Pétur Lúðvígsson

Major depression has been shown to increase the risk for development of epilepsy, but prior studies have not evaluated whether this is due to specific symptoms of depression. We conducted a population-based case-control study of all newly diagnosed unprovoked seizures among Icelandic children and adults aged 10 years and older to test the hypothesis that major depression is a risk factor for developing unprovoked seizure and epilepsy, and to address whether specific symptoms of depression account for this increased risk. Cases were matched to the next two same sex births from the population registry. Using standardized interviews, we ascertained symptoms of major depression to make a Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) diagnosis. A history of major depression was 1.7-fold more common among cases than among controls (95% confidence interval, 1.1-2.7). A history of attempted suicide was 5.1-fold more common among cases than among controls (95% confidence interval, 2.2-11.5). Attempted suicide increased seizure risk even after adjusting for age, sex, cumulative alcohol intake, and major depression or number of symptoms of depression. Major depression and attempted suicide independently increase the risk for unprovoked seizure. These data suggest that depression and suicide attempt may be due to different underlying neurochemical pathways, each of which is important in the development of epilepsy.

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) occurs more frequently than expected in prevalent cohorts with epilepsy. The association has been attributed to the epilepsy or its treatment, although it is impossible to determine in previous studies which condition occurs first. OBJECTIVES: To conduct a population-based case-control study of all newly diagnosed unprovoked seizures among Icelandic children younger than 16 years to address the question of time order. DESIGN: Children with seizures were matched to the next 2 same-sex births from the population registry. The Diagnostic Interview Schedule for Children was used to make a DSM-IV diagnosis of ADHD in a standardized fashion among cases and controls aged 3 to 16 years. RESULTS: A history of ADHD was 2.5-fold more common among children with newly diagnosed seizures than among control subjects (95% confidence interval [CI], 1.1-5.5). The association was restricted to ADHD predominantly inattentive type (odds ratio [OR], 3.7; 95% CI, 1.1-12.8), not ADHD predominantly hyperactive-impulsive type (OR, 1.8; 95% CI, 0.6-5.7) or ADHD combined type (OR, 2.5; 95% CI, 0.3-18.3). Seizure type, etiology, sex, or seizure frequency at diagnosis (1 or >1) did not affect findings. CONCLUSION: Attention-deficit/hyperactivity disorder occurs more often than expected before unprovoked seizures, suggesting a common antecedent for both conditions.