Sankt Hans Hospital

The current coronavirus (COVID-19) pandemic is again reminding us of the importance of using telehealth to deliver care, especially as means of reducing the risk of cross-contamination caused by close contact. For telehealth to be effective as part of an emergency response it first needs to become a routinely used part of our health system. Hence, it is time to step back and ask why telehealth is not mainstreamed. In this article, we highlight key requirements for this to occur. Strategies to ensure that telehealth is used regularly in acute, post-acute and emergency situations, alongside conventional service delivery methods, include flexible funding arrangements, training and accrediting our health workforce. Telehealth uptake also requires a significant change in management effort and the redesign of existing models of care. Implementing telehealth proactively rather than reactively is more likely to generate greater benefits in the long-term, and help with the everyday (and emergency) challenges in healthcare.

[3H]Diazepam appears to bind specifically to a single, saturable, binding site located on rat brain membranes, with an affinity constant near 3 nM at pH 7.4. Specific binding constitutes more than 90% of total binding at 0 degrees and less than 10% of total binding at 37 degrees. Arrhenius plots suggest a sharp conformational change in the diazepam receptor near 18 degrees. Mitochondrial fractions from rat kidney, liver, and lung exhibit some [3H]diazepam binding that can be displaced by nonradioactive diazepam and several other benzodiazepines. However, Ro-4864, which is almost inactive in displacing [3H]diazepam from brain membranes, is extremely potent in displacing it from kidney mitochondria. Conversely, clonazepam, the most potent inhibitor of brain binding, is an extremely weak inhibitor of kidney binding. Furthermore, diazepam binding to kidney mitochondria has an affinity constantof 40 nM, about 15 times higher than that in brain. No specific diazepam binding was detected in intestine or skeletal muscle. Thus, specific [3H]diazepam binding to membranes appears to be restricted to brain, where it is unevenly distributed: the density of diazepam receptors is about five times higher in cortex (the highest density) than in pons-meddula (lowest density). Trypsin and chymotrypsin completely abolished specific [3H]diazepambinding in brain and kidney.

Abstract La Cour, P. & Gallagher, K. (1990). Presentation and evaluation of Rivermead Behavioural Memory Test. Nordisk Psykologi, 42, 130–141. The article presents an evaluation of the Rivermead Behavioural Memory Test, a test battery for illuminating impaired memory function. The RBMT has recently been published in Danish together with a short review of its background and contents. Results from 10 examinations where both RBMT and a traditional test battery were applied lead to a discussion regarding the tests merits and shortcomings. The test battery has shown to be of benefit where everyday memory functions are estimated.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

OBJECTIVES: To evaluate the effects of integrated treatment for patients with a first episode of psychotic illness. DESIGN: Randomised clinical trial. SETTING: Copenhagen Hospital Corporation and Psychiatric Hospital Aarhus, Denmark. PARTICIPANTS: 547 patients with first episode of schizophrenia spectrum disorder. INTERVENTIONS: Integrated treatment and standard treatment. The integrated treatment lasted for two years and consisted of assertive community treatment with programmes for family involvement and social skills training. Standard treatment offered contact with a community mental health centre. MAIN OUTCOME MEASURES: Psychotic and negative symptoms (each scored from 0 to a maximum of 5) at one and two years' follow-up. RESULTS: At one year's follow-up, psychotic symptoms changed favourably to a mean of 1.09 (standard deviation 1.27) with an estimated mean difference between groups of -0.31 (95% confidence interval -0.55 to -0.07, P = 0.02) in favour of integrated treatment. Negative symptoms changed favourably with an estimated difference between groups of -0.36 (-0.54 to -0.17, P < 0.001) in favour of integrated treatment. At two years' follow-up the estimated mean difference between groups in psychotic symptoms was -0.32 (-0.58 to -0.06, P = 0.02) and in negative symptoms was -0.45 (-0.67 to -0.22, P < 0.001), both in favour of integrated treatment. Patients who received integrated treatment had significantly less comorbid substance misuse, better adherence to treatment, and more satisfaction with treatment. CONCLUSION: Integrated treatment improved clinical outcome and adherence to treatment. The improvement in clinical outcome was consistent at one year and two year follow-ups.

The gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex, which is composed of distinct proteins embedded in the neuronal plasma membrane, is important for several effects of benzodiazepines, including protection afforded against convulsions. During structural modification of ethyl beta-carboline-3-carboxylate an agent was discovered which has high affinity for brain benzodiazepine receptors but which is a potent convulsant. Also in contrast to benzodiazepines, this type of benzodiazepine receptor ligand favors benzodiazepine receptors in the non-GABA-stimulated conformation, which may explain the convulsive properties.

