| 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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| 3. |
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| 4. |
- 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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| 5. |
- Eliasson, Bengt, et al.
(författare)
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Laser acceleration of monoenergetic protons via a double layer emerging from an ultra-thin foil
- 2009
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Ingår i: New Journal of Physics. - : IOP Publishing Ltd and Deutsche Physikalische Gesellschaft. - 1367-2630. ; 11, s. 073006-073025
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Tidskriftsartikel (refereegranskat)abstract
- We present theoretical and numerical studies of the acceleration of monoenergetic protons in a double layer formed by the laser irradiation of an ultra-thin film. The ponderomotive force of the laser light pushes the electrons forward, and the induced space charge electric field pulls the ions and makes the thin foil accelerate as a whole. The ions trapped by the combined electric field and inertial force in the accelerated frame, together with the electrons trapped in the well of the ponderomotive and ion electric field, form a stable double layer. The trapped ions are accelerated to monoenergetic energies up to 100 MeV and beyond, making them suitable for cancer treatment. We present an analytic theory for the laser-accelerated ion energy and for the amount of trapped ions as functions of the laser intensity, foil thickness and the plasma number density. We also discuss the underlying physics of the trapped and untrapped ions in a double layer. The analytical results are compared with those obtained from direct Vlasov simulations of the fully nonlinear electron and ion dynamics that is controlled by the laser light.
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| 6. |
- Eliasson, Bengt, et al.
(författare)
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Laser radiation pressure acceleration of monoenergetic protons in an ultra-thin foil
- 2009
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Ingår i: New Developments in Nonlinear Plasma Physics. - : American Institute of Physics. - 9780735407541 ; , s. 35-49
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Konferensbidrag (refereegranskat)abstract
- Wepresent theoretical and numerical studies of the acceleration of monoenergeticprotons in a double layer formed by the laser irradiationof an ultra-thin film. The stability of the foil isinvestigated by direct Vlasov-Maxwell simulations for different sets of laser-plasmaparameters. It is found that the foil is stable, dueto the trapping of both electrons and ions in thethin laser-plasma interaction region, where the electrons are trapped ina potential well composed of the ponderomo-tive potential of thelaser light and the electrostatic potential due to the ions,and the ions are trapped in a potential well composedof the inertial potential in an accelerated frame and theelectrostatic potential due to the electrons. The result is astable double layer, where the trapped ions are accelerated tomonoenergetic energies up to 100 MeV and beyond, which makesthem suitable for medical applications cancer treatment. The underlying physicsof trapped and untapped ions in a double layer isalso investigated theoretically and numerically.
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| 7. |
- Liu, Chuan S., et al.
(författare)
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Laser acceleration of quasi-monoenergetic protons via radiation pressure driven thin foil
- 2010
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Ingår i: Modern challenges in nonlinear plasma physics. - : AIP. - 9780735408753 ; , s. 104-110
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Konferensbidrag (refereegranskat)abstract
- We present a theoretical and simulation study of laser acceleration of quasi-monoenergetic protons in a thin foil irradiated by high intensity laser light. The underlying physics of radiation pressure acceleration (RPA) is discussed, including the importance of optimal thickness and circularly polarized light for efficient acceleration of ions to quasimonoenergetic beams. Preliminary two-dimensional simulation studies show that certain parameter regimes allow for stabilization of the Rayleigh-Taylor instability and possibility of acceleration of monoenergetic ions to an excess of 200MeV, making them suitable for important applications such as medical cancer therapy and fast ignition. © 2010 American Institute of Physics.
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| 8. |
- Tripathi, V. K., et al.
(författare)
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Laser acceleration of monoenergetic protons in a self-organized double layer from thin foil
- 2009
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Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 0741-3335 .- 1361-6587. ; 51, s. 024014-024022
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Tidskriftsartikel (refereegranskat)abstract
- We present a theory for the acceleration of monoenergetic protons, trapped in a self-organized double layer, by short pulse laser irradiation on a thin foil with the specific thickness suggested by the simulation study of Yan et al (2008 Phys. Rev. Lett. 100 135003). The laser ponderomotive force pushes the electrons forward, leaving the ions behind until the space charge electric field balances the ponderomotive force at a distance Δ. For the optimal target thickness D = Δ > c/ωp, the electron sheath is piled up at the rear surface and the sheath electric field accelerates the protons until they are reflected by the inertial force in the accelerated frame. These protons are therefore trapped by the combined forces of the electrostatic field of the electron sheath and the inertial force of the accelerating target. Together with the electron layer, they form a double layer and are collectively accelerated by the laser ponderomotive force, leading to monoenergetic ion production.
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| 9. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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