Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Differential effect of zinc finger deletions on the binding of CTCF to the promoter of the amyloid precursor protein gene.

High levels of transcription from the amyloid precursor protein promoter are dependent on the binding of CTCF to the APBbeta core recognition sequence located between positions -82 and -93 upstream from the transcriptional start site. CTCF comprises 727 amino acids and contains 11 zinc finger motifs arranged in tandem that are flanked by 267 amino acids on the N-terminal side and 150 amino acids on the C-terminal side. Deletion of either the N- or the C-terminal regions outside of the zinc finger domain had no detrimental effect on the binding of CTCF to APBbeta. However, internal deletions of zinc fingers 5-7 completely abolished binding. The binding of full-length CTCF generated a DNase I protected domain extending from position -78 to -116, which was interrupted by a hypersensitive site at position -99. Selective deletions from the N- and C-terminal sides of the zinc finger domain showed that the N-terminal end of the zinc finger domain was aligned toward the transcriptional start site. Furthermore, deletions of zinc fingers peripheral to the essential zinc fingers 5-7 decreased the stability of the binding complex by interrupting sequence-specific interactions.

Genetic approaches to the neurobiology of electroconvulsive therapy.

Although electroconvulsive therapy effectively treats severe psychiatric disorders, its neurobiologic mechanisms are not fully understood. Also unclear is the basis for variability in seizure threshold and duration among patients. We used multiple strains of rats and mice to test for genetic variation in the properties of seizures induced by electroconvulsive shock (ECS). We specifically measured seizure duration, sensitivity to proconvulsant actions of caffeine, and relative refractoriness to postictal induction of further seizures, all of which showed significant interstrain variability. In addition, tonic-clonic seizure durations correlated with rates of immediate mortality, suggesting variations in underlying levels of cellular excitability across strains. By using quantitative autoradiography to relate these findings to neurobiologic mechanisms, we found significant correlations between hippocampal A1-receptor binding, cortical and striatal N-methyl-D-aspartate (NMDA)-receptor binding, and the modification of seizure duration by caffeine. These studies suggest that heritable factors modulate the neurobiologic determinants of electrically induced seizures. Furthermore, they suggest that genetic factors may contribute to clinically observed variability in seizure thresholds. Finally, the data provide a basis for future molecular genetic approaches to link ECS-induced changes in seizure properties to relevant transmitter systems.

Intractable sneezing as a conversion symptom.

A literature review of reported cases of intractable sneezing reveals that intractable sneezing typically occurs in children or adolescents and is a manifestation of conversion disorder. Analysis of these cases demonstrates a number of features that are helpful in differentiating psychogenic from organic sneezing. Also discussed are aspects of patient management once a diagnosis of conversion disorder is established.

Animal studies of electroconvulsive therapy: foundations for future research.

Since the introduction of electroconvulsive therapy (ECT) in 1938, research studies in animals have made significant contributions to the clinical practice of ECT. In our search for the underlying mechanism by which ECT exerts its therapeutic and adverse effects, animal studies have yielded additional clues. This paper reviews existing animal literature on electroconvulsive seizures (ECS). It emphasizes ways in which animal data informs our clinical practice and illuminates possible mechanisms of ECT's actions. Finally, recommendations are made for future studies in ECS.

Morphogenesis in Volvox: analysis of critical variables.

Inversion, the process by which Volvox embryos turn inside out, was analyzed by a combination of geometrical and experimental techniques. It was shown that simple geometric figures are adequate to represent cell shapes during inversion and that cell volumes remain constant as cell shapes change and the embryo inverts. The first stage of inversion, phialopore opening, results from the release of compressive forces as the embryo withdraws from its surrounding vesicle during a two-stage contraction of each cell around its radial axis. Premature phialopore opening occurs when withdrawal of the embryo from the vesicle is elicited artificially by exposure to either calcium ionophore or hypertonic solutions. The major event of inversion, generation of negative curvature, requires both microtubule-driven elongation of cells (to produce a classical "flask" shape) and cytochalasin-sensitive active migration of cytoplasmic bridges to the outermost ends of flask cells. Colchicine, cyclic GMP and isobutyl methyl xanthine (individually) block both normal elongation and bridge migration; cytochalasin D blocks bridge migration selectively. Flask cell formation and bridge migration are adequate to account for the negative curvature observed. An asymmetric bending of flask cell stalks along the ring of maximum curvature accounts for the fact that the embryo is not constricted in a "purse-string" fashion as negative curvature is generated. Inversion of the posterior hemisphere involves an elastic snap-through resulting from a combination of compressive stresses generated by inversion of the anterior hemisphere and the circumferential restraint imposed by cells at the equator. We conclude that the observed changes in cell shape and the migration of cytoplasmic bridges are the result of an ordered process of membrane-cytoskeletal interactions, and both necessary and sufficient to account for the morphogenetic process of inversion in Volvox.