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- Blokland, G. A. M., et al.
(author)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Journal article (peer-reviewed)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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- de Jong, S, et al.
(author)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Journal article (peer-reviewed)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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- Jonsson, Lina, 1982, et al.
(author)
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Characterisation of age and polarity at onset in bipolar disorder
- 2021
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In: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
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Journal article (peer-reviewed)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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- Donchev, V., et al.
(author)
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Optical properties of thick GaInAs(Sb)N layers grown by liquid-phase epitaxy
- 2017
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In: 19TH INTERNATIONAL SCHOOL ON CONDENSED MATTER PHYSICS (ISCMP): ADVANCES IN NANOSTRUCTURED CONDENSED MATTER: RESEARCH AND INNOVATIONS. - : IOP PUBLISHING LTD.
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Conference paper (peer-reviewed)abstract
- We present an experimental and theoretical study of GaInAs(Sb)N layers with thickness around 2 mu m, grown by liquid-phase epitaxy (LPE) on n-type GaAs substrates. The samples are studied by surface photovoltage (SPV) spectroscopy and by photoluminescence spectroscopy. A theoretical model for the band structure of Sb-containing dilute nitrides is developed within the semi-empirical tight-binding approach in the sp(3)d(5)s*s(N) parameterisation and is used to calculate the electronic structure for different alloy compositions. The SPV spectra measured at room temperature clearly show a red shift of the absorption edge with respect to the absorption of the GaAs substrate. The shifts are in agreement with theoretical calculations results obtained for In, Sb and N concentrations corresponding to the experimentally determined ones. Photoluminescence measurements performed at 300K and 2 K show a smaller red shift of the emission energy with respect to GaAs as compared to the SPV results. The differences are explained by a tail of slow defect states below the conduction band edge, which are probed by SPV, but are less active in the PL experiment.
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| 17. |
- Karlberg, Tobias, et al.
(author)
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14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, an amphipathic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3 beta: ExoS and -ExoT complexes presented here reveal an extensive hydrophobic interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the amphipathic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the amphipathic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the amphipathic C-terminal segment.
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| 19. |
- Milanova, M., et al.
(author)
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Experimental study of the effect of local atomic ordering on the energy band gap of melt grown InGaAsN alloys
- 2017
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In: Semiconductor Science and Technology. - : IOP PUBLISHING LTD. - 0268-1242 .- 1361-6641. ; 32:8
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Journal article (peer-reviewed)abstract
- We present a study of melt grown dilute nitride InGaAsN layers by x-ray photoelectron spectroscopy (XPS), Raman and photoluminescence (PL) spectroscopy. The purpose of the study is to determine the degree of atomic ordering in the quaternary alloy during the epitaxial growth at near thermodynamic equilibrium conditions and its influence on band gap formation. Despite the low In concentration (similar to 3%) the XPS data show a strong preference toward In-N bonding configuration in the InGaAsN samples. Raman spectra reveal that most of the N atoms are bonded to In instead of Ga atoms and the formation of N-centred In3Ga1 clusters. PL measurements reveal smaller optical band gap bowing as compared to the theoretical predictions for random alloy and localised tail states near the conduction band minimum.
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| 20. |
- Milanova, M., et al.
(author)
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Investigation of LPE grown dilute nitride InGaAs(Sb)N layers for photovoltaic applications
- 2019
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In: 10TH JUBILEE CONFERENCE OF THE BALKAN PHYSICAL UNION. - : AMER INST PHYSICS. - 9780735418035
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Conference paper (peer-reviewed)abstract
- We report on LPE growth and characterization of dilute nitride InGaAs(Sb)N layers nearly lattice matched to GaAs. In order to obtain high quality epitaxial layers without phase separation low-temperature variant of LPE method has been used. The composition and crystalline quality of the grown InGaAs(Sb)N layers have been determined by energy dispersive X-ray microanalysis and X-ray diffraction methods. SEM and AFM measurements on grown samples revealed flat interfaces and surface roughness in the range 0.2 - 0.3 nm. In order to identify the N-bonding mechanism in the alloys and the nature of nitrogen related clusters IR absorption and Raman scattering spectroscopy have been applied. The optical band gap of the samples is studied by photoluminescence (PL) spectroscopy at low and room temperatures and by surface photovoltage (SPV) spectroscopy at room temperature. The SPV and PL spectra reveal a red shift of the absorption edge and PL peak position as compared to GaAs, as well as localized states near the conduction band minimum. However, the optical band gap bowing of the samples appears smaller with respect to the random alloy, which is explained by the short-range ordering favored by LPE growth at near-equilibrium conditions. Variable angle ellipsometry is applied to determine the spectral behavior of the complex refractive index and estimate the band gap energy of the samples.
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