| 1. |
- Jonsson, Lina, 1982, et al.
(författare)
-
Characterisation of age and polarity at onset in bipolar disorder
- 2021
-
Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 2. |
- Soda, T., et al.
(författare)
-
International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic)
- 2020
-
Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 270:7, s. 921-932
-
Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.
|
|
| 3. |
- Brunes, M., et al.
(författare)
-
Impact of hysterectomy on analgesic, psychoactive and neuroactive drug use in women with endometriosis : nationwide cohort study
- 2021
-
Ingår i: British Journal of Obstetrics and Gynecology. - : John Wiley & Sons. - 1470-0328 .- 1471-0528. ; 128:5, s. 846-855
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate how hysterectomy affects the prescription of analgesic, psychotropic and neuroactive drugs in women with endometriosis using population-based nationwide registers.Design: Nationwide cohort study.Setting: Swedish national registers, from 1 January 2009 to 31 December 2018.Population: Women with benign disease undergoing a total hysterectomy during the 4-year period of 2012-2015. Women with endometriosis (n = 1074) were identified and compared with women who did not have endometriosis (n = 10 890).Methods: Prospectively collected data from two population-based registers were linked: the Swedish National Quality Register of Gynaecological Surgery and the Swedish National Drug Register. Multivariate logistic regression was used as the main statistical method.Main outcome measures: Changes in drug prescription over time for 3 years prior to and 3 years after hysterectomy.Results: The frequency of prescription of analgesics was higher in women with endometriosis compared with women without endometriosis (OR 2.2, 95% CI 1.7-2.9). Among women with endometriosis, the prescription of analgesics (OR 1.0, 95% CI 0.8-1.2) did not decrease 3 years after hysterectomy compared with the 3 years prior to surgery. There was also a significantly higher rate of prescription of psychoactive (OR 1.6, 95% CI 1.4-2.0) and neuroactive drugs (OR 1.9, 95% CI 1.3-2.7) in the long term postoperatively.Conclusions: In women undergoing hysterectomy, endometriosis was associated with a higher prescription rate of analgesics. In the endometriosis group the prescription of analgesic, psychoactive and neuroactive drugs did not decrease when comparing prescription rates for the 3 years prior to and the 3 years after surgery. Tweetable abstract In women with endometriosis, the long-term prescription of analgesics did not decrease after hysterectomy.
|
|
| 4. |
- Salehi, Alireza M., et al.
(författare)
-
Serum profiling of anorexia nervosa : A 1H NMR-based metabolomics study
- 2021
-
Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 49, s. 1-10
-
Tidskriftsartikel (refereegranskat)abstract
- Our understanding of pathophysiological mechanisms underlying anorexia nervosa (AN) is incomplete. The aim was to conduct a metabolomics profiling of serum samples from women with AN (n = 65), women who have recovered from AN (AN-REC, n = 65), and age-matched healthy female controls (HC, n = 65). Serum concentrations of 21 metabolites were measured using proton nuclear magnetic resonance (1H NMR). We used orthogonal partial least-squares discriminant analysis (OPLS-DA) modeling to assign group classification based on the metabolites. Analysis of variance (ANOVA) was used to test for metabolite concentration differences across groups. The OPLS-DA model could distinguish between the AN and HC groups (p = 9.05 × 10–11 R2Y = 0.36, Q2 = 0.37) and between the AN-REC and HC groups (p = 8.47 × 10–6, R2Y = 0.36, Q2 = 0.24,), but not between the AN and AN-REC groups (p = 0.63). Lower methanol concentration in the AN and AN-REC group explained most of the variance. Likewise, the strongest finding in the univariate analyses was lower serum methanol concentration in both AN and AN-REC compared with HC, which withstood adjustment for body mass index (BMI). We report for the first time lower serum concentrations of methanol in AN. The fact that low methanol was also found in recovered AN suggests that low serum concentration of methanol could either be trait marker or a scar effect of AN.
|
|
| 5. |
- Folkersen, Lasse, et al.
(författare)
-
Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
-
Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
-
Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
|
|
| 6. |
- Bezin, Y., et al.
(författare)
-
Multibody simulation benchmark for dynamic vehicle-track interaction in switches and crossings: results and method statements
- 2023
-
Ingår i: Vehicle System Dynamics. - : Informa UK Limited. - 1744-5159 .- 0042-3114. ; 61:3, s. 660-697
-
Tidskriftsartikel (refereegranskat)abstract
- A Benchmark of railway multibody dynamics software application to switches and crossings (S&C) is presented, comparing all major commercially available software and a few independent codes. Two different representative S&C have been implemented, using the Manchester Benchmark passenger vehicle. The final results show that all software offer a reliable and efficient way to understand the kinematic and dynamics forces between the wheels and the track elements. The highest challenges are found when modelling a combination of multiple rails in simultaneous contact with a wheel (check-stock or switch-stock), large longitudinal variations in rail shape (crossings) and high lateral steering forces (diverging cases in tight radius). In those cases, the codes able to account for the exact relative motion of each wheels with respect to each rails independently are the most apt. The most significant variations between software are found in the contact prediction with an influence on the detailed contact tangential and normal forces. The user variability is found to be very small, with the most time-consuming and error prone being the task of handling the input data for the variable rails definition. All software could benefit from improvements to assist the user and ensure higher reliability and efficiency generally.
|
|
| 7. |
- Clements, C. C., et al.
(författare)
-
Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy
- 2021
-
Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:10
-
Tidskriftsartikel (refereegranskat)abstract
- Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.
|
|
| 8. |
- Groß, Rüdiger, et al.
(författare)
-
Macromolecular Viral Entry Inhibitors as Broad-Spectrum First-Line Antivirals with Activity against SARS-CoV-2
- 2022
-
Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 9:20
-
Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of viral cell entry based on poly(styrene sulfonate) and its core–shell nanoformulations based on gold nanoparticles are investigated against a panel of viruses, including clinical isolates of SARS-CoV-2. Macromolecular inhibitors are shown to exhibit the highly sought-after broad-spectrum antiviral activity, which covers most analyzed enveloped viruses and all of the variants of concern for SARS-CoV-2 tested. The inhibitory activity is quantified in vitro in appropriate cell culture models and for respiratory viral pathogens (respiratory syncytial virus and SARS-CoV-2) in mice. Results of this study comprise a significant step along the translational path of macromolecular inhibitors of virus cell entry, specifically against enveloped respiratory viruses.
|
|
| 9. |
- Hörbeck, Elin, 1984, et al.
(författare)
-
Dissecting the impact of complement component 4A in bipolar disorder.
- 2023
-
Ingår i: Brain, behavior, and immunity. - 1090-2139. ; 116, s. 150-159
-
Tidskriftsartikel (refereegranskat)abstract
- The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N=1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI.
|
|
| 10. |
- Joas, Erik, et al.
(författare)
-
Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder.
- 2023
-
Ingår i: The pharmacogenomics journal. - : Springer Science and Business Media LLC. - 1473-1150 .- 1470-269X. ; 23:1, s. 28-35
-
Tidskriftsartikel (refereegranskat)abstract
- Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005-2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR]=1.3, 95% CI=1.04-1.62, p=0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR=1.46, 95% CI=1.05-2.02, p=0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.
|
|
