| 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. |
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| 3. |
- de Jong, S, et al.
(författare)
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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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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Tidskriftsartikel (refereegranskat)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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| 4. |
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| 5. |
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| 6. |
- Czamara, D, et al.
(författare)
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Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2548-
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Arnau-Soler, A, et al.
(författare)
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Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland
- 2019
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 14-
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Tidskriftsartikel (refereegranskat)abstract
- Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10−6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10−9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10−8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10−8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10−6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10−3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Benkert, P., et al.
(författare)
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Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study
- 2022
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Ingår i: The Lancet Neurology. - 1474-4422 .- 1474-4465. ; 21:3, s. 246-257
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Tidskriftsartikel (refereegranskat)abstract
- Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1–2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0–8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08–6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry. Interpretation: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials. Funding: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche. © 2022 Elsevier Ltd
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| 17. |
- Bigdeli, TB, et al.
(författare)
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Genetic effects influencing risk for major depressive disorder in China and Europe
- 2017
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:3, s. e1074-
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Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30–40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
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| 18. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Jokubavicius, Valdas, et al.
(författare)
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Effects of source material on epitaxial growth of fluorescent SiC
- 2012
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Ingår i: Thin Solid Films. - : Elsevier. - 0040-6090 .- 1879-2731. ; 522, s. 7-10
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Tidskriftsartikel (refereegranskat)abstract
- The growth of fluorescent SiC using Fast Sublimation Growth Process was demonstrated using different types of SiC source materials. These were prepared by (i) high-temperature hot pressing, (ii) chemical vapor deposition and (iii) physical vapor transport. The optimized growth rates of 50 μm/h, 170 μm/h and 200 μm/h were achieved using the three types of sources, respectively. The best results in respect to growth rates are obtained using higher density sources. Fluorescent SiC layers with mirror-like morphology, very good crystal quality and yellowish or warm white light photoluminescence at room temperature were grown using all three types of the source materials.
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| 23. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 24. |
- Grivickas, V., et al.
(författare)
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Carrier lifetimes and influence of in-grown defects in N-B Co-doped 6H-SiC
- 2014
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Ingår i: IOP Conference Series. - : Institute of Physics Publishing (IOPP). ; 56:1, s. 012004-
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Konferensbidrag (refereegranskat)abstract
- The thick N-B co-doped epilayers were grown by the fast sublimation growth method and the depth-resolved carrier lifetimes have been investigated by means of the free-carrier absorption (FCA) decay under perpendicular probe-pump measurement geometry. In some samples, we optically reveal in-grown carbon inclusions and polycrystalline defects of substantial concentration and show that these defects slow down excess carrier lifetime and prevent donor-acceptor pair photo luminescence (DAP PL). A pronounced electron lifetime reduction when injection level approaches the doping level was observed. It is caused by diffusion driven non-radiative recombination. However, the influence of surface recombination is small and insignificant at 300 K.
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| 25. |
- Kaiser, M., et al.
(författare)
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Nucleation and growth of polycrystalline SiC
- 2014
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Ingår i: IOP Conference Series. - : Institute of Physics Publishing (IOPP). ; 56:1, s. 012001-
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Konferensbidrag (refereegranskat)abstract
- The nucleation and bulk growth of polycrystalline SiC in a 2 inch PVT setup using isostatic and pyrolytic graphite as substrates was studied. Textured nucleation occurs under near-thermal equilibrium conditions at the initial growth stage with hexagonal platelet shaped crystallites of 4H, 6H and 15R polytypes. It is found that pyrolytic graphite results in enhanced texturing of the nucleating gas species. Reducing the pressure leads to growth of the crystallites until a closed polycrystalline SiC layer containing voids with a rough surface is developed. Bulk growth was conducted at 35 mbar Ar pressure at 2250°C in diffusion limited mass transport regime generating a convex shaped growth form of the solid-gas interface leading to lateral expansion of virtually [001] oriented crystallites. Growth at 2350°C led to the stabilization of 6H polytypic grains. The micropipe density in the bulk strongly depends on the substrate used.
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| 26. |
- Kaiser, M., et al.
(författare)
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Polycrystalline SiC as source material for the growth of fluorescent SiC layers
- 2013
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Ingår i: Silicon Carbide And Related Materials 2012. - : Trans Tech Publications Inc.. - 9783037856246 ; , s. 39-42
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Konferensbidrag (refereegranskat)abstract
- Polycrystalline doped SiC act as source for fluorescent SiC. We have studied the growth of individual grains with different polytypes in the source material. We show an evolution and orientation of grains of different polytypes in polycrystalline SiC ingots grown by the Physical Vapor Transport method. The grain influence on the growth rate of fluorescent SiC layers grown by a sublimation epitaxial process is discussed in respect of surface kinetics.
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| 27. |
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| 28. |
- Ou, H., et al.
(författare)
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Fluorescent SiC for white light-emitting diodes
- 2012
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Ingår i: Asia Commun. Photonics Conf.. - Washington, D.C. : OSA.
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Konferensbidrag (refereegranskat)abstract
- The strong photoluminescence from f-SiC was achieved after the optimization of the B and N concentrations. Surface nanostructures were successfully applied to enhance the extraction efficiency. f-SiC is a promising wavelength convertor for white LEDs.
