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1.
JMIR Form Res ; 5(4): e24180, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33872181

RESUMO

BACKGROUND: During the COVID-19 pandemic, people had to adapt their daily life routines to the currently implemented public health measures, which is likely to have resulted in a lack of in-person social interactions, physical activity, or sleep. Such changes can have a significant impact on mental health. Mobile sensing apps can passively record the daily life routines of people, thus making them aware of maladaptive behavioral adjustments to the pandemic. OBJECTIVE: This study aimed to explore the views of people on mobile sensing apps that passively record behaviors and their potential to increase awareness and helpfulness for self-managing mental health during the pandemic. METHODS: We conducted an anonymous web-based survey including people with and those without mental disorders, asking them to rate the helpfulness of mobile sensing apps for the self-management of mental health during the COVID-19 pandemic. The survey was conducted in May 2020. RESULTS: The majority of participants, particularly those with a mental disorder (n=106/148, 72%), perceived mobile sensing apps as very or extremely helpful for managing their mental health by becoming aware of maladaptive behaviors. The perceived helpfulness of mobile sensing apps was also higher among people who experienced a stronger health impact of the COVID-19 pandemic (ß=.24; 95% CI 0.16-0.33; P<.001), had a better understanding of technology (ß=.17; 95% CI 0.08-0.25; P<.001), and had a higher education (ß=.1; 95% CI 0.02-0.19; P=.02). CONCLUSIONS: Our findings highlight the potential of mobile sensing apps to assist in mental health care during the pandemic.

2.
Mol Psychiatry ; 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863996

RESUMO

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles  and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

3.
JMIR Med Inform ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33684052

RESUMO

BACKGROUND: The COVID-19 pandemic has caused a global health crisis that affects many aspects of human lives. In the absence of vaccines and antivirals, several behavioural change and policy initiatives, such as physical distancing, have been implemented to control the spread of the coronavirus. Social media data can reveal public perceptions toward how governments and health agencies across the globe are handling the pandemic, as well as the impact of the disease on people regardless of their geographic locations in line with various factors that hinder or facilitate the efforts to control the spread of the pandemic globally. OBJECTIVE: This paper aims to investigate the impact of the COVID-19 pandemic on people globally using social media data. METHODS: We apply natural language processing (NLP) and thematic analysis to understand public opinions, experiences, and issues with respect to the COVID-19 pandemic using social media data. First, we collect over 47 million COVID-19-related comments from Twitter, Facebook, YouTube, and three online discussion forums. Second, we perform data preprocessing which involves applying NLP techniques to clean and prepare the data for automated keyphrase extraction. Third, we apply NLP approach to extract meaningful keyphrases from over 1 million randomly-selected comments, as well as compute sentiment scores for each keyphrase and assign sentiment polarity (i.e., positive, negative, or neutral) based on the scores using lexicon-based technique. Fourth, we grouped related negative and positive keyphrases into categories or broad themes. RESULTS: A total of 34 negative themes emerged, out of which 15 are health-related issues, psychosocial issues, and social issues related to the COVID-19 pandemic from the public perspective. Some of the health-related issues are increased mortality, health concerns, struggling health systems, and fitness issues; while some of the psychosocial issues include frustrations due to life disruptions, panic shopping, and expression of fear. Social issues include harassment, domestic violence, and wrong societal attitude. In addition, 20 positive themes emerged from our results. Some of the positive themes include public awareness, encouragement, gratitude, cleaner environment, online learning, charity, spiritual support, and innovative research. CONCLUSIONS: We uncover various negative and positive themes representing public perceptions toward the COVID-19 pandemic and recommend interventions that can help address the health, psychosocial, and social issues based on the positive themes and other research evidence. These interventions will help governments, health professionals and agencies, institutions, and individuals in their efforts to curb the spread of COVID-19 and minimize its impact, as well as in reacting to any future pandemics.

4.
Front Psychiatry ; 11: 313, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581855

RESUMO

Schizophrenia (SCZ) is a severe mental disorder with immense personal and societal costs; identifying individuals at risk is therefore of utmost importance. Genomic risk profile scores (GRPS) have been shown to significantly predict cases-control status. Making use of a large-population based sample from Sweden, we replicate a previous finding demonstrating that the GRPS is strongly associated with admission frequency and chronicity of SCZ. Furthermore, we were able to show a substantial gap in prediction accuracy between males and females. In sum, our results indicate that prediction accuracy by GRPS depends on clinical and demographic characteristics.