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Removal of excitatory amino acids from the extracellular fluid is essential for synaptic transmission and for avoiding excitotoxicity. The removal is accomplished by glutamate transporters located in the plasma membranes of both neurons and astroglia. The uptake system consists of several different transporter proteins that are carefully regulated, indicating more refined functions than simple transmitter inactivation. Here we show by chemical cross-linking, followed by electrophoresis and immunoblotting, that three rat brain glutamate transporter proteins (GLAST, GLT and EAAC) form homomultimers. The multimers exist not only in intact brain membranes but also after solubilization and after reconstitution in liposomes. Increasing the cross-linker concentration increased the immunoreactivity of the bands corresponding to trimers at the expense of the dimer and monomer bands. However, the immunoreactivities of the dimer bands did not disappear, indicating a mixture of dimers and trimers. GLT and GLAST do not complex with each other, but as demonstrated by double labeling post-embedding electron microscopic immunocytochemistry, they co-exist side by side in the same astrocytic cell membranes. The oligomers are held together noncovalently in vivo. In vitro, oxidation induces formation of covalent bonds (presumably -S-S-) between the subunits of the oligomers leading to the appearance of oligomer bands on SDS-polyacrylamide gel electrophoresis. Immunoprecipitation experiments suggest that GLT is the quantitatively dominant glutamate transporter in the brain. Radiation inactivation analysis gives a molecular target size of the functional complex corresponding to oligomeric structure. We postulate that the glutamate transporters operate as homomultimeric complexes. Removal of excitatory amino acids from the extracellular fluid is essential for synaptic transmission and for avoiding excitotoxicity. The removal is accomplished by glutamate transporters located in the plasma membranes of both neurons and astroglia. The uptake system consists of several different transporter proteins that are carefully regulated, indicating more refined functions than simple transmitter inactivation. Here we show by chemical cross-linking, followed by electrophoresis and immunoblotting, that three rat brain glutamate transporter proteins (GLAST, GLT and EAAC) form homomultimers. The multimers exist not only in intact brain membranes but also after solubilization and after reconstitution in liposomes. Increasing the cross-linker concentration increased the immunoreactivity of the bands corresponding to trimers at the expense of the dimer and monomer bands. However, the immunoreactivities of the dimer bands did not disappear, indicating a mixture of dimers and trimers. GLT and GLAST do not complex with each other, but as demonstrated by double labeling post-embedding electron microscopic immunocytochemistry, they co-exist side by side in the same astrocytic cell membranes. The oligomers are held together noncovalently in vivo. In vitro, oxidation induces formation of covalent bonds (presumably -S-S-) between the subunits of the oligomers leading to the appearance of oligomer bands on SDS-polyacrylamide gel electrophoresis. Immunoprecipitation experiments suggest that GLT is the quantitatively dominant glutamate transporter in the brain. Radiation inactivation analysis gives a molecular target size of the functional complex corresponding to oligomeric structure. We postulate that the glutamate transporters operate as homomultimeric complexes. INTRODUCTIONThe majority of excitatory signals in the mammalian central nervous system may be transmitted by glutamate (1Fonnum F. J. Neurochem. 1984; 42: 1-11Crossref PubMed Scopus (1670) Google Scholar). The extracellular glutamate concentration has to be kept low, both to secure a high signal-to-noise (background) ratio and because excessive glutamate receptor activation can lead to neuronal damage (2Olney J.W. Annu. Rev. Pharmacol. Toxicol. 1990; 30: 47-71Crossref PubMed Scopus (378) Google Scholar). This is achieved by the action of sodium-dependent glutamate transporters located in the plasma membranes of both glial cells and neurons (3Danbolt N.C. Prog. Neurobiol. (New York). 1994; 44: 377-396Crossref PubMed Scopus (213) Google Scholar). Several glutamate transporters have been cloned: GLAST 1The abbreviations used are: GLASTrat glutamate aspartate transporter (4Storck T. Schulte S. Hofmann K. Stoffel W. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10955-10959Crossref PubMed Scopus (1092) Google Scholar)CHAPS3-[(3-cholamido-propyl)dimethylammonio]- 1-propanesulfonateDTNB5,5′-dithio-bis(2-nitrobenzoic acid)DTTdithiothreitolEAACan EAAC1-type transporterEAAC1rabbit excitatory amino acid carrier (7Kanai Y. Hediger M.A. Nature. 1992; 360: 467-471Crossref PubMed Scopus (1192) Google Scholar)GLTa GLT-1-type transporterGLT-1rat glutamate transporter (5Pines G. Danbolt N.C. Bjørås M. Zhang Y. Bendahan A. Eide L. Koepsell H. Seeberg E. Storm-Mathisen J. Seeberg E. Kanner B.I. Nature. 1992; 360: 464-467Crossref PubMed Scopus (1131) Google Scholar6Kanner B.I. FEBS Lett. 1993; 325: 95-99Crossref PubMed Scopus (123) Google Scholar)GLYT1rat glycine transporter (33Smith K.E. Borden L.A. Hartig P.R. Branchek T. Weinshank R.L. Neuron. 1992; 8: 927-935Abstract Full Text PDF PubMed Scopus (379) Google Scholar)NaPisodium phosphate buffer with pH 7.4PMSFphenylmethanesulfonyl fluoriderEAAC1rat excitatory amino acid carrier (36Bjørås M. Gjesdal O. Erickson J.D. Torp R. Levy L.M. Ottersen O.P. Degree M. Storm-Mathisen J. Seeberg E. Danbolt N.C. Mol. Brain Res. 1996; 36: 163-168Crossref PubMed Scopus (58) Google Scholar)PAGEpolyacrylamide gel electrophoresisTEMEDN,N,N′,N′-tetramethylethylenediamine. (4Storck T. Schulte S. Hofmann K. Stoffel W. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10955-10959Crossref PubMed Scopus (1092) Google Scholar), GLT-1 (5Pines G. Danbolt N.C. Bjørås M. Zhang Y. Bendahan A. Eide L. Koepsell H. Seeberg E. Storm-Mathisen J. Seeberg E. Kanner B.I. Nature. 1992; 360: 464-467Crossref PubMed Scopus (1131) Google Scholar, 6Kanner B.I. FEBS Lett. 1993; 325: 95-99Crossref PubMed Scopus (123) Google Scholar), EAAC1 (7Kanai Y. Hediger M.A. Nature. 1992; 360: 467-471Crossref PubMed Scopus (1192) Google Scholar), and EAAT4 (8Fairman W.A. Vandenberg R.J. Arriza J.L. Kavanaugh M.P. Amara S.G. Nature. 1995; 375: 599-603Crossref PubMed Scopus (1006) Google Scholar). The transporters are regulated (9Casado M. Bendahan A. Zafra F. Danbolt N.C. Aragón C. Giménez C. Kanner B.I. J. Biol. Chem. 1993; 268: 27313-27317Abstract Full Text PDF PubMed Google Scholar, 10Levy L.M. Lehre K.P. Walaas S.I. Storm-Mathisen J. Danbolt N.C. Eur. J. Neurosci. 1995; 7: 2036-2041Crossref PubMed Scopus (124) Google Scholar, 11Trotti D. Volterra A. Lehre K.P. Rossi D. Gjesdal O. Racagni G. Danbolt N.C. J. Biol. Chem. 1995; 270: 9890-9895Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar) and highly differentially localized (12Torp R. Danbolt N.C. Babaie E. Bjørås M. Seeberg E. Storm-Mathisen J. Ottersen O.P. Eur. J. Neurosci. 1994; 6: 936-942Crossref PubMed Scopus (170) Google Scholar, 13Rothstein J.D. Martin L. Levey A.I. Dykes-Hoberg M. Jin L. Wu D. Nash N. Kuncl R.W. Neuron. 1994; 13: 713-725Abstract Full Text PDF PubMed Scopus (1449) Google Scholar, 14Chaudhry F.A. Lehre K.P. van Lookeren-Campagne M. Ottersen O.P. Danbolt N.C. Storm-Mathisen J. Neuron. 1995; 15: 711-720Abstract Full Text PDF PubMed Scopus (693) Google Scholar, 15Lehre K.P. Levy L.M. Ottersen O.P. Storm-Mathisen J. Danbolt N.C. J. Neurosci. 1995; 15: 1835-1853Crossref PubMed Google Scholar). Recent studies indicate that they modify glutamate receptor activation (16Barbour B. Keller B.U. Llano I. Marty A. Neuron. 1994; 12: 1331-1343Abstract Full Text PDF PubMed Scopus (316) Google Scholar, 17Maki R. Robinson M.B. Dichter M.A. J. Neurosci. 1994; 14: 6754-6762Crossref PubMed Google Scholar, 18Mennerick S. Zorumsky C.F. Nature. 1994; 368: 59-62Crossref PubMed Scopus (290) Google Scholar, 19Tong G. Jahr C.E. Neuron. 1994; 13: 1195-1203Abstract Full Text PDF PubMed Scopus (306) Google Scholar, 20Takahashi M. Kovalchuck Y. Attwell D. J. Neurosci. 1995; 15: 5693-5702Crossref PubMed Google Scholar). Thus, the functions of these carriers may be more refined than simple removal of excitatory amino acids.It is legitimate to ask whether the glutamate transporters might form oligomeric complexes. Several glutamate transporter subtypes exist (see above). These proteins have been reported to aggregate (21Danbolt N.C. Storm-Mathisen J. Kanner B.I. Neuroscience. 1992; 51: 295-310Crossref PubMed Scopus (368) Google Scholar, 22Levy L.M. Lehre K.P. Rolstad B. Danbolt N.C. FEBS Lett. 1993; 317: 79-84Crossref PubMed Scopus (112) Google Scholar, 23Rothstein J.D. Van Kammen M. Levey A.I. Martin L.J. Kuncl R.W. Ann. Neurol. 