| 11. |
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| 12. |
- Mullins, Niamh, et al.
(författare)
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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
- 2019
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
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Tidskriftsartikel (refereegranskat)abstract
- Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
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| 13. |
- Chang, Hong, et al.
(författare)
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Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1.
- 2017
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Ingår i: Molecular neurobiology. - : Springer Science and Business Media LLC. - 1559-1182 .- 0893-7648. ; 54:7
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P meta = 5.72 × 10(-4)), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10(-16)). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a "proxy phenotype" of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is ∼1.2 Mb 3' downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis.
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| 14. |
- Chien, Yin-Hsiu, et al.
(författare)
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Mudd's disease (MAT I/III deficiency) : a survey of data for MAT1A homozygotes and compound heterozygotes
- 2015
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine beta-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. Purpose of the study: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. Results and Discussion: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 mu M or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.
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| 15. |
- Irani, Ido, et al.
(författare)
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On the Origin of SN 2016hil-A Type II Supernova in the Remote Outskirts of an Elliptical Host
- 2019
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 887:2
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Tidskriftsartikel (refereegranskat)abstract
- Type II supernovae (SNe) stem from the core collapse of massive (>8 M-circle dot) stars. Due to their short lifespan, we expect a very low rate of such events in elliptical hosts, where the star formation rate is low, and which are mostly comprised of an old stellar population. SN 2016hil (iPTF16hil) is an SN II located in the extreme outskirts of an elliptical galaxy at z.=.0.0608 (projected distance 27.2 kpc). It was detected near peak (M-r similar to -17 mag) 9 days after the last non-detection. The event has some potentially peculiar properties: it presented an apparently double-peaked light curve, and its spectra suggest low metallicity content (Z < 0.4 Z(circle dot)). We place a tentative upper limit on the mass of a potential faint host at log M/M-circle dot = 7.27(-0.24)(+0.43) using deep optical imaging from Keck/LRIS. In light of this, we discuss the possibility of the progenitor forming locally and other more exotic formation scenarios such as a merger or common-envelope evolution causing a time-delayed explosion. Further observations of the explosion site in the UV are needed in order to distinguish between the cases. Regardless of the origin of the transient, observing a population of such seemingly hostless SNe II could have many uses, including an estimate the amount of faint galaxies in a given volume, and tests of the prediction of a time-delayed population of core-collapse SNe in locations otherwise unfavorable for the detection of such events.
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| 16. |
- Rietschel, Liz, et al.
(författare)
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Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes.
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
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| 17. |
- Altenburger, R., et al.
(författare)
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Future water quality monitoring: improving the balance between exposure and toxicity assessments of real-world pollutant mixtures
- 2019
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Ingår i: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4715 .- 2190-4707. ; 31
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Tidskriftsartikel (refereegranskat)abstract
- Environmental water quality monitoring aims to provide the data required for safeguarding the environment against adverse biological effects from multiple chemical contamination arising from anthropogenic diffuse emissions and point sources. Here, we integrate the experience of the international EU-funded project SOLUTIONS to shift the focus of water monitoring from a few legacy chemicals to complex chemical mixtures, and to identify relevant drivers of toxic effects. Monitoring serves a range of purposes, from control of chemical and ecological status compliance to safeguarding specific water uses, such as drinking water abstraction. Various water sampling techniques, chemical target, suspect and non-target analyses as well as an array of in vitro, in vivo and in situ bioanalytical methods were advanced to improve monitoring of water contamination. Major improvements for broader applicability include tailored sampling techniques, screening and identification techniques for a broader and more diverse set of chemicals, higher detection sensitivity, standardized protocols for chemical, toxicological, and ecological assessments combined with systematic evidence evaluation techniques. No single method or combination of methods is able to meet all divergent monitoring purposes. Current monitoring approaches tend to emphasize either targeted exposure or effect detection. Here, we argue that, irrespective of the specific purpose, assessment of monitoring results would benefit substantially from obtaining and linking information on the occurrence of both chemicals and potentially adverse biological effects. In this paper, we specify the information required to: (1) identify relevant contaminants, (2) assess the impact of contamination in aquatic ecosystems, or (3) quantify cause-effect relationships between contaminants and adverse effects. Specific strategies to link chemical and bioanalytical information are outlined for each of these distinct goals. These strategies have been developed and explored using case studies in the Danube and Rhine river basins as well as for rivers of the Iberian Peninsula. Current water quality assessment suffers from biases resulting from differences in approaches and associated uncertainty analyses. While exposure approaches tend to ignore data gaps (i.e., missing contaminants), effect-based approaches penalize data gaps with increased uncertainty factors. This integrated work suggests systematic ways to deal with mixture exposures and combined effects in a more balanced way, and thus provides guidance for future tailored environmental monitoring.
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