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Objectives: Three recent studies revealed a haplotypic association of alcohol dependence with the gene encoding the {alpha}2 subunit of the {gamma}-aminobutyric acid type A (GABAA) receptor (GABRA2). The present study examined whether variation of the GABRA2 gene confers susceptibility to different subtypes of alcohol dependence in the German population. Methods: A total of 257 German alcohol-dependent patients and 88 healthy population controls were genotyped for six single-nucleotide polymorphisms covering the middle part and the 3′ end of GABRA2. Allelic, genotypic and haplotypic comparisons were done for subgroups of alcohol-dependent patients with a presumed high genetic load. Results: The overall alcohol-dependent patients vs. control group comparison confirmed positive allelic association for five of six single-nucleotide polymorphisms mapping from intron 3 to the 3′ end of GABRA2 (P=0.01–0.02). Haplotype analysis revealed two common haplotypes accounting for approximately 90% of the chromosomes within the patients and controls. The less frequent haplotype was significantly more prevalent among the alcohol-dependent patients (45%) than among the controls [29%; odds ratio (OR)=1.97, 95% confidence interval (CI): 1.30–2.96]. The strength of association increased, if the subsets of alcohol-dependent patients with a positive family history (OR=2.60, 95% CI: 1.63–4.13), withdrawal seizures (OR=2.22, 95% CI: 1.30–3.79) or an early onset (OR=2.19, 95% CI: 1.24–3.88) were analyzed. Conclusions: Although our study was limited by the number of cases being larger than the number of controls, the results confirm GABRA2 as a susceptibility gene for alcohol dependence in the German population. We found a consistent increase of the susceptibility effect in alcohol-dependent patients with a presumed strong genetic predisposition.

Purpose: Mutation analysis of the gene encoding the GABA δ subunit ( GABRD ) identified a common missense variation (c.659G>A; Arg220His) of which the His220 allele displayed decreased GABA A α 1 β 2 δ receptor current amplitudes. The present association study tested whether the functional GABRD His220 allele confers susceptibility to common syndromes of idiopathic generalized epilepsy (IGE). Methods: Five hundred and sixty two unrelated German IGE patients and 664 healthy population controls were genotyped for the c.659G>A polymorphism in exon 6 of the GABRD gene. Results: His220 allele frequencies did not differ significantly between IGE patients (2.3%) and the controls (2.8%; P =0.46). Likewise, no evidence for an allelic association was found with juvenile myoclonic epilepsy ( n =218; 2.8%; P =0.97) or idiopathic absence epilepsy ( n =260; 2.3%; P =0.56). Conclusion: Our results provide no evidence that the functional GABRD His220 allele mediates a substantial susceptibility effect to common IGE syndromes in the German population.

Converging lines of evidence point to brain-derived neurotrophic factor (BDNF) as a factor in the pathophysiology of depression. Recently, it was shown that the Val allele of the BDNF Val66Met substitution polymorphism showed a significant association with higher mean neuroticism scores of the NEO-Five Factor Inventory (NEO-FFI) in healthy subjects, and previous studies suggested the Val allele to be increased in bipolar disorder families. The association to anxiety-related traits has not been investigated so far.We tested a total of 343 unrelated subjects of German descent (171 male, 172 female, age: 39.0+/-14.6 years) who were carefully screened for psychiatric health. The self-ratable State-Trait Anxiety Inventory (STAI), which allows anxiety to be quantified as a comparatively stable personality trait, and the NEO-Five Factor Inventory (NEO-FFI) was applied.In the trait-related anxiety score, a significant (F=3.2, df=2, p0.042) effect of the genotype was observed with higher levels of trait anxiety in Val/Val (35.0+/-7.4) compared to Val/Met (33.4+/-6.5) and Met/Met (32.0+/-4.6) genotypes. The NEO neuroticism scores were also higher in Val/Val (29.5+/-7.0) than in Val/Met (28.4+/-6.5) or Met/Met (26.8+/-5.8) genotype, but not at a significant rate.Our findings support the hypothesis that anxiety- and depression-related personality traits are associated with the BDNF polymorphism although the explained variance is low.

