Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

• MeSH
• bipolární porucha klasifikace   genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické lokusy * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• psychotické poruchy genetika   MeSH
• schizofrenie genetika   MeSH
• studie případů a kontrol MeSH
• systémová biologie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

Regulation of Na+/K+-ATPase in bipolar disorder and lithium therapy has been investigated for more than 40 years. Contradictory results in this area may be caused by the difference between acute and long-term Li effects on cell metabolism and variance in responsiveness of different cell types. We compared the time-course of Li action focusing on Na+/K+-ATPase and lipid peroxidation in two widely different cell models-Jurkat and HEK293. Na+/K+-ATPase expression level was determined in cells cultivated in the absence or presence of 1 mM Li for different time spans (1, 7, and 28 days) using [3H] ouabain binding and immunoblot assay of α-subunit. In parallel samples, the formation of malondialdehyde (MDA) was quantified by HPLC, and 4-hydroxy-2-nonenal (4-HNE) protein adducts were determined by immunoblot. Cultivation of Jurkat cells in 1 mM Li medium resulted in downregulation of Na+/K+-ATPase (decrease of [3H] ouabain-biding sites and intensity of immunoblot signals) in all Li-groups. In HEK293 cells, the decrease of Na+/K+-ATPase was observed after the acute, 1-day exposure only. The long-term treatment with Li resulted in Na+/K+-ATPase upregulation. MDA and 4-HNE modified proteins were decreased in Jurkat cells in all Li-groups. On the other hand, in HEK293 cells, MDA concentration was decreased after the acute, 1-day Li exposure only; the long-term cultivations, for 7 or 28 days, resulted in a significant increase of lipid peroxidation products. The Li-induced decrease of lipid peroxidation products was associated with the decrease of Na+/K+-ATPase level and vice versa.

• MeSH
• bipolární porucha farmakoterapie   metabolismus   MeSH
• časové faktory MeSH
• HEK293 buňky MeSH
• Jurkat buňky MeSH
• lidé MeSH
• lipidové peroxidy metabolismus   MeSH
• peroxidace lipidů účinky léků   MeSH
• regulace genové exprese účinky léků   MeSH
• sloučeniny lithia aplikace a dávkování   metabolismus   farmakologie   MeSH
• sodíko-draslíková ATPasa genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Evidence for a neuroprotective effect of lithium has accumulated over the last 2 decades, and this phenomenon has been regarded as an important mechanism of lithium action in mood disorders. It has been reflected by an increase in cerebral gray matter volume in lithium-treated subjects and by the favorable influence of lithium on cognitive functions. A neuroprotective effect of lithium also makes this ion a possible candidate for use as a therapeutic drug in neurology, especially in neurodegenerative disorders. In this paper, neurochemical mechanisms of neuroprotective action of lithium will be characterized. A possible association between the effect of lithium on brain structures reflected in neuroimaging studies, as well as on cognitive functions, and its neuroprotective action, will be considered. Data from experimental, epidemiological, and clinical studies have also pointed to an antidementia effect of lithium, bringing about some promise of using lithium in the treatment of mild cognitive impairment and Alzheimer's disease. The results of attempts of employing lithium in other neurodegenerative disorders will also be discussed.

• MeSH
• lidé MeSH
• nemoci mozku diagnostické zobrazování   farmakoterapie   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• sloučeniny lithia terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH