| 11. |
- Lewis, Katie J S, et al.
(författare)
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Comparison of Genetic Liability for Sleep Traits Among Individuals With Bipolar Disorder I or II and Control Participants.
- 2020
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:3, s. 303-310
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Tidskriftsartikel (refereegranskat)abstract
- Insomnia, hypersomnia, and an evening chronotype are common in individuals with bipolar disorder (BD), but whether this reflects shared genetic liability is unclear. Stratifying by BD subtypes could elucidate this association and inform sleep and BD research.To assess whether polygenic risk scores (PRSs) for sleep traits are associated with BD subtypes I and II.This case-control study was conducted in the United Kingdom and Sweden with participants with BD and control participants. Multinomial regression was used to assess whether PRSs for insomnia, daytime sleepiness, sleep duration, and chronotype are associated with BD subtypes compared with control participants. Affected individuals were recruited from the Bipolar Disorder Research Network. Control participants were recruited from the 1958 British Birth Cohort and the UK Blood Service. Analyses were repeated in an independent Swedish sample from August 2018 to July 2019. All participants were of European ancestry.Standardized PRSs derived using alleles from genome-wide association studies of insomnia, sleep duration, daytime sleepiness, and chronotype. These were adjusted for the first 10 population principal components, genotyping platforms, and sex.Association of PRSs with BD subtypes, determined by semistructured psychiatric interview and case notes.The main analysis included 4672 participants with BD (3132 female participants [67.0%]; 3404 with BD-I [72.9%]) and 5714 control participants (2812 female participants [49.2%]). Insomnia PRS was associated with increased risk of BD-II (relative risk [RR], 1.14 [95% CI, 1.07-1.21]; P=8.26×10-5) but not BD-I (RR, 0.98 [95% CI, 0.94-1.03]; P=.409) relative to control participants. Sleep-duration PRS was associated with BD-I (RR, 1.10 [95% CI, 1.06-1.15]; P=1.13×10-5) but not BD-II (RR, 0.99 [95% CI, 0.93-1.06]; P=.818). Associations between (1) insomnia PRS and BD-II and (2) sleep-duration PRS and BD-I were replicated in the Swedish sample of 4366 individuals with BD (2697 female participants [61.8%]; 2627 with BD-I [60.2%]) and 6091 control participants (3767 female participants [61.8%]). Chronotype and daytime-sleepiness PRS were not associated with BD subtypes.Per this analysis, BD subtypes differ in genetic liability to insomnia and hypersomnia, providing further evidence that the distinction between BD-I and BD-II has genetic validity. This distinction will be crucial in selecting participants for future research on the role of sleep disturbance in BD.
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| 12. |
- Ruderfer, Douglas M., et al.
(författare)
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Mosaic copy number variation in schizophrenia
- 2013
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 21:9, s. 1007-1011
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Tidskriftsartikel (refereegranskat)abstract
- Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n = 3518; control, n = 4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.
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| 13. |
- Amare, Azmeraw, et al.
(författare)
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Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
- 2023
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Ingår i: Research square. - : Research Square Platform LLC.
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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| 14. |
- Bauer, Michael, et al.
(författare)
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Association between solar insolation and a history of suicide attempts in bipolar I disorder.
- 2019
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Ingår i: Journal of psychiatric research. - : Elsevier BV. - 1879-1379 .- 0022-3956. ; 113, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p<0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.
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| 15. |
- Herrera-Rivero, Marisol, et al.
(författare)
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Exploring the genetics of lithium response in bipolar disorders.
- 2023
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Ingår i: Research square.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
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| 16. |
- Palmer, Duncan S., et al.
(författare)
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Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia
- 2022
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 54:5, s. 541-547
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Tidskriftsartikel (refereegranskat)abstract
- We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10−9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.
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| 17. |
- Pardiñas, Antonio F., et al.
(författare)
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Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia
- 2022
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Ingår i: JAMA psychiatry. - Chicago, IL, United States : American Medical Association. - 2168-6238 .- 2168-622X. ; 79:3, s. 260-269
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Tidskriftsartikel (refereegranskat)abstract
- Importance About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts.Objective To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples.Design, Setting, and Participants Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]).Main Outcomes and Measures GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition.Results The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04).Conclusions and Relevance In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.
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| 18. |
- Babbitt, Patricia C., et al.
(författare)
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Creating a specialist protein resource network : a meeting report for the protein bioinformatics and community resources retreat
- 2015
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Ingår i: Database. - : Oxford University Press (OUP). - 1758-0463.
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Tidskriftsartikel (refereegranskat)abstract
- During 11-12 August 2014, a Protein Bioinformatics and Community Resources Retreat was held at the Wellcome Trust Genome Campus in Hinxton, UK. This meeting brought together the principal investigators of several specialized protein resources (such as CAZy, TCDB and MEROPS) as well as those from protein databases from the large Bioinformatics centres (including UniProt and RefSeq). The retreat was divided into five sessions: (1) key challenges, (2) the databases represented, (3) best practices for maintenance and curation, (4) information flow to and from large data centers and (5) communication and funding. An important outcome of this meeting was the creation of a Specialist Protein Resource Network that we believe will improve coordination of the activities of its member resources. We invite further protein database resources to join the network and continue the dialogue.
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| 19. |
- Fekadu, Abebaw, et al.
(författare)
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Validity of the concept of minor depression in a developing country setting
- 2008
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Ingår i: Journal of Nervous and Mental Disease. - 0022-3018 .- 1539-736X. ; 196:1, s. 22-28
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for validity of the diagnostic construct of minor depressive disorder comes primarily from reports on subthreshold depressive states rather than minor depressive disorder per se. We report on the prevalence, impact, and sociodemographic correlates of minor depressive disorder in a developing country setting as further validation of this diagnostic construct. Diagnostic assessment of 1714 adults of an island population in Ethiopia was carried out using the Composite International Diagnostic Interview. The lifetime prevalence of minor depressive disorder was 20.5% (95% confidence interval 18.6, 22.5%). One-third of cases had sought help and expressed suicidal ideation. Being divorced/widowed, middle-aged, and having somatic pain were independently associated with having minor depressive disorder. Only being divorced/widowed was a shared risk factor for both minor depressive disorder and bereavement. Minor depressive disorder seems to be a useful and valid diagnostic construct with particular clinical significance in this and, possibly, similar developing country settings.
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| 20. |
- Martin, Joanna, et al.
(författare)
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A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder
- 2018
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 83:12, s. 1044-1053
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases.METHODS: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls).RESULTS: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with r(g) estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15).CONCLUSIONS: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.
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