1995; 38: 73-84Crossref PubMed Scopus (1189) Google Scholar). GLAST and GLT have been observed in the same cells (15Lehre K.P. Levy L.M. Ottersen O.P. Storm-Mathisen J. Danbolt N.C. J. Neurosci. 1995; 15: 1835-1853Crossref PubMed Google Scholar). Recent reports conclude that some other co-transporters may exist in vivo as oligomers (24Béliveau R. Demeule M. Ibnoul-Khatib H. Bergeron M. Beauregard G. Potier M. Biochem. J. 1988; 252: 807-813Crossref PubMed Scopus (43) Google Scholar, 25Hebert D.N. Carruthers A. J. Biol. Chem. 1992; 267: 23829-23838Abstract Full Text PDF PubMed Google Scholar, 26Berger S.P. Farrell K. Conant D. Kempner E.S. Paul S.M. Mol. Pharmacol. 1994; 46: 726-731PubMed Google Scholar, 27Milner H.E. Béliveau R. Jarvis S.M. Biochim. Biophys. Acta. 1994; 1190: 185-187Crossref PubMed Scopus (46) Google Scholar, 28Wang Y. Tate S.S. FEBS Lett. 1995; 368: 389-392Crossref PubMed Scopus (61) Google Scholar. The glutamate transporters behave like a combination of carriers and chloride channels (18Mennerick S. Zorumsky C.F. Nature. 1994; 368: 59-62Crossref PubMed Scopus (290) Google Scholar, 29Wadiche J.I. Amara S.G. Kavanaugh M.P. Neuron. 1995; 15: 721-728Abstract Full Text PDF PubMed Scopus (451) Google Scholar). Several neurotransmitter receptors, including ionotropic glutamate receptors, operate as hetero-oligomeric complexes (30McBain C.J. Mayer M.L. Physiol. Rev. 1994; 74: 723-760Crossref PubMed Scopus (0) Google Scholar, 31Bettler B. Mulle C. Neuropharmacology. 1995; 34: 123-139Crossref PubMed Scopus (419) Google Scholar).Here we show by double labeling post-embedding electron microscopic immunocytochemistry that the two glial glutamate transporters GLT and GLAST are expressed in the same cell membranes. Furthermore, we demonstrate that GLT and GLAST, as well as the neuronal glutamate transporter EAAC, form oligomeric complexes but that GLT and GLAST do not complex with each other. Evidence suggests that oligomeric structure is required for transport activity.EXPERIMENTAL PROCEDURESMaterials—Sodium dodecyl sulfate (SDS) of high purity (.99% C12 alkyl sulfate) and bis(sulfosuccinimidyl) suberate were from Pierce. Nitrocellulose sheets (0.22-mm pores, 100% nitrocellulose) and electrophoresis equipment were from Hoefer Scientific Instruments (San Francisco, CA). N,N9-Methylenebisacrylamide, acrylamide, ammonium persulfate, TEMED, and alkaline phosphatase substrates (nitro blue tetrazolium and 5-bromo-4-chloro-3-indolyl phosphate) were from Promega (Madison, WI). Alkaline phosphatase conjugated to mouse monoclonal anti-rabbit IgG (A-2556, clone RG-96) was obtained from Sigma and used at 1:10,000. Glutaraldehyde, EM grade, was from TAAB (Reading, UK). Lowicryl HM20 was from (Lowi, Switzerland). (S)-[3H]Glutamic acid (50 Ci/mmol), molecular mass markers for SDSpolyacrylamide gel electrophoresis (SDS-PAGE), and colloidal gold-labeled second antibodies (GAR15, GAR30) were from Amersham (Buckinghamshire, UK). Cholic acid was purified with activated charcoal and by recrystallization from 70% ethanol. Wheat germ agglutinin was immobilized to agarose as described previously (21,). All other reagents were either obtained from Sigma or from Fluka (Buchs, Switzerland).Production of Antibodies—Anti-peptide antibodies against three glutamate transporters (15Lehre K.P. Levy L.M. Ottersen O.P. Storm-Mathisen J. Danbolt N.C. J. Neurosci. 1995; 15: 1835-1853Crossref PubMed Google Scholar) and one glycine transporter (32Zafra F. Aragón C. Olivares L. Danbolt N.C. Giménez C. Storm-Mathisen J. J. Neurosci. 1995; 15: 3952-3969Crossref PubMed Google Scholar) were prepared as described using synthetic peptides as antigens. The peptides representing parts of GLAST (rat EAAT1), GLT-1 (rat EAAT2), EAAC1 (rabbit EAAT3), and GLYT1 are referred to by capital letters A, B, C, and G, respectively, followed by numbers indicating the corresponding amino acid residues in the sequences (given in parentheses): A522-541 (PYQLIAQDNEPEKPVADSET), B12-26 (KQVEVRMHDSHLSSE), B493-508 (YHLSKSELDTIDSQHR), C510-524 (VDKSDTISFTQTSQF), and G623-638 (IVGSNGSSRLQDSRI) (4Storck T. Schulte S. Hofmann K. Stoffel W. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10955-10959Crossref PubMed Scopus (1092) Google Scholar, 5Pines G. Danbolt N.C. Bjørås M. Zhang Y. Bendahan A. Eide L. Koepsell H. Seeberg E. Storm-Mathisen J. Seeberg E. Kanner B.I. Nature. 