Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosomal origins of those influences conflict. One early study reported that human leukocyte antigen (HLA) markers were genetically linked to juvenile myoclonic epilepsy (JME); this was confirmed in a later study. Other reports did not find linkage to HLA markers. One found evidence of linkage to markers on chromosome 15, another to markers on chromosome 6, centromeric to HLA. We identified families through a patient with JME and genotyped markers throughout chromosome 6. Linkage analysis assuming equal male-female recombination probabilities showed evidence for linkage (LOD score 2.5), but at a high recombination fraction (theta), suggesting heterogeneity. When linkage analysis was redone to allow independent male-female thetas, the LOD score was significantly higher (4.2) at a male-female theta of.5,.01. Although the overall pattern of LOD scores with respect to male-female theta could not be explained solely by heterogeneity, the presence of heterogeneity and predominantly maternal inheritance of JME might explain it. By analyzing loci between HLA-DP and HLA-DR and stratifying the families on the basis of evidence for or against linkage, we were able to show evidence of heterogeneity within JME and to propose a marker associated with the linked form. These data also suggest that JME may be predominantly maternally inherited and that the HLA-linked form is more likely to occur in families of European origin.
The long alleles (Ն6 repeats) of the dopamine D4 dopamine receptor exon III polymorphism have been linked in some, but not all, studies to Novelty Seeking (NS), one of four personality traits defined by Cloninger's tridimensional personality questionnarie (TPQ). In order to further examine the robustness of our original observation we have recruited an additional cohort similar in demographic structure to the original cohort. Although no significant difference in mean NS scores was observed when the new subjects (n = 94) were grouped by presence (NS = 17.83 ± 1.16) or absence (NS = 16.45 ± 0.65) of the 7 repeat allele, a significant difference in range of NS scores was observed (non-parametric Moses range test, P = 0.01). The effect of the seven allele was also significant in those individuals scoring highest on NS (Ͼ1 standard deviation from the mean; t-test, t = 5.13, P = 0.002). In the expanded cohort (n = 218) a significant effect of the seven allele on NS is demonstrated by both parametric (t = 2.26, P = 0.01) and non-parametric (range test, P = 0.004) statistical tests. The effect is also observed in both principal ethnic groups (Ashkenazi and non-Ashkenazi Jews). In the expanded cohort the effect is significant in female (t = 2.2, P = 0.03, n = 98) but not in male subjects (t = 1.12, P Ͼ 0.1, n = 116). We discuss both direct and indirect evidence that in our opinion continues to support a modest role for the long alleles of the dopamine D4 receptor repeat polymorphism in the determination of NS behavior at least in some population groups.Keywords: personality; temperament; dopamine D4 receptor; polymorphism; novelty seeking; tridimensional personality questionnaire (TPQ) Introduction observation, we have recruited a second cohort similar in demographic structure and size to the first group. Twin studies have shown that adult human temperaThe 94 new subjects were genotyped and administered ment is partially determined by genes which account Cloninger's Tridimensional Personality Questionnaire for up to 50% of the variance between individuals. [1][2][3] (TPQ) 3,16 which distinguishes four personality dimenHowever, only recently have common genetic polysions: Novelty Seeking (NS), Harm Avoidance (HA), morphisms been identified which have been associated Reward Dependence (RD134) and Persistence (RD2). with specific personality traits. Our report, 4 and itsThe association between high NS scores and the seven quick confirmation by another laboratory in an ethniallele of the D4DR gene 3-5,15 is observed in the new cally distinct population, 5 of an association between subjects when the range of NS scores are compared, the seven (long) repeat polymorphism in the dopamine although not by parametric (independent samples t-D4 receptor and the personality trait of Novelty Seektest) comparison of means. The subgroup of subjects ing (NS) has prompted a number of similar investiwith high NS scores shows a significant association gations. 6-15 Some of these studies across diverse ethnic between the seven allele and th...
Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.
Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinically, IGE can be divided into different syndromes. Varying lines of evidence point to the involvement of several interacting genes in the etiology of IGE. We performed a genome scan in 91 families ascertained through a proband with adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic clonic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (lod score 4.4/5.2 multipoint/two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified locus on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 influencing non-JME forms of IGE (lod score 3.8/2.5), and, more tentatively, two newly discovered loci for absence seizures on chromosome 5 (lod scores 3.8/2.8 and 3.4/1.9). Our data also suggest that the genetic classification of different forms of IGE is likely to cut across the clinical classification of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes seen in IGE families.
Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested to map to chromosome 8. We investigated families with adolescent-onset idiopathic generalized epilepsy (IGE), for linkage to markers spanning chromosome 8. The IGEs that we studied included juvenile myoclonic epilepsy (JME), epilepsy with only generalized tonic-clonic seizures occurring either randomly during the day (random grand mal) or on awakening (awakening grand mal), and juvenile absence epilepsy (JAE). We looked for a gene common to all these IGEs, but we also investigated linkage to specific subforms of IGE. We found evidence for linkage to chromosome 8 in adolescent-onset IGE families in which JME was not present. The maximum multipoint LOD score was 3.24 when family members with IGE or generalized spike-and-waves (SW) were considered affected. The LOD score remained very similar (3.18) when clinically normal family members with SW were not considered to be affected. Families with either pure grand mal epilepsy or absence epilepsy contributed equally to the positive LOD score. The area where the LOD score reaches the maximum encompasses the location of the gene for the beta3-subunit of the nicotinic acetylcholine receptor (CHRNB3), thus making this gene a possible candidate for these specific forms of adolescent-onset IGE. The data excluded linkage of JME to this region. These results indicate genetic heterogeneity within IGE and provide no evidence, on chromosome 8, for a gene common to all IGEs.
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