| 11. |
- Ferreira, Manuel A R, et al.
(författare)
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Eleven loci with new reproducible genetic associations with allergic disease risk.
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 143:2, s. 691-699
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.OBJECTIVE: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects.METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study.RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses.CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.
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| 12. |
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| 13. |
- Huusko, Johanna M, et al.
(författare)
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Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.
- 2018
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2-4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB.
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| 14. |
- Lo, Min-Tzu, et al.
(författare)
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Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 152-156
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Tidskriftsartikel (refereegranskat)abstract
- Personality is influenced by genetic and environmental factors(1) and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci(2,3), significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132-260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422-18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit- hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).
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| 15. |
- Lo, Min-Tzu, et al.
(författare)
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Modeling prior information of common genetic variants improves gene discovery for neuroticism
- 2017
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:22, s. 4530-4539
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Tidskriftsartikel (refereegranskat)abstract
- Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remain unclear. Inconsistent genetic variants identified by different genome-wide association studies (GWAS) may be attributable to low statistical power. We proposed a novel framework to improve the power for gene discovery by incorporating prior information of single nucleotide polymorphisms (SNPs) and combining two relevant existing tools, relative enrichment score (RES) and conditional false discovery rate (FDR). Here, SNP's conditional FDR was estimated given its RES based on SNP prior information including linkage disequilibrium (LD)-weighted genic annotation scores, total LD scores and heterozygosity. A known significant locus in chromosome 8p was excluded before estimating FDR due to long-range LD structure. Only one significant LD-independent SNP was detected by analyses of unconditional FDR and traditional GWAS in the discovery sample (N = 59 225), and notably four additional SNPs by conditional FDR. Three of the five SNPs, all identified by conditional FDR, were replicated (P < 0.05) in an independent sample (N = 170 911). These three SNPs are located in intronic regions of CADM2, LINGO2 and EP300 which have been reported to be associated with autism, Parkinson's disease and schizophrenia, respectively. Our approach using a combination of RES and conditional FDR improved power of traditional GWAS for gene discovery providing a useful framework for the analysis of GWAS summary statistics by utilizing SNP prior information, and helping to elucidate the links between neuroticism and complex diseases from a genetic perspective.
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| 16. |
- Sharma, Yashvi, et al.
(författare)
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Dramatic Rebrightening of the Type-changing Stripped-envelope Supernova SN 2023aew
- 2024
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 966:2
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Tidskriftsartikel (refereegranskat)abstract
- Multipeaked supernovae with precursors, dramatic light-curve rebrightenings, and spectral transformation are rare, but are being discovered in increasing numbers by modern night-sky transient surveys like the Zwicky Transient Facility. Here, we present the observations and analysis of SN 2023aew, which showed a dramatic increase in brightness following an initial luminous (−17.4 mag) and long (∼100 days) unusual first peak (possibly precursor). SN 2023aew was classified as a Type IIb supernova during the first peak but changed its type to resemble a stripped-envelope supernova (SESN) after the marked rebrightening. We present comparisons of SN 2023aew's spectral evolution with SESN subtypes and argue that it is similar to SNe Ibc during its main peak. P-Cygni Balmer lines are present during the first peak, but vanish during the second peak's photospheric phase, before Hα resurfaces again during the nebular phase. The nebular lines ([O i], [Ca ii], Mg i], Hα) exhibit a double-peaked structure that hints toward a clumpy or nonspherical ejecta. We analyze the second peak in the light curve of SN 2023aew and find it to be broader than that of normal SESNe as well as requiring a very high 56Ni mass to power the peak luminosity. We discuss the possible origins of SN 2023aew including an eruption scenario where a part of the envelope is ejected during the first peak and also powers the second peak of the light curve through interaction of the SN with the circumstellar medium.
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| 17. |
- Bilderbeck, Amy C., et al.
(författare)
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Psychoeducation and online mood tracking for patients with bipolar disorder : A randomised controlled trial
- 2016
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Ingår i: Journal of Affective Disorders. - : ELSEVIER SCIENCE BV. - 0165-0327 .- 1573-2517. ; 205, s. 245-251
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Tidskriftsartikel (refereegranskat)abstract
- Background: Psychoeducation is an effective adjunct to medications in bipolar disorder (BD). Brief psychoeducational approaches have been shown to improve early identification of relapse. However, the optimal method of delivery of psychoeducation remains uncertain. Here, our objective was to compare a short therapist-facilitated vs. self-directed psychoeducational intervention for BD. Methods: BD outpatients who were receiving medication-based treatment were randomly assigned to 5 psychoeducation sessions administered by a therapist (Facilitated Integrated Mood Management; FIMM; n=60), or self-administered psychoeducation (Manualized Integrated Mood Management; MIMM; n=61). Follow-up was based on patients' weekly responses to an electronic mood monitoring programme over 12 months. Results: Over follow-up, there were no group differences in weekly self-rated depression symptoms or relapse/readmission rates. However, knowledge of BD (assessed with the Oxford Bipolar Knowledge questionnaire (OBQ)) was greater in the FIMM than the MIMM group at 3 months. Greater illness knowledge at 3 months was related to a higher proportion of weeks well over 12 months. Limitations: Features of the trial may have reduced the sensitivity to our psychoeducation approach, including that BD participants had been previously engaged in self-monitoring. Conclusions: Improved OBQ score, while accelerated by a short course of therapist-administered psychoeducation (FIMM), was seen after both treatments. It was associated with better outcome assessed as weeks well. When developing and testing a new psychosocial intervention, studies should consider proximal outcomes (e.g., acquired knowledge) and their short-term impact on illness course in bipolar disorder. (C) 2016 Elsevier B.V. All rights reserved.
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| 18. |
- DeWitt, Douglas S., et al.
(författare)
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Pre-clinical testing of therapies for traumatic brain injury
- 2018
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 35:23, s. 2737-2754
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Tidskriftsartikel (refereegranskat)abstract
- Despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials. To develop recommendations and guidelines for pre-clinical testing of pharmacological or biological therapies for TBI, the Moody Project for Translational Traumatic Brain Injury Research hosted a symposium attended by investigators with extensive experience in pre-clinical TBI testing. The symposium participants discussed issues related to pre-clinical TBI testing including experimental models, therapy and outcome selection, study design, data analysis, and dissemination. Consensus recommendations included the creation of a manual of standard operating procedures with sufficiently detailed descriptions of modeling and outcome measurement procedures to permit replication. The importance of the selection of clinically relevant outcome variables, especially related to behavior testing, was noted. Considering the heterogeneous nature of human TBI, evidence of therapeutic efficacy in multiple, diverse (e.g., diffuse vs. focused) rodent models and a species with a gyrencephalic brain prior to clinical testing was encouraged. Basing drug doses, times, and routes of administration on pharmacokinetic and pharmacodynamic data in the test species was recommended. Symposium participants agreed that the publication of negative results would reduce costly and unnecessary duplication of unsuccessful experiments. Although some of the recommendations are more relevant to multi-center, multi-investigator collaborations, most are applicable to pre-clinical therapy testing in general. The goal of these consensus guidelines is to increase the likelihood that therapies that improve outcomes in pre-clinical studies will also improve outcomes in TBI patients.
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| 19. |
- Tsoi, Lam C., et al.
(författare)
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Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.
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