1992; 360: 464-467Crossref PubMed Scopus (1131) Google Scholar, 7Kanai Y. Hediger M.A. Nature. 1992; 360: 467-471Crossref PubMed Scopus (1192) Google Scholar, 33Smith K.E. Borden L.A. Hartig P.R. Branchek T. Weinshank R.L. Neuron. 1992; 8: 927-935Abstract Full Text PDF PubMed Scopus (379) Google Scholar). The corresponding anti-peptide antibodies are referred to as anti-A522 (rabbit 68488), anti-B12 (rabbit 68518), anti-B493 (rabbit 84946), anti-C510 (rabbit 69738), or anti-G623 (rabbit The antibodies (rabbit (21Danbolt N.C. Storm-Mathisen J. Kanner B.I. Neuroscience. 1992; 51: 295-310Crossref PubMed Scopus (368) Google Scholar), were and purified against a purified glutamate transporter N.C. G. Kanner B.I. 1990; PubMed Scopus Google Scholar), were from the same purified as that previously described F.A. Lehre K.P. van Lookeren-Campagne M. Ottersen O.P. Danbolt N.C. Storm-Mathisen J. Neuron. 1995; 15: 711-720Abstract Full Text PDF PubMed Scopus (693) Google Scholar, N.C. Storm-Mathisen J. Kanner B.I. Neuroscience. 1992; 51: 295-310Crossref PubMed Scopus (368) Google Scholar, 22Levy L.M. Lehre K.P. Rolstad B. Danbolt N.C. FEBS Lett. 1993; 317: 79-84Crossref PubMed Scopus (112) Google Scholar). The anti-A522 antibodies from were by with GLAST from rat and antibodies from the using the The two anti-A522 antibodies from and labeling anti-A522 to antibodies from was with with in in Lowicryl HM20 at and as described using the same antibodies and F.A. Lehre K.P. van Lookeren-Campagne M. Ottersen O.P. Danbolt N.C. Storm-Mathisen J. Neuron. 1995; 15: 711-720Abstract Full Text PDF PubMed Scopus (693) Google Scholar). experiments between the labeling was by the of and PubMed Scopus Google Scholar), with as for the and for the one of the antibodies to of by the corresponding of in cells were in and with GLT (5Pines G. Danbolt N.C. Bjørås M. Zhang Y. Bendahan A. Eide L. Koepsell H. Seeberg E. Storm-Mathisen J. Seeberg E. Kanner B.I. Nature. 1992; 360: 464-467Crossref PubMed Scopus (1131) Google Scholar) or (36Bjørås M. Gjesdal O. Erickson J.D. Torp R. Levy L.M. Ottersen O.P. Degree M. Storm-Mathisen J. Seeberg E. Danbolt N.C. Mol. Brain Res. 1996; 36: 163-168Crossref PubMed Scopus (58) Google Scholar) using the system (36Bjørås M. Gjesdal O. Erickson J.D. Torp R. Levy L.M. Ottersen O.P. Degree M. Storm-Mathisen J. Seeberg E. Danbolt N.C. Mol. Brain Res. 1996; 36: 163-168Crossref PubMed Scopus (58) Google Scholar, W. B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, B. Mol. Biol. 7: PubMed Scopus Google Scholar, G. Amara S.G. Biochem. PubMed Scopus Google Scholar). The was a from B. of The cells were from the and by for of both were by and The and were in of using a was not The was to cell membranes. of membranes from cells was in the same the membranes are referred to as membranes were prepared as described N.C. G. Kanner B.I. 1990; PubMed Scopus Google Scholar) by in of the and of the membranes after of of proteins in intact the (see were in buffer pH to a concentration of and in the or a cross-linker was suberate not to of or from a prepared in the was by pH to a concentration of the membranes were in buffer pH D. Volterra A. Lehre K.P. Rossi D. Gjesdal O. Racagni G. Danbolt N.C. J. Biol. Chem. 1995; 270: 9890-9895Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar) on with the buffer and on (see of for of were in of buffer and of membranes was with of ammonium sulfate and of solubilization buffer of buffer and pH with a or and the was with buffer and to of or The ammonium sulfate was with for experiments (see or the membranes were with of of of was with either anti-A522 or with and with buffer pH and The buffer the gel was were (see with were to of the of and of buffer pH were to each and or the were for reconstitution of transport (see and for The was from the by in buffer with and to The proteins were with or and The IgG that been in buffer and was by the of transporters were purified from rat by N.C. G. Kanner B.I. 1990; PubMed Scopus Google Scholar) and from the in buffer with a or was to the purified of the were with (see were in the the proteins on and the by with in the proteins were with high and and for transport (see of rat from were kept at and to using the at The of was using The were was in of the were to for at to that they the The were from to the was kept at was This and the equipment have been by inactivation of of molecular a of M. J. Sci. 1984; PubMed Scopus (46) Google Scholar, M. T. C. Biochem. Pharmacol. 