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.

Photosensitivity or photoparoxysmal response (PPR) is a common and highly heritable electroencephalographic trait characterized by an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. PPR occurs frequently associated with idiopathic generalized epilepsies (IGEs). The present genomewide linkage scan was designed to map susceptibility loci for PPR and to explore their genetic relationship with IGE. The study included 60 families with at least two siblings displaying PPR. To dissect PPR-specific and IGE-related susceptibility loci, we defined two distinct family subgroups, comprising 19 families with predominantly pure PPR and photosensitive seizures (PPR-families) and 25 families, in which PPR was strongly associated with IGE (PPR/IGE-families). MOD score analyses provided significant evidence for linkage to the region 6p21.2 in the PPR-families (empirical p = 0.00004) and suggestive evidence for linkage to the region 13q31.3 in the PPR/IGE families (p = 0.00015), both with a best-fitting recessive mode of inheritance. In the PPR/IGE-families, linkage evidence was even stronger (p = 0.00003) when the trait definition was broadened by IGE traits. Our study shows two PPR-related susceptibility loci, depending on the familial background of IGE. The locus on 6p21.2 seems to predispose to PPR itself, whereas the locus on 13q31.3 also confers susceptibility to IGE.

Genetic factors play a major role in the etiology of idiopathic generalized epilepsies (IGE). An oligogenic or polygenic predisposition is suspected in the majority of families with common IGE syndromes. It has been hypothesized that some IGE genes might increase the general level of neuronal excitability while others specify the age of onset and the seizure type. The EFHC1 gene on 6p12-p11 was previously described as the first susceptibility gene for juvenile myoclonic epilepsy (JME). EFHC1 codes for a protein of unknown function that is characterized by Ca 2+ -binding EF-hand motifs and DM10 domains. We have now cloned the brain-expressed paralog EFHC2 (Xp11.3) and carried out an association study of six single nucleotide polymorphisms (SNPs) in a large sample of 654 German IGE patients and 662 population controls. A tentative association was found between the amino acid exchange S430Y in exon 9 of EFHC2 and 97 male JME patients ( χ 2 =4.705, d.f.=1, P =0.030; OR=2.17; 95-CI: 1.06–4.43). The allelic association was even stronger for the 81 males with "classical" JME (JME without absence seizures) ( χ 2 =6.06, d.f.=1, P =0.014; OR=2.46; 95-CI: 1.18–5.13). An association with the gonosomal gene EFHC2 would be in accordance with the observed preponderance of maternal inheritance in JME maternal inheritance of JME. Independent replication studies are needed to further analyse the tentative association described here.

Purpose: Quantitative trait loci (QTL) mapping in mice revealed a seizure-related QTL ( Szs1 ), for which the inward-rectifying potassium channel Kcnj10 is the most compelling candidate gene. Association analysis of the human KCNJ10 gene identified a common KCNJ10 missense variation (Arg271Cys) that influences susceptibility to focal and generalized epilepsies. The present replication study tested the initial finding that the KCNJ10 Cys271 allele is associated with seizure resistance to common syndromes of idiopathic generalized epilepsy (IGE). Methods: The study sample comprised 563 German IGE patients and 660 healthy population controls. To search for seizure type-specific effects, two IGE subgroups were formed, comprising 258 IGE patients with typical absences (IAE group) and 218 patients with juvenile myoclonic epilepsy (JME group). A TaqMan nuclease assay was used to genotype the KCNJ10 single nucleotide polymorphism c.1037C>T (dbSNP: rs1130183) that alters amino acid at position 271 from arginine to cysteine. Results: Replication analysis revealed a significant decrease of the Cys271 allele frequency in 446 IGE patients compared to controls ( χ 2 =3.52, d.f.=1, P =0.030, one-sided; OR Cys271+ =0.69; 95% CI: 0.50–0.95). Among the IGE subgroups, lack of the Cys271 allele was accentuated in the JME group ( χ 2 =5.20, d.f.=1, P =0.011, one-sided). Conclusion: Our results support previous evidence that the common KCNJ10 Arg271Cys missense variation influences seizure susceptibility of common IGE syndromes.