6.
Mol Psychiatry ; 25(12): 3292-3303, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31748690

RESUMO

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

7.
Autism Res ; 13(1): 134-144, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31464107

RESUMO

Evidence supports no link between maternal smoking in pregnancy and autism spectrum disorder (autism) overall. To address remaining questions about the unexplained heterogeneity between study results and the possibility of risk for specific autism sub-phenotypes, we conducted a whole-population cohort study in Denmark. We followed births 1991-2011 (1,294,906 persons, including 993,301 siblings in 728,271 families), from 1 year of age until an autism diagnosis (13,547), death, emigration, or December 31, 2012. Autism, with and without attention deficit hyperactivity disorder (ADHD) and with and without intellectual disability (ID) were based on ICD-8 and ICD-10 codes from Danish national health registers, including 3,319 autism + ADHD, 10,228 autism - no ADHD, 2,205 autism + ID, and 11,342 autism - no ID. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) between any maternal smoking (from birth records) and autism (or sub-phenotypes) using survival models with robust standard errors, stratifying by birth year and adjusting for child sex, parity, and parental age, education, income, and psychiatric history. To additionally address confounding using family designs, we constructed a maternal cluster model (adjusting for the smoking proportion within the family), and a stratified sibling model. Associations with maternal smoking and autism were elevated in conventional adjusted analyses (HR of 1.17 [1.13-1.22]) but attenuated in the maternal cluster (0.98 [0.88-1.09]) and sibling (0.86 [0.64-1.15]) models. Similarly, risks of autism sub-phenotypes with maternal smoking were attenuated in the family-based models. Together these results support that smoking in pregnancy is not linked with autism or select autism comorbid sub-phenotypes after accounting for familial confounding. Autism Res 2020, 13: 134-144. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Smoking during pregnancy has many harmful impacts, which may include harming the baby's developing brain. However, in a study of thousands of families in Denmark, it does not appear that smoking in pregnancy leads to autism or autism in combination with intellectual problems or attention deficits, once you account for the way smoking patterns and developmental disabilities run in families.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Família , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar/epidemiologia , Adulto , Criança , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Mães/estatística & dados numéricos , Pais , Gravidez , Modelos de Riscos Proporcionais , Fatores de Risco , Irmãos , Adulto Jovem
8.
Mol Psychiatry ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712720

RESUMO

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

9.
JAMA Psychiatry ; 76(9): 924-932, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31116379

RESUMO

Importance: Anxiety and stress-related disorders are among the most common mental disorders. Although family and twin studies indicate that both genetic and environmental factors play an important role underlying their etiology, the genetic underpinnings of anxiety and stress-related disorders are poorly understood. Objectives: To estimate the single-nucleotide polymorphism-based heritability of anxiety and stress-related disorders; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to evaluate the association of psychiatric comorbidities with genetic findings. Design, Setting, Participants: This genome-wide association study included individuals with various anxiety and stress-related diagnoses and controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers. Genes of interest were further evaluated in mice exposed to chronic social defeat. The study was conducted between June 2016 and November 2018. Main Outcomes and Measures: Diagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders. Results: The study sample included 12 655 individuals with various anxiety and stress-related diagnoses and 19 225 controls. Overall, 17 740 study participants (55.6%) were women. A total of 7308 participants (22.9%) were born between 1981-1985, 8840 (27.7%) between 1986-1990, 8157 (25.6%) between 1991-1995, 5918 (18.6%) between 1996-2000, and 1657 (5.2%) between 2001-2005. Standard association analysis revealed variants in PDE4B to be associated with anxiety and stress-related disorder (rs7528604; P = 5.39 × 10-11; odds ratio = 0.89; 95% CI, 0.86-0.92). A framework of sensitivity analyses adjusting for mental comorbidity supported this result showing consistent association of PDE4B variants with anxiety and stress-related disorder across analytical scenarios. In mouse models, alterations in Pde4b expression were observed in those mice displaying anxiety-like behavior after exposure to chronic stress in the prefrontal cortex (P = .002; t = -3.33) and the hippocampus (P = .001; t = -3.72). We also found a single-nucleotide polymorphism heritability of 28% (standard error = 0.027) and that the genetic signature of anxiety and stress-related overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success. Conclusions and Relevance: This study highlights anxiety and stress-related disorders as complex heritable phenotypes with intriguing genetic correlations not only with psychiatric traits, but also with educational outcomes and multiple obesity-related phenotypes. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to the potential of PDE4B inhibitors in treatment of these disorders.

10.
Curr Psychiatry Rep ; 21(3): 16, 2019 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-30826936

RESUMO

PURPOSE OF REVIEW: Anxiety disorders are among the most common mental disorders with a lifetime prevalence of over 20%. Clinically, anxiety is not thought of as a homogenous disorder, but is subclassified in generalized, panic, and phobic anxiety disorder. Anxiety disorders are moderately heritable. This review will explore recent genetic and epigenetic approaches to anxiety disorders explaining differential susceptibility risk. RECENT FINDINGS: A substantial portion of the variance in susceptibility risk can be explained by differential inherited and acquired genetic and epigenetic risk. Available data suggest that anxiety disorders are highly complex and polygenic. Despite the substantial progress in genetic research over the last decade, only few risk loci for anxiety disorders have been identified so far. This review will cover recent findings from large-scale genome-wide association studies as well as newer epigenome-wide studies. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. We discuss prospects for clinical translation of genetic findings and future directions for research.


Assuntos
Transtornos de Ansiedade/genética , Predisposição Genética para Doença , Epigenômica , Estudo de Associação Genômica Ampla , Humanos , Transtornos Fóbicos/genética
11.
Eur Neuropsychopharmacol ; 29(1): 156-170, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503783

RESUMO

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Adolescente , Adulto , Idoso , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Escalas de Graduação Psiquiátrica , Adulto Jovem
12.
Sci Rep ; 8(1): 17692, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30523285

RESUMO

Clues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12-1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia.


Assuntos
Esquizofrenia/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/sangue , Adolescente , Adulto , Calcifediol/sangue , Estudos de Casos e Controles , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Fatores de Risco , Esquizofrenia/sangue , Estações do Ano , Vitamina D/análogos & derivados , Deficiência de Vitamina D/sangue , Adulto Jovem
13.
Br J Psychiatry ; 213(3): 555-560, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29925436

RESUMO

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) and anxiety disorders have been proposed as precursors of bipolar disorder, but their joint and relative roles in the development of bipolar disorder are unknown.AimsTo test the prospective relationship of ADHD and anxiety with onset of bipolar disorder. METHOD: We examined the relationship