1. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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2. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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5. |
- Jonsson, Lina, 1982, et al.
(författare)
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Characterisation of age and polarity at onset in bipolar disorder
- 2021
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Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
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Tidskriftsartikel (refereegranskat)abstract
- Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (beta = -0.34 years, s.e. = 0.08), major depression (beta = -0.34 years, s.e. = 0.08), schizophrenia (beta = -0.39 years, s.e. = 0.08), and educational attainment (beta = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
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6. |
- Witt, S. H., et al.
(författare)
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Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia
- 2017
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P = 4.42 x 10(-7)) and PKP4 (P = 8.67 x 10(-7)); and gene-set analysis yielded a significant finding for exocytosis (GO: 0006887, PFDR = 0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (r(g) = 0.28 [P = 2.99 x 10(-3)]), SCZ (r(g) = 0.34 [P = 4.37 x 10(-5)]) and MDD (r(g) = 0.57 [P = 1.04 x 10(-3)]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
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9. |
- Charity, R. J., et al.
(författare)
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Two-proton decay of the 6Be ground state and the double isobaric analog of 11Li
- 2013
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 420:1
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Konferensbidrag (refereegranskat)abstract
- Two-proton decay is discussed in a number of light isobaric multiplets. For the lightest two-proton emitter, 6Be, the momentum correlations between the three decay products were measured and found to be consistent with quantum-mechanical three-cluster-model calculations. Two-proton decay was also found for two members of the A=8 and A=11 quintets. Finally, a third member of the A=11 sextet, the double isobaric analog of the halo nucleus 11Li in 11B was observed by its two-proton decay.
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10. |
- Amare, Azmeraw T, et al.
(författare)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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11. |
- Petri, M., et al.
(författare)
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Structure of C-16: Testing shell model and ab initio approaches
- 2012
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Ingår i: Physical Review C - Nuclear Physics. - 2469-9985 .- 2469-9993. ; 86:4, s. Art. no. 044329-
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Tidskriftsartikel (refereegranskat)abstract
- Excited states in C-16 were populated via the Be-9(N-17,C-16+gamma)X one-proton knockout reaction. The lifetime of the 2(1)(+) state in C-16 was measured using the recoil distance method. The extracted lifetime of tau(+)(21) = 11.4(-0.9)(+0.8)(stat) +/- 0.7(syst(B rho))(-1.5)(+0.0)(syst(feeding)) ps yields a deduced B(E2;2(1)(+) -> 0(1)(+)) = 4.21(-0.26)(+0.34)(stat)(-0.24)(+0.28)(syst(B rho))(-0.00)(+0.64)(syst(feeding)) e(2)fm(4) value in good agreement with a previous measurement. The one-proton knockout cross section is used to extract the proton amplitude of the C-16 2(1)(+) state, which confirms the neutron dominant character of this state. Gamma-ray branching ratios between the 2(2)(+) state and the 2(1)(+) and ground states were also determined. The results are compared with p-sd shell model and no-core shell model (with NN and NN + NNN) calculations. The inclusion of three-body forces are essential in order for the no-core shell model calculations to reproduce the experimental findings on the gamma-ray branching ratios.
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12. |
- Albers, M., et al.
(författare)
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Single-particle and collective excitations in Ni 62
- 2016
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Ingår i: Physical Review C - Nuclear Physics. - 0556-2813. ; 94:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Level sequences of rotational character have been observed in several nuclei in the A=60 mass region. The importance of the deformation-driving πf7/2 and νg9/2 orbitals on the onset of nuclear deformation is stressed. Purpose: A measurement was performed in order to identify collective rotational structures in the relatively neutron-rich Ni62 isotope. Method: The Mg26(Ca48,2α4nγ)Ni62 complex reaction at beam energies between 275 and 320 MeV was utilized. Reaction products were identified in mass (A) and charge (Z) with the fragment mass analyzer (FMA) and γ rays were detected with the Gammasphere array. Results: Two collective bands, built upon states of single-particle character, were identified and sizable deformation was assigned to both sequences based on the measured transitional quadrupole moments, herewith quantifying the deformation at high spin. Conclusions: Based on cranked Nilsson-Strutinsky calculations and comparisons with deformed bands in the A=60 mass region, the two rotational bands are understood as being associated with configurations involving multiple f7/2 protons and g9/2 neutrons, driving the nucleus to sizable prolate deformation.
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13. |
- Albers, M., et al.
(författare)
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Single-particle and collective excitations in Ni-63
- 2013
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 88:5
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Tidskriftsartikel (refereegranskat)abstract
- A study of excited states in Ni-63 up to an excitation energy of 28 MeV and a probable spin of 57/2 was carried out with the Mg-26(Ca-48,2 alpha 3n gamma)Ni-63 reaction at beam energies between 275 and 320 MeV. Three collective bands, built upon states of single-particle character, were identified. For two of the three bands, the transition quadrupole moments were extracted, herewith quantifying the deformation at high spin. The results have been compared with shell-model and cranked Nilsson-Strutinsky calculations. Despite the Z = 28 shell closure and the approach to the purported N = 40 subshell, the Ni-63 isotope is able to sustain collective excitations at moderate and high spin.
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14. |
- Kalman, Janos L, et al.
(författare)
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Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.
- 2019
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Ingår i: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18years] vs adulthood [>18years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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15. |
- Bartolini Bussi, M G, et al.
(författare)
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Mathematics in context: focusing on students
- 2009
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Ingår i: Challenging Mathematics In and Beyond the Classroom – The 16th ICMI Study. - New York : Springer Science+Business Media B.V.. - 9780387096032 ; , s. 171-203
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Bokkapitel (refereegranskat)abstract
- This chapter presents nine case studies in which school students engage in challenging mathematics outside their immediate classroom environment. In each case, students are encouraged to collaborate in investigations that go beyond the standard curriculum and creatively use the ingredients of the particular context. In Italy, students visit a mathematical laboratory to understand and utilize mathematical machines. Morning assembly at an Indian school brings students from many classes together in the solution of mathematical problems. Four of the projects are from France: students analyze the configuration of a heap of sand, pursue astronomical investigations with software, obtain a flavor of research by having secondary school teams investigate interesting problems, and are presented at all levels with open-ended research problems. There are three programs from the United States, the first, an advanced geometry sequence for secondary students completing the regular syllabus early, the second, activities arising from exhibits in an art museum, and the third, using the school lawn to deepen student understanding of geometric constructions. All such activities need to be evaluated for their effectiveness, so that they move from just being initiatives of dynamic individuals to serve as the foundation for systemic improvements in the way in which students learn, understand and use mathematics. In the early part of this chapter, we briefly mention how research into such activities might be approached.
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16. |
- Forcato, M., et al.
(författare)
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Chiral, enantiopure aluminum(III) and titanium(IV) azatranes
- 2006
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Ingår i: European Journal of Inorganic Chemistry. - : Wiley. - 1434-1948 .- 1099-1948 .- 1099-0682. ; :5, s. 1032-1040
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Tidskriftsartikel (refereegranskat)abstract
- Al-III and Ti-IV complexes of C-3-symmetric tetradentate trisamidoamme ligands with trigonal bipyramidal coordination geometry, containing chlorine or dialkylamido groups, or with a free coordination site in the apical position, have been synthesised by salt metathesis and amine elimination. Products with threefold symmetry were generally obtained for tetravalent titanium, whereas for the aluminium complexes either asymmetric structures with two of the three podand arms taking part in coordination to the metal or symmetric arrangements possessing the full threefold symmetry were formed depending on the steric properties of the ligands.
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17. |
- Llewellyn, R. D. O., et al.
(författare)
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Establishing the Maximum Collectivity in Highly Deformed N = Z Nuclei
- 2020
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Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 124:15
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Tidskriftsartikel (refereegranskat)abstract
- The lifetimes of the first excited 2(+) states in the N = Z nuclei Zr-80, Y-78, and Sr-76 have been measured using the gamma-ray line shape method following population via nucleon-knockout reactions from intermediate-energy rare-isotope beams. The extracted reduced electromagnetic transition strengths yield new information on where the collectivity is maximized and provide evidence for a significant, and as yet unexplained, odd-odd vs even-even staggering in the observed values. The experimental results are analyzed in the context of state-of-the-art nuclear density-functional model calculations.
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18. |
- Llewellyn, R. D. O., et al.
(författare)
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Spectroscopy of proton-rich Zr-79 : Mirror energy differences in the highly-deformed fpg shell
- 2020
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 811
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Tidskriftsartikel (refereegranskat)abstract
- Energy differences between isobaric analogue states have been extracted for the A = 79, Zr-79/Y-79 mirror pair following their population via nucleon-knockout reactions from intermediate-energy rare-isotope beams. These are the heaviest nuclei where such measurements have been made to date. The deduced mirror energy differences (MED) are compared with predictions from a new density-functional based approach, incorporating isospin-breaking effects of both Coulomb and nuclear charge-symmetry breaking and configuration mixing.
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19. |
- Voss, P., et al.
(författare)
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Excited-state transition-rate measurements in C-18
- 2012
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Ingår i: Physical Review C - Nuclear Physics. - 2469-9985 .- 2469-9993. ; 86:1
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Tidskriftsartikel (refereegranskat)abstract
- Excited states in C-18 were populated by the one-proton knockout reaction of an intermediate energy radioactive N-19 beam. The lifetime of the first 2(+) state was measured with the Koln/NSCL plunger via the recoil distance method to be tau (2(1)(+)) = 22.4 +/- 0.9(stat)(-2.2)(+3.3)(syst) ps, which corresponds to a reduced quadrupole transition strength of B(E2; 2(1)(+) -> 0(1)(+)) = 3.64(-0.14)(+ 0.15)(stat)(-0.47)(+0.40)(syst) e(2)fm(4). In addition, an upper limit on the lifetime of a higher-lying state feeding the 2(1)(+) state was measured to be tau
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20. |
- Brown, J, et al.
(författare)
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Frontotemporal dementia linked to chromosome 3
- 2004
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 17:4, s. 274-276
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Tidskriftsartikel (refereegranskat)abstract
- A large pedigree with autosomal dominant frontotemporal dementia has been identified. Positional cloning has linked the disease gene to the pericentromeric region of chromosome 3. Clinical, neuropsychological, imaging, pathological and molecular genetic data are presented. The genetic mutation responsible for the disease has not been identified.
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21. |
- Deshmukh, A. A., et al.
(författare)
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Investigating the Applicability and Limitations of Glass-Forming Criteria Based on Bond Parameters on Thermal Stability in Mg-Based Multicomponent Bulk Metallic Glasses
- 2018
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Ingår i: Transactions of the Indian Institute of Metals. - : SPRINGER INDIA. - 0972-2815 .- 0975-1645. ; 71:11, s. 2631-2634
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, correlation of thermal stability () with the bond parameters such as electronegativity (), atomic radius mismatch (), and valence electron concentration () for Mg-based multicomponent bulk metallic glasses (BMGs) have been evaluated. A statistical approach of regression analysis has been adopted to investigate correlations among these parameters. Available experimental data have been used for the systematic investigation from ternary to multicomponent Mg-based BMGs. In addition, the applicability of the criteria has been assessed for the systems with and without rare earth (RE) elements. We have found that BMG systems containing RE group elements have significant effect on width of supercooled liquid region. Results obtained from our modified empirical equation have been compared with that of earlier models and have shown better correlations.
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22. |
- Gydesen, S, et al.
(författare)
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Chromosome 3 linked frontotemporal dementia (FTD-3)
- 2002
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Ingår i: Neurology. - 1526-632X. ; 59:10, s. 1585-1594
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Tidskriftsartikel (refereegranskat)abstract
- Background: The authors have identified and studied a large kindred in which frontotemporal dementia (FTD) is inherited as an autosomal dominant trait. The trait has been mapped to the pericentromeric region of chromosome 3. Methods: The authors report on the clinical, neuroimaging, neuropsychological, and pathologic features in this unique pedigree collected during 17 years of study. Results: Twenty-two individuals in three generations have been affected; the age at onset varies between 46 and 65 years. The disease presents with a predominantly frontal lobe syndrome but there is also evidence for temporal and dominant parietal lobe dysfunction. Late in the illness individuals develop a florid motor syndrome with pyramidal and extrapyramidal features. Structural imaging reveals generalized cerebral atrophy; H-2 O-15-PET scanning in two individuals relatively early and late in the disease shows a striking global reduction in cerebral blood flow affecting all lobes. On macroscopic pathologic examination, there is generalized cerebral atrophy affecting the frontal lobes preferentially. Microscopically, there is neuronal loss and gliosis without specific histopathologic features. Conclusions: FTD-3 shares clinical and pathologic features with other forms of FTD and fulfills international consensus criteria for FTD. There is involvement of the parietal lobes clinically, radiologically, and pathologically in FTD-3 in contrast to some forms of FTD. This more diffuse involvement of the cerebral cortex leads to a distinctive, global pattern of reduced blood flow on PET scanning.
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