics.

Adult↗

PubMed2000

Exonic variants of the GABA(B) receptor gene and panic disorder.

The enhancement of GABAergic neurotransmission has been closely linked to antipanic drug efficacy. This is the first study to investigate a putative association of exonic sequence variants of the human GABA(B) receptor 1 (GABA(B)R1) gene and susceptibility to panic disorder. Three DNA sequence variants in exons 1a1, 7 and 11 were assessed by polymerase chain reaction-based restriction fragment length polymorphism in a case-control study among patients with panic disorder with and without agoraphobia (DSM III-R criteria) and blood donors. There was no indication of an increased vulnerability to panic disorder or agoraphobia with respect to the allelic variants under study.

Agoraphobia↗

PubMed1999

Association analysis of exonic variants of the gene encoding the GABAB receptor and idiopathic generalized epilepsy.

The gene encoding the GABAB receptor (GABABR1) maps close to the HLA-F locus on chromosome 6p21.3 in the same region to which a major susceptibility locus for common subtypes of idiopathic generalized epilepsy (IGE), designated as EJM1, has been localized. Moreover, animal models suggest that the GABAB receptor plays a critical role in the epileptogenesis of absence seizures. Accordingly, the present association study tested the candidate gene hypothesis that genetic variants of the human GABABR1 gene confer susceptibility to common subtypes of IGE. Three DNA sequence variants in exons 1a1, 7, and 11 of the GABABR1 gene were assessed by PCR-based restriction fragment length polymorphisms in 248 unrelated probands of German descent, comprising 72 patients with juvenile myoclonic epilepsy (JME), 46 patients with idiopathic absence epilepsy (IAE), and 130 control subjects without a history of epileptic seizures and lack of generalized spike-wave discharges in their electroencephalogram. The results revealed no evidence for an allelic association of any of the GABABR1 sequence variants with either JME or IAE (P > 0.18). Thus, we failed to demonstrate that any of the three exonic GABABR1 variants themselves, or other so-far unidentified mutations, which are in strong linkage disequilibrium with the investigated variants, are involved in the pathogenesis of common IGE subtypes.

Adolescent↗

PubMed1999

The voltage gated potassium channel KCNQ2 and idiopathic generalized epilepsy.

Mutations in the voltage gated potassium channel gene KCNQ2 and the homologous gene KCNQ3 have been found to cause a rare monogenic subtype of idiopathic generalized epilepsy, the benign familial neonatal convulsions. Recently, the heteromeric KCNQ2/KCNQ3 channel was found to contribute to the native M-current, one of the most important regulators of neuronal excitability. By performing a systematic mutation scan of the coding region and an association study involving a frequent Thr752Asn substitution polymorphism, we, therefore, investigated whether allelic variation of the KCNQ2 gene confers susceptibility to common subtypes of idiopathic generalized epilepsy. Our results do not provide evidence that allelic variation of the KCNQ2 gene contributes a common and relevant effect to the pathogenesis of common subtypes of idiopathic generalized epilepsy.

Amino Acid Substitution↗

PubMed1999

Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism.

We analyzed a novel functional 30-bp repeat polymorphism in the promoter region of the X-chromosomal monoamine oxidase A gene (MAOA) to test whether length variation of the repeat polymorphism contributes to variation in the individual vulnerability to antisocial behavior and liability to alcohol dependence. The repeat number (3-5) of the MAOA polymorphism was assessed in 488 male subjects of German descent, a sample comprising 185 psychiatrically screened control subjects and 303 alcohol-dependent subjects including 59 alcoholics with antisocial personality disorder. The frequency of the low-activity 3-repeat allele was significantly increased in 59 antisocial alcoholics compared to 185 control subjects (51 vs. 35%; P = 0.031) and to 244 alcoholics without antisocial personality disorder (51 vs. 32%; P = 0.008), respectively. We found no significant difference in the frequency of the 3-repeat allele between 244 alcoholics without an antisocial personality disorder and the control subjects. Our findings suggest that the low-activity 3-repeat allele of the MAOA promoter polymorphism confers increased susceptibility to antisocial behavior rather than alcohol dependence per se in alcohol-dependent males.

Adult↗

PubMed1999

Association analysis between a Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene and neuronal hyperexcitability.

Transgenic mice lacking a functional 5-HT2c receptor gene are extremely susceptible to audiogenic seizures, suggesting that 5-HT2c receptors mediate inhibition of neuronal network excitability. The present association study tested the hypothesis that a Cys23Ser substitution polymorphism within the human 5-HT2c receptor gene modulates neuronal excitability. Genotypes of the Cys23Ser polymorphism were assessed in 454 subjects of German descent, comprising: 1) 93 severely affected alcohol-dependent males with a history of alcohol withdrawal seizure or delirium, 2) 119 patients affected by an idiopathic generalized epilepsy, and 3) 242 controls. Both sexes were analyzed separately because of the X-chromosomal location of the 5-HT2c receptor gene. The allele frequencies of the Cys23Ser variants did not differ significantly between the controls and either the severely affected alcohol-dependent males (P = 0.34), or patients with idiopathic generalized epilepsy (P > 0.57). Our results suggest that the common Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene does not confer susceptibility to neuronal hyperexcitability in either idiopathic generalized epilepsy or alcohol withdrawal seizure or delirium.

Adult↗

PubMed1999

Evaluation of a putative major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q14.

Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy (IGE). Significant evidence for linkage has been reported for a susceptibility locus for JME in the chromosomal region 15q14 that harbors the gene encoding the alpha7 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA7). The present study was designed to test the earlier linkage finding and to explore whether this susceptibility locus is involved in the epileptogenesis of a broader spectrum of IGE syndromes. Multipoint parametric and nonparametric linkage analyses with seven microsatellite polymorphisms encompassing the region of the CHRNA7 gene were performed using two diagnostic schemes of JME-related traits in two groups of multiplex families ascertained through probands with either JME (n = 27) or idiopathic absence epilepsy (n = 30). The present linkage study failed to replicate evidence for a major susceptibility locus for JME in the region encompassing the CHRNA7 gene. In addition, we found no hint in favor of linkage to 15q14 under the broad diagnostic scheme in any of the sets of families. If genetic variation in this region confers susceptibility to JME, then its effect size might be too small or its occurrence too rare to be detected in the investigated families.

Adolescent↗

PubMed1999

Comparison of detection platforms and post-polymerase chain reaction DNA purification methods for use in conjunction with Cleavase fragment length polymorphism analysis.

The removal of impurities and contaminants from PCR-amplified fragments is important for mutation detection methods which identify mutations based on shifts in electrophoretic mobility. This is particularly critical for assays and detection methods which use target DNA that is labeled prior to analysis and electrophoretic detection. We examined several procedures for purifying DNA amplified by the polymerase chain reaction (PCR) and their use in conjunction with a novel DNA scanning method, the Cleavase fragment length polymorphism (CFLP)* assay. In this study, a 480 bp DNA fragment, fluorescently labeled on the 5'-end of one strand, was amplified and subjected to various widely used purification procedures, including several commercially available clean-up kits. We demonstrate that visualization of the fluorescent label, as opposed to simple ethidium bromide staining, reveals the presence of considerable levels of labeled, truncated, amplification products. The various procedures were evaluated on the basis of their ability to remove these unwanted DNA fragments as well as on the degree to which they inhibited or promoted the CFLP reaction. Several procedures are recommended for use with CFLP analysis, including isopropanol precipitation, gel excision, and several commercially available spin columns. Concurrently, we evaluated (compared) a number of commonly used visualization platforms, including fluorescence imaging, chemiluminescence, and post-electrophoretic staining, for the ability to detect CFLP pattern changes. The advantages and disadvantages of different methods are discussed and amounts of DNA to be used for CFLP analysis on different detection platforms are recommended.

DNA↗

PubMed1999

mu-opioid receptor variants and dopaminergic sensitivity in alcohol withdrawal.

OBJECT: The endogenous opioid system plays an important role in the reinforcing properties of alcohol by an interconnected activation of the mesolimbic dopamine system. The Asn40Asp substitution polymorphism of the human mu-opioid-receptor (OPRM) influences binding of opioids and signal transduction and may, thereby, contribute to the development of alcoholism. The present study tested whether the Asn40Asp substitution polymorphism of the OPRM gene is associated with a variation in central dopaminergic sensitivity during alcohol withdrawal in alcoholics. METHOD: Sensitivity of central dopamine receptors was assessed by apomorphine-induced growth hormone (GH) secretion in 97 alcohol-dependent patients before and 1 week after alcohol cessation, and in a subgroup of 19 alcoholics after 3 months of abstinence. GH response was defined as area under the hormone/time curve. Comparisons of the GH response were conducted between alcoholics carrying the Asn40Asp genotype versus those with the Asn40Asn genotype using U-test statistics. RESULTS: Marginal differences in apomorphine-induced GH response were found between both genotype groups before detoxification (P = 0.799 (n = 97)/P = 0.459 (n = 19)) and after 3 months of abstinence (P = 0.331 (n = 19)). In contrast, the GH response measured seven days after alcohol withdrawal was significantly increased in alcoholics with the Asn40Asp genotype compared with those carrying the Asn40Asn genotype (P = 0.013 (n = 97)/P = 0.026 (n = 19)). CONCLUSION: Our results suggest that genetic variation of the mu-opioid receptor modulates the central dopaminergic sensitivity during acute alcohol withdrawal.

Adult↗

PubMed1999

Length variation of a polyglutamine array in the gene encoding a small-conductance, calcium-activated potassium channel (hKCa3) and susceptibility to idiopathic generalized epilepsy.

The present association study tested whether length variations of two adjacent polymorphic CAG repeats in the coding sequence of a small-conductance, calcium-activated potassium channel (hKCa3) confer susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). We found no significant difference in the allelic length distribution of the CAG repeats between 290 healthy German controls and the entire sample of 126 German IGE patients (Wilcoxon rank-sum test, P = 0.44) or two subgroups, comprising either 78 patients with juvenile myoclonic epilepsy (Wilcoxon rank-sum test, P = 0.74) or 59 patients with idiopathic absence epilepsies (Wilcoxon rank-sum test, P = 0.44). Moreover, the allelic distribution in parents-child trios of 46 IGE offspring did not differ significantly between the transmitted and non-transmitted parental alleles (Wilcoxon rank-sum test, P = 0.48). Therefore, our association study provides no evidence that length variations of polyglutamine arrays in the N-terminus of the hKCa3 channel exert a frequent and relevant effect in the epileptogenesis of common subtypes of IGE.

Adult↗

PubMed1999

Association analysis of a regulatory promoter polymorphism of the PAX-6 gene with idiopathic generalized epilepsy.

The PAX-6 gene is a member of the paired-box-containing (PAX) gene family, encoding a transcriptional activator, that plays an important role in the development of the central nervous system. The present association study tested the hypothesis that length variation of a novel regulatory dinucleotide repeat polymorphism in the promoter region of the PAX-6 gene (PAX-6 gene-linked polymorphic region, PAX-6LPR) confers susceptibility to the epileptogenesis of common subtypes of idiopathic generalized epilepsy (IGE). The repeat length of the regulatory dinucleotide repeat polymorphism was assessed in 354 German control subjects and 125 German IGE patients, comprising 70 patients with juvenile myoclonic epilepsy (JME) and 55 patients with an idiopathic absence epilepsy (IAE). The allelic distribution of the PAX-6LPR did not deviate significantly between the controls and the IGE patients (Wilcoxon Rank-Sum test: P > 0.76), or both subgroups of either JME patients (P > 0.78) or IAE patients (P > 0.87). Our results do not provide evidence that length variation of the polymorphic dinucleotide sequence in the PAX-6LPR contributes a frequent and relevant effect to the pathogenesis of common subtypes of IGE.

Alleles↗

PubMed1999

Association analysis of exonic variants of the gene encoding the GABAB receptor and alcohol dependence.

The present association study tested whether genetic variation of the GABAB receptor (GABABR1) gene confers vulnerability to alcohol dependence. The genotypes of three DNA sequence variants in exons 1a1, 7 and 11 of the GABABR1 gene were assessed in 234 German controls and 350 German alcohol-dependent subjects, including three more homogeneous subgroups of alcoholics, marked by (1) history of parental alcoholism (n = 121); (2) history of alcohol withdrawal seizure or delirium (n = 108); and (3) comorbidity of dissocial personality disorder (n = 60). The allele frequencies of none of the investigated GABABR1 variants differed significantly between the controls and the groups of alcoholics when a correction for multiple testing was taken into account (P > 0.004). However, trends (P < 0.10) towards an excess of the Ser489 allele of the exon 7 polymorphism were found in the subgroups of alcoholics, and of the common allele of the exon 11 polymorphism in the entire sample of alcoholics (P = 0.032), alcoholics with parental alcoholism (P = 0.084) and the dissocial alcoholics (P = 0.037). Our findings suggest that the investigated GABABR1 variants do not contribute a substantial effect (RR > 3) to the genetic variance of alcohol dependence. Nevertheless, the hints towards potential allelic associations of the exon 7 and 11 polymorphisms with dissocial alcoholism emphasize further studies to test more defined phenotype-genotype relationships.

Adult↗

PubMed1999

Association analysis of sequence variants of GABA(A) alpha6, beta2, and gamma2 gene cluster and alcohol dependence.

Quantitative trait analyses in mice suggest a vulnerability locus for physiological alcohol withdrawal severity on a chromosomal segment that harbors the genes encoding the alpha1, alpha6, beta2, and gamma2 subunits of the gamma-aminobutyric acid type-A receptor (GABR). We tested whether genetic variation at the human GABA(A) alpha6, beta2, and gamma2 gene cluster on chromosome 5q33 confers vulnerability to alcohol dependence. The genotypes of three nucleotide substitution polymorphisms of the GABRA6, GABRB2, and GABRG2 genes were assessed in 349 German alcohol-dependent subjects and in 182 ethnically matched controls. To eliminate some of the genetic variance, three more homogeneous subgroups of alcoholics were formed by: (1) a history of alcohol withdrawal seizure or delirium (n = 106); (2) a history of parental alcoholism (n = 120); and (3) a comorbidity of dissocial personality disorder (n = 57). We found no evidence that any of the investigated allelic variants confers vulnerability to either alcohol dependence or severe physiological alcohol withdrawal symptoms or familial alcoholism (p > 0.05). The frequency of the T allele of the GABRA6 polymorphism was significantly increased in dissocial alcoholics [f(T) = 0.799] compared with the controls [f(T) = 0.658; p = 0.002; OR(T+) = 7.26]. Taking into account the high a priori risk of false-positive association findings due to multiple testing, further replication studies are necessary to examine the tentative phenotype-genotype relationship of GABRA6 gene variants and dissocial alcoholism.

Adult↗

PubMed1999

Lack of an allelic association between polymorphisms of the dopamine D2 receptor gene and alcohol dependence in the German population.

Our study examined recent claims of an association of the TaqI A1 allele and the functional -141C Ins allele of the dopamine D2 receptor (DRD2) gene with alcohol dependence. Genotypes of the TaqI A and -141C insertion/deletion polymorphisms were assessed in 196 German nonalcoholic controls and 310 German alcohol-dependent subjects, including two more homogeneous subgroups selected by either a history of parental alcoholism (n = 108) or by a history of severe physiological alcohol withdrawal symptoms (n = 99). We found no association between any of the biallelic variants or the A1/Ins haplotype and alcohol dependence (p > 0.05). Our present association results failed to replicate evidence that either the TaqI A1 allele or the functional Ins allele or the A1/Ins haplotype of the DRD2 gene confers vulnerability to alcohol dependence in the German population.

Alcoholism↗

PubMed1998

Serotonin transporter gene variants in alcohol-dependent subjects with dissocial personality disorder.

BACKGROUND: We tested the hypothesis that a functional biallelic repetitive element in the 5' regulatory region of the human serotonin transporter gene (SLC6A4) confers susceptibility to serotonin-related personality traits underlying alcohol dependence with dissocial behavior. METHODS: The association study was focused on 64 alcohol-dependent subjects with a dissocial personality disorder (according to ICD-10) who were derived from 315 German alcohol-dependent subjects. The Tridimensional Personality Questionnaire (TPQ) was applied to assess personality dimensions in 101 alcohol-dependent men, including 39 dissocial alcoholics. RESULTS: Our association analyses revealed a trend towards a higher frequency of the short (S) allele of the SLC6A4 polymorphism in dissocial alcoholics compared to 216 German controls (chi 2 = 2.81, df = 1, p = 0.094). Dissocial alcoholics carrying the S/S genotype exhibited significant lower scores of harm avoidance compared to those lacking it (U-test, p = 0.015). Significantly higher novelty seeking scores were obtained in dissocial alcoholics carrying the S allele relative to those lacking it (U-test, p = 0.021). CONCLUSIONS: Our tentative association findings in dissocial alcoholics suggest that the S allele of the 5' regulatory SLC6A4 polymorphism confers susceptibility to a temperamental profile of high novelty seeking and low harm avoidance that has been postulated to underlie dissocial (type-2) alcoholism according to Cloninger's neurogenetic theory of personality.

Adult↗