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Rolandic epilepsy (RE) and its atypical variants (atypical rolandic epilepsy, ARE) along the spectrum of epilepsy-aphasia disorders are characterized by a strong but largely unknown genetic basis. Two genes with a putative (ELP4) or a proven (SRPX2) function in neuronal migration were postulated to confer susceptibility to parts of the disease spectrum: the ELP4 gene to centrotemporal spikes and SRPX2 to ARE. To reexamine these findings, we investigated a cohort of 280 patients of European ancestry with RE/ARE for the etiological contribution of these genes and their close interaction partners. We performed next-generation sequencing and single-nucleotide polymorphism (SNP)-array based genotyping to screen for sequence and structural variants. In comparison to European controls we could not detect an enrichment of rare deleterious variants of ELP4, SRPX2, or their interaction partners in affected individuals. The previously described functional p.N327S variant in the X chromosomal SRPX2 gene was detected in two affected individuals (0.81%) and also in controls (0.26%), with some preponderance of male patients. We did not detect an association of SNPs in the ELP4 gene with centrotemporal spikes as previously reported. In conclusion our data do not support a major role of ELP4 and SRPX2 in the etiology of RE/ARE., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Background: Drug-induced bodyweight gain (BWG) is a serious concern in pharmacotherapy with second-generation antipsychotics. The interindividual variability is likely to be modulated by genetic factors. In the past, pharmacogenetic studies yielded conflicting results, and none of the identified genetic alterations exerts sufficient predictive value for this severe side effect of psychopharmacotherapy., Aim: We aimed to contribute to the replication and extension of prior association findings and investigated the genes encoding serotonin 2C receptor (HTR2C), insulin-induced gene 2 (INSIG2) and leptin (LEP)., Patients & Methods: We investigated the association of HTR2C, LEP and INSIG2 SNPs with antipsychotic-induced BWG in 128 German schizophrenic patients. Genotyping was performed for nine SNPs (HTR2C: rs498207, rs3813928, rs6318 and rs3813929; INSIG2: rs17587100, rs10490624, rs17047764 and rs7566605; LEP: rs7799039). Association analysis included logistic regression analysis and Pearson s chi(2) tests., Results: We report a significant association of three HTR2C SNPs (rs498207, rs3813928 and rs3813929) and of the respective haplotype with antipsychotic-induced BWG. Regarding the X-chromosomal SNP rs498207, individuals with AA/A genotype gained more weight than those with GG/G genotype. The association observed with the SNP rs498207 was also significant after correcting for multiple testing (p = 0.0196). No association was found for INSIG2 and LEP SNPs., Conclusion: The results contribute to the accumulating evidence for an association of the X-chromosomal HTR2C gene with antipsychotic-induced BWG. The proposed underlying mechanisms include decreased HTR2C gene expression with reduced 5-HT-modulated activation of hypothalamic proopiomelanocortin-neurons, and inverse 5-HT(2C) agonism in the presence of D(2) receptor antagonism.

Rationale: It has been suggested that a susceptibility locus near the gene encoding the brain-derived neurotrophic factor (BDNF) contributes to individual differences in human addiction vulnerability. BDNF modulates several behaviors that are associated with addictive drugs, and upregulation of BDNF was found to be associated with several drugs of abuse such as amphetamine, cocaine, and nicotine. In this study, we addressed the question if a common BDNF missense variation (Val66Met) influences the risk for smoking behavior in otherwise healthy human volunteers., Materials and Methods: In total, 320 healthy unrelated volunteers (155 male, 165 female, mean age: 38.4 +/- 14.1 years) consisting of 43.3% never smokers, 20.9% former smokers, and 35.6% current smokers were investigated., Results: The frequency of both Met/Met genotype and Met allele was significantly increased in current and in former smokers when compared to never smokers (chi (2) = 10.856, df = 2, p = 0.004 and chi (2) = 4.350, df = 1, p = 0.045, respectively)., Conclusions: Our results suggest that humans who carry the Met allele of the BDNF missense polymorphism might be more vulnerable to initiate and also maintain smoking.

Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy. Recently, linkage of JME to the chromosomal region 15q14, as well as an allelic and genotypic association between the synonymous coding single nucleotide polymorphism c.588C>T (dbSNP: rs3743123, S196S) of the positional candidate gene connexin-36 (CX36) and JME have been reported. The present replication study examined this tentative association in 247 German JME patients and 621 population controls. The frequency of the c.588T allele was significantly increased in the JME patients (35%) compared to controls (29.7%; P=0.016, one-tailed). Consistent to the original report, we also observed a significant increase of T/T homozygotes (13.4%) in the JME patients compared to controls (8.7%; P=0.019, one-tailed; OR(T/T+)=1.62; 95%-CI: 1.02-2.57). The present results provide confirmatory evidence for an allelic and genotypic association of the CX36 gene with JME.

Purpose: Linkage disequilibrium mapping revealed allelic and haplotypic associations between single-nucleotide polymorphisms (SNPs) of the gene encoding the malic enzyme 2 (ME2) and adolescent-onset idiopathic generalized epilepsy (IGE). Homozygote carriers of the associated ME2 haplotype had a sixfold higher risk of IGE compared with any other genotype. The present population-based association study tested whether genetic variation of the ME2 gene confers susceptibility to common IGE syndromes in the German population., Methods: The study included 666 German healthy control subjects and 660 German IGE patients (IGE group), of which 416 patients had an age at onset in adolescence (IGEado group). Genotyping was performed for six SNPs and one dinucleotide repeat polymorphism, all located in the ME2 region., Results: Neither allele nor genotype frequencies of any ME2 polymorphism differed significantly between the controls and the IGE groups (p > 0.22). No hint of an association of the putative risk-conferring haplotype was seen, when present homozygously, in both IGE groups compared with controls (p > 0.18)., Conclusions: These results do not support previous evidence that genetic variation of the ME2 gene predisposes to common IGE syndromes. Thus if a recessively inherited ME2 mutation is present, then the size of the epileptogenic effect might be too small or not frequent enough to detect it in the present IGE sample.

Quantitative trait loci studies in inbred mice have identified a locus on chromosome 1 (Szs1) of fundamental importance to seizure susceptibility. High-ranking candidate genes in this susceptibility region include KCNJ9, KCNJ10 and ATP1A2. We performed a systematic mutation scan of the coding region of the human ATP1A2 gene and performed a case-control association study with seven common markers. Genotypes were assessed in 152 idiopathic generalized epilepsy (IGE) patients of German ancestry and 111 healthy German controls for all seven polymorphisms. No significant differences were found in genotype or allele frequencies for any of the variations between the IGE patients and controls. No haplotypes were associated with IGE when compared to controls. Linkage disequilibrium was demonstrated throughout the gene. Results suggest that the polymorphisms we studied in the ATP1A2 gene do not represent major susceptibility factors for common forms of IGE.

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.

Gamma-aminobutyric acid (GABA)A-receptors play a crucial role in the generation of electroencephalogram (EEG) oscillations and evoked potentials (ERPs). The present association study was designed to test whether EEG and ERPs are modulated by genetic variations of the human GABAA beta2 (GABRB2) and gamma2 (GABRG2) genes on chromosome 5q33. The genotypes of two nucleotide substitution polymorphisms of the GABRB2 and GABRG2 genes were assessed in 95 psychiatrically healthy subjects of German descent. Neurophysiological phenotyping was performed with four factorized EEG/ERP parameters: EEG activation, anterior and posterior EEG synchronization, and event-related activity (N100/ P200-complex). No genotypic association was found for the GABRB2 nucleotide exchange polymorphism with any electrophysiological parameter. A significant association was found between the genotype of the intronic GABRG2 G-->A nucleotide exchange and the event-related N100/P200 (ANOVA: F=3.81; df=2; P=0.026). A comparison of homozygous subjects carrying either the G/G or A/A genotype of the GABRG2 polymorphism consistently revealed an even stronger difference in the effect-size (ANOVA: F=11.13; df=1; P=0.002). Post hoc analysis of this association with current density analysis in three-dimensional neuroanatomic Talairach space-time showed a reduction in the event-related signal power after 120 ms in the right dorsolateral prefrontal cortex. Taking into account the risk of false-positive association findings attributable to multiple testing, our results encourage further replication studies to examine the phenotype-genotype relationship of GABRG2 gene variants and event-related prefrontal activity.

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.

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.

Neurophysiological and pharmacological studies suggest a major role of the GABAB receptor in the epileptogenesis of absence seizures. The gene encoding the human GABABR1 receptor (GABABR1) has recently been mapped to human chromosome 6p21.3 by in situ hybridization, a region that harbors a susceptibility locus (EJM1) for idiopathic generalized epilepsy (IGE). We investigated the hypothesis that the GABABR1 gene (GABBR1) represents a candidate gene for EJM1 by: (1) defining the precise localization approximately 130 kilobases telomeric to the HLA-F locus, (2) by characterizing its genomic organization, and (3) by mutation screening of the entire coding region of GABBR1 in 18 German patients with juvenile myoclonic epilepsy (JME) who were derived from families with evidence for linkage to chromosome 6p21.3 (cumulative lod score Z=3.17 at HLA-DQ). The GABAB receptor gene consists of 22 translated exons. The two alternative transcripts, GABABR1a and GABABR1b, are derived from the same locus but they differ in their alternative 5'-exons. Mutation analyses in JME revealed several DNA sequence polymorphisms, two of which result in amino acid changes occurring in all IGE-affected members of two families. However, clinically unaffected relatives did carry the same variations, excluding these amino acid substitutions as the cause for IGE in these families.

Mu-Opioid receptor-mediated neurotransmission is involved in the reward, tolerance, and withdrawal effects of alcohol. The present association study tested the hypothesis that the common Asn40Asp substitution polymorphism in the N-terminal domain of the human mu-opioid receptor (OPRM) confers vulnerability to subtypes of alcohol dependence. The genotypes of the Asn40Asp substitution polymorphism were assessed in 327 German alcohol-dependent subjects (according to ICD-10) and in 340 control subjects of German descent, using an assay based on allele-specific polymerase chain reaction. To select alcoholics with a presumed high genetic load, three subgroups were delineated, marked by (1) a family history of parental alcoholism (n = 114); (2) the inability to abstain from alcohol before the age of 26 years (n = 73); and (3) a history of alcohol withdrawal seizure or delirium (n = 107). The frequency of the Asp40 allele did not differ significantly between the controls [f(Asp40) = 0.078] and either the entire group of alcoholics [f(Asp40) = 0.107; p = 0.066], or the alcoholics with parental alcoholism [f(Asp40) = 0.114; p = 0.094], or the early-onset alcoholics [f(Asp40) = 0.096; p = 0.471,[ or the alcoholics with severe withdrawal symptoms [f(Asp40) = 0.098; p = 0.350]. Our results do not provide evidence that the common Asn40Asp substitution polymorphism of the OPRM gene contributes a major effect to the pathogenesis of alcohol dependence.

Juvenile absence epilepsy (JAE) is a common subtype of idiopathic generalized epilepsy (IGE). Hereditary factors play a major role in its etiology. The important function of glutamate receptors (GluRs) in excitatory neurotransmission, synaptic plasticity, and neurodevelopment suggests their involvement in epileptogenesis. A tetranucleotide repeat polymorphism in the non-coding region of the kainate-selective GluR5 receptor gene (GRIK1) on chromosome 21q22.1 provides the tool to investigate this candidate gene. The present association and linkage study tested the hypothesis that allelic variants of GRIK1 confer genetic susceptibility to the pathogenesis of JAE. Our family-based association analysis using the haplotype-based haplotype relative risk statistic revealed an association of JAE with the nine-repeat containing allele of the GRIK1 tetranucleotide polymorphism (chi2 = 8.31, df = 1, P = 0.004). Supportive evidence for linkage to a JAE related IGE spectrum (Zmax = 1.67 at GRIK1) under an autosomal dominant mode of inheritance and significant allele sharing (P < 0.05) among the affected family members suggest that allelic variants of GRIK1 contribute a major genetic determinant to the pathogenesis of JAE-related phenotypes.