34: PubMed Scopus Google Scholar, M. C. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar). from the that the in the is and that is not required in However, to the of the the of and to and the of were The were in buffer (50 pH and and The were for using the The were either used for of as described M. T. C. Biochem. Pharmacol. 34: PubMed Scopus Google Scholar) or with of solubilization buffer pH on and as The were in of and to reconstitution (see of in was as described D. Volterra A. Lehre K.P. Rossi D. Gjesdal O. Racagni G. Danbolt N.C. J. Biol. Chem. 1995; 270: 9890-9895Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, N.C. G. Kanner B.I. 1990; PubMed Scopus Google Scholar). with glutamate transporters and either or was with of a on and to on with the of was as described N.C. G. Kanner B.I. 1990; PubMed Scopus Google Scholar). the uptake was by of with amino acid and The was by and The were with the R. A. Biochem. J. PubMed Scopus Google and (15Lehre K.P. Levy L.M. Ottersen O.P. Storm-Mathisen J. Danbolt N.C. J. Neurosci. 1995; 15: 1835-1853Crossref PubMed Google Scholar, Nature. PubMed Scopus Google Scholar) was with of or The electrophoresis with kept at electrophoresis the proteins were either N.C. G. Kanner B.I. 1990; PubMed Scopus Google Scholar) or membranes (15Lehre K.P. Levy L.M. Ottersen O.P. Storm-Mathisen J. Danbolt N.C. J. Neurosci. 1995; 15: 1835-1853Crossref PubMed Google Scholar, H. T. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The were to (15Lehre K.P. Levy L.M. Ottersen O.P. Storm-Mathisen J. Danbolt N.C. J. Neurosci. 1995; 15: 1835-1853Crossref PubMed Google of were by the of R.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar) using as IgG was at using IgG as INTRODUCTIONThe majority of excitatory signals in the mammalian central nervous system may be transmitted by glutamate (1Fonnum F. J. Neurochem. 1984; 42: 1-11Crossref PubMed Scopus (1670) Google Scholar). The extracellular glutamate concentration has to be kept low, both to secure a high signal-to-noise (background) ratio and because excessive glutamate receptor activation can lead to neuronal damage (2Olney J.W. Annu. Rev. Pharmacol. Toxicol. 1990; 30: 47-71Crossref PubMed Scopus (378) Google Scholar). This is achieved by the action of sodium-dependent glutamate transporters located in the plasma membranes of both glial cells and neurons (3Danbolt N.C. Prog. Neurobiol. (New York). 1994; 44: 377-396Crossref PubMed Scopus (213) Google Scholar). Several glutamate transporters have been cloned: GLAST 1The abbreviations used are: GLASTrat glutamate aspartate transporter (4Storck T. Schulte S. Hofmann K. Stoffel W. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10955-10959Crossref PubMed Scopus (1092) Google Scholar)CHAPS3-[(3-cholamido-propyl)dimethylammonio]- 1-propanesulfonateDTNB5,5′-dithio-bis(2-nitrobenzoic acid)DTTdithiothreitolEAACan EAAC1-type transporterEAAC1rabbit excitatory amino acid carrier (7Kanai Y. Hediger M.A. Nature. 1992; 360: 467-471Crossref PubMed Scopus (1192) Google Scholar)GLTa GLT-1-type transporterGLT-1rat glutamate transporter (5Pines G. Danbolt N.C. Bjørås M. Zhang Y. Bendahan A. Eide L. Koepsell H. Seeberg E. Storm-Mathisen J. Seeberg E. Kanner B.I. Nature. 1992; 360: 464-467Crossref PubMed Scopus (1131) Google Scholar6Kanner B.I. FEBS Lett. 1993; 325: 95-99Crossref PubMed Scopus (123) Google Scholar)GLYT1rat glycine transporter (33Smith K.E. Borden L.A. Hartig P.R. Branchek T. Weinshank R.L. Neuron. 1992; 8: 927-935Abstract Full Text PDF PubMed Scopus (379) Google Scholar)NaPisodium phosphate buffer with pH 7.4PMSFphenylmethanesulfonyl fluoriderEAAC1rat excitatory amino acid carrier (36Bjørås M. Gjesdal O. Erickson J.D. Torp R. Levy L.M. Ottersen O.P. Degree M. Storm-Mathisen J. Seeberg E. Danbolt N.C. Mol. Brain Res. 1996; 36: 163-168Crossref PubMed Scopus (58) Google Scholar)PAGEpolyacrylamide gel electrophoresisTEMEDN,N,N′,N′-tetramethylethylenediamine. (4Storck T. Schulte S. Hofmann K. Stoffel W. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10955-10959Crossref PubMed Scopus (1092) Google Scholar), GLT-1 (5Pines G. Danbolt N.C. Bjørås M. Zhang Y. Bendahan A. Eide L. 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Evidence suggests that oligomeric structure is required for transport

Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures.

BACKGROUND: Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. METHODS AND FINDINGS: Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10-6, and hippocampus, p = 7.9 × 10-5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use. CONCLUSIONS: We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease.

Abstract Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk ( P &lt;5 × 10 −8 ), implicating genes involved in sex steroid hormone pathways ( FN1 , CCDC170 , ESR1 , SYNE1 and FSHB ). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.

Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the rate-limiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P < 0.001) decreased protein expression of the catalytic GCL subunit (GCLC). Genetic analysis of a trinucleotide repeat (TNR) polymorphism in the GCLC gene showed a significant association with schizophrenia in two independent case-control studies. The most common TNR genotype 7/7 was more frequent in controls [odds ratio (OR) = 0.6, P = 0.003], whereas the rarest TNR genotype 8/8 was three times more frequent in patients (OR = 3.0, P = 0.007). Moreover, subjects with disease-associated genotypes had lower GCLC protein expression (P = 0.017), GCL activity (P = 0.037), and GSH contents (P = 0.004) than subjects with genotypes that were more frequent in controls. Taken together, the study provides genetic and functional evidence that an impaired capacity to synthesize GSH under conditions of oxidative stress is a vulnerability factor for schizophrenia.

BACKGROUND: Neurodevelopmental brain disorders such as schizophrenia, autism and attention deficit hyperactivity disorder are complex disorders with heterogeneous etiologies. Schizophrenia and autism are difficult to treat and often cause major individual suffering largely owing to our limited understanding of the disease biology. Thus our understanding of the biological pathogenesis needs to be substantiated to enable development of more targeted treatment options with improved efficacy. Insights into the pre-morbid disease dynamics, the morbid condition and the underlying biological disease mechanisms may come from studies of subjects with homogenous etiologies. Breakthroughs in psychiatric genetics have shown that several genetic anomalies predispose for neurodevelopmental brain disorders. We have established a Danish research initiative to study the common microdeletion at chromosome 22q11.2, which is one of the genetic anomalies that confer high risk of schizophrenia, autism and attention deficit hyperactivity disorder. METHODS/DESIGN: The study applies a "cause-to-outcome" strategy to identify pre-morbid pathogenesis and underlying biological disease mechanisms of psychosis and secondarily the morbid condition of autism and attention deficit hyperactivity disorder. We use a population based epidemiological design to inform on disease prevalence, environmental risk factors and familial disposition for mental health disorders and a case control study design to map the functional effects across behavioral and neurophysiological traits of the 22q11 deletion in a recruited sample of Danish individuals. DISCUSSION: Identification of predictive pre-morbid clinical, cognitive, functional and structural brain alterations in 22q11 deletion carriers may alter current clinical practice from symptomatic therapy of manifest mental illness into early intervention strategies, which may also be applicable to at risk subjects without known etiology. Hopefully new insights into the biological disease mechanisms, which are mandatory for novel drug developments, can improve the outcome of the pharmacological interventions in psychiatry.

Two hundred and sixteen psychiatric patients (183 men and 33 women) hospitalized in Sct. Hans Hospital were treated with clozapine between 1971-1983. All had been treated previously with one or more neuroleptic(s) and had either failed to respond adequately, or their response was limited by side effects. Eighty-five patients were treated exclusively with clozapine, while the remaining 131 received additional medication, mainly other neuroleptic drugs. The mean clozapine dosage was 317 mg/day (range 50-1200), and the mean duration of treatment was 23/4 years (range 1/12-12). The tolerability to clozapine was determined by an evaluation of haematological changes, pronounced side effects and mortality. One patient treated with clozapine (8 months) and nitrofurantoin (8 days) developed a reversible granulocytopenia. One patient (treated with a combination of drugs) had clinically insignificant depression of the leucocytes and three of segmented granulocytes. Seven had a reduction in thrombocytes. Two patients developed cardiac insufficiency, and four epileptic seizures. None of the patients treated exclusively with clozapine developed neurological side effects. A global estimation of therapeutic effect revealed that clozapine alone or in combination with other neuroleptic drugs was significantly better than previous antipsychotic therapy, although 47-63% of the patients showed no change. It is concluded that clozapine is a potent antipsychotic drug offering particular advantages in the treatment of schizophrenic patients with a pronounced symptomatology and tendency towards developing extrapyramidal side effects. Caution is advised in patients with cardiac insufficiency and epilepsy. There appears to be a slight risk of granulocytopenia, and therefore the present monitoring of WBC should continue in order to prevent this reaction and to obtain more complete information regarding risk of granulocytopenia.