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| 29. |
- Schimmel, S., et al.
(författare)
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Step-flow growth of fluorescent 4H-SiC layers on 4 degree off-axis substrates
- 2013
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Ingår i: Silicon Carbide and Related Materials 2012. - : Trans Tech Publications Inc.. - 9783037856246 ; , s. 185-188
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Konferensbidrag (refereegranskat)abstract
- Homoepitaxial layers of fluorescent 4H-SiC were grown on 4 degree off-axis substrates by sublimation epitaxy. Luminescence in the green spectral range was obtained by co-doping with nitrogen and boron utilizing donor-acceptor pair luminescence. This concept opens possibilities to explore green light emitting diodes using a new materials platform.
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| 30. |
- Schimmel, S., et al.
(författare)
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The role of defects in fluorescent silicon carbide layers grown by sublimation epitaxy
- 2014
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Ingår i: IOP Conference Series. - : Institute of Physics Publishing (IOPP). ; 56:1, s. 012002-
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Konferensbidrag (refereegranskat)abstract
- Donor-acceptor co-doped SiC is a promising light converter for novel monolithic all-semiconductor white LEDs due to its broad-band donor-acceptor pair luminescence and potentially high internal quantum efficiency. Besides sufficiently high doping concentrations in an appropriate ratio yielding short radiative lifetimes, long nonradiative lifetimes are crucial for efficient light conversion. The impact of different types of defects is studied by characterizing fluorescent silicon carbide layers with regard to photoluminescence intensity, homogeneity and efficiency taking into account dislocation density and distribution. Different doping concentrations and variations in gas phase composition and pressure are investigated.
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| 31. |
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| 32. |
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| 33. |
- Syväjärvi, Mikael, et al.
(författare)
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Cubic silicon carbide as a potential photovoltaic material
- 2016
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Ingår i: Solar Energy Materials and Solar Cells. - : Elsevier. - 0927-0248 .- 1879-3398. ; 145, s. 104-108
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Tidskriftsartikel (refereegranskat)abstract
- In this work we present a significant advancement in cubic silicon carbide (3C-SiC) growth in terms of crystal quality and domain size, and indicate its potential use in photovoltaics. To date, the use of 3C-SiC for photovoltaics has not been considered due to the band gap of 2.3 eV being too large for conventional solar cells. Doping of 3C-SiC with boron introduces an energy level of 0.7 eV above the valence band. Such energy level may form an intermediate band (IB) in the band gap. This IB concept has been presented in the literature to act as an energy ladder that allows absorption of sub-bandgap photons to generate extra electron-hole pairs and increase the efficiency of a solar cell. The main challenge with this concept is to find a materials system that could realize such efficient photovoltaic behavior. The 3C-SiC bandgap and boron energy level fits nicely into the concept, but has not been explored for an IB behavior. For a long time crystalline 3C-SiC has been challenging to grow due to its metastable nature. The material mainly consists of a large number of small domains if the 3C polytype is maintained. In our work a crystal growth process was realized by a new approach that is a combination of initial nucleation and step-flow growth. In the process, the domains that form initially extend laterally to make larger 3C-SiC domains, thus leading to a pronounced improvement in crystalline quality of 3C-SiC. In order to explore the feasibility of IB in 3C-SiC using boron, we have explored two routes of introducing boron impurities; ion implantation on un-doped samples and epitaxial growth on un-doped samples using pre-doped source material. The results show that 3C-SiC doped with boron is an optically active material, and thus is interesting to be further studied for IB behavior. For the ion implanted samples the crystal quality was maintained even after high implantation doses and subsequent annealing. The same was true for the samples grown with pre-doped source material, even with a high concentration of boron impurities. We present optical emission and absorption properties of as-grown and boron implanted 3C-SiC. The low-temperature photoluminescence spectra indicate the formation of optically active deep boron centers, which may be utilized for achieving an IB behavior at sufficiently high dopant concentrations. We also discuss the potential of boron doped 3C-SiC base material in a broader range of applications, such as in photovoltaics, biomarkers and hydrogen generation by splitting water.
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| 34. |
- Syväjärvi, Mikael, et al.
(författare)
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Fluorescent SiC as a new material for white LEDs
- 2012
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Ingår i: Physica scripta. T. - 0281-1847 .- 0031-8949 .- 1402-4896. ; T148, s. 014002-
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Tidskriftsartikel (refereegranskat)abstract
- Current III–V-based white light-emitting diodes (LEDs) are available. However, their yellow phosphor converter is not efficient at high currents and includes rare-earth metals, which are becoming scarce. In this paper, we present the growth of a fluorescent silicon carbide material that is obtained by nitrogen and boron doping and that acts as a converter using a semiconductor. The luminescence is obtained at room temperature, and shows a broad luminescence band characteristic of donor-to-acceptor pair recombination. Photoluminescence intensities and carrier lifetimes reflect a sensitivity to nitrogen and boron concentrations. For an LED device, the growth needs to apply low-off-axis substrates. We show by ultra-high-resolution analytical transmission electron microscopy using aberration-corrected electrons that the growth mechanism can be stable and that there is a perfect epitaxial relation from the low-off-axis substrate and the doped layer even when there is step-bunching.
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