Membrane proteins are regulated by the lipid bilayer composition. Specific lipid-protein interactions rarely are involved, which suggests that the regulation is due to changes in some general bilayer property (or properties). The hydrophobic coupling between a membrane-spanning protein and the surrounding bilayer means that protein conformational changes may be associated with a reversible, local bilayer deformation. Lipid bilayers are elastic bodies, and the energetic cost of the bilayer deformation contributes to the total energetic cost of the protein conformational change. The energetics and kinetics of the protein conformational changes therefore will be regulated by the bilayer elasticity, which is determined by the lipid composition. This hydrophobic coupling mechanism has been studied extensively in gramicidin channels, where the channel-bilayer hydrophobic interactions link a "conformational" change (the monomer<-->dimer transition) to an elastic bilayer deformation. Gramicidin channels thus are regulated by the lipid bilayer elastic properties (thickness, monolayer equilibrium curvature, and compression and bending moduli). To investigate whether this hydrophobic coupling mechanism could be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (beta-octyl-glucoside, Genapol X-100, Triton X-100, and reduced Triton X-100) that make lipid bilayers less "stiff", as measured using gA channels, shift the voltage dependence of sodium channel inactivation toward more hyperpolarized potentials. At low amphiphile concentration, the magnitude of the shift is linearly correlated to the change in gA channel lifetime. Cholesterol-depletion, which also reduces bilayer stiffness, causes a similar shift in sodium channel inactivation. These results provide strong support for the notion that bilayer-protein hydrophobic coupling allows the bilayer elastic properties to regulate membrane protein function.

BACKGROUND: Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. METHODOLOGY/PRINCIPAL FINDINGS: We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. CONCLUSIONS/SIGNIFICANCE: We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.

ABSTRACT Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P&lt;1×10 -4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters ( CACNA1C , GRIN2A , SCN2A , SLC4A1 ), synaptic components ( RIMS1 , ANK3 ), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~ 73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~ 17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

Ethyl beta-carboline-3-carboxylate (beta-CCE) is a mixed-type inhibitor of [3H]flunitrazepam ([3H]FNM) binding to benzodiazepine receptors in noncerebellar regions of rat brain. These findings may represent the presence of either receptor multiplicity or negative cooperativity among benzodiazepine receptors. [3H]Propyl beta-carboline-3-carboxylate ([3H]PrCC) has previously been shown to bind specifically to benzodiazepine receptors of rat cerebellum. In the present study we found no indication of the presence of true negative cooperativity among benzodiazepine receptors when [3H]PrCC was used as radioligand. However, we observed that [3H]PrCC labelled only 57% of [3H]FNM binding sites in rat hippocampus (Bmax values) and 71% in rat cerebral cortex, whereas the number of receptors labelled by both ligands was equal in the cerebellum. Hofstee analyses of the shallow inhibition curves seen in hippocampus and cerebral cortex when [3H]FNM binding was inhibited by beta-CCE indicate that beta-CCE and some other beta-carboline-3-carboxylate derivatives interact preferentially with a subclass of receptors, and that the percentage of this subclass is equivalent to the number of receptors labelled by [3H]PrCC. We conclude that [3H]PrCC at low concentration (0.3-0.4 X 10(-9) M) labels a subclass of benzodiazepine receptors, BZ1, while another class, BZ2 receptors, are not labelled by [3H]PrCC when filtration assays are used. By parallel determinations of the proportion between [3H]FNM and [3H]PrCC binding we calculated the percentage of BZ1 receptors in several regions of rat, guinea pig and calf brain and in mouse forebrain. The values ranged from approximately 50% in hippocampus to 90% in the guinea pig pons.

Importance: Anxiety and stress-related disorders are among the most common mental disorders. Although family and twin studies indicate that both genetic and environmental factors play an important role underlying their etiology, the genetic underpinnings of anxiety and stress-related disorders are poorly understood. Objectives: To estimate the single-nucleotide polymorphism-based heritability of anxiety and stress-related disorders; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to evaluate the association of psychiatric comorbidities with genetic findings. Design, Setting, Participants: This genome-wide association study included individuals with various anxiety and stress-related diagnoses and controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers. Genes of interest were further evaluated in mice exposed to chronic social defeat. The study was conducted between June 2016 and November 2018. Main Outcomes and Measures: Diagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders. Results: The study sample included 12 655 individuals with various anxiety and stress-related diagnoses and 19 225 controls. Overall, 17 740 study participants (55.6%) were women. A total of 7308 participants (22.9%) were born between 1981-1985, 8840 (27.7%) between 1986-1990, 8157 (25.6%) between 1991-1995, 5918 (18.6%) between 1996-2000, and 1657 (5.2%) between 2001-2005. Standard association analysis revealed variants in PDE4B to be associated with anxiety and stress-related disorder (rs7528604; P = 5.39 × 10-11; odds ratio = 0.89; 95% CI, 0.86-0.92). A framework of sensitivity analyses adjusting for mental comorbidity supported this result showing consistent association of PDE4B variants with anxiety and stress-related disorder across analytical scenarios. In mouse models, alterations in Pde4b expression were observed in those mice displaying anxiety-like behavior after exposure to chronic stress in the prefrontal cortex (P = .002; t = -3.33) and the hippocampus (P = .001; t = -3.72). We also found a single-nucleotide polymorphism heritability of 28% (standard error = 0.027) and that the genetic signature of anxiety and stress-related overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success. Conclusions and Relevance: This study highlights anxiety and stress-related disorders as complex heritable phenotypes with intriguing genetic correlations not only with psychiatric traits, but also with educational outcomes and multiple obesity-related phenotypes. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to the potential of PDE4B inhibitors in treatment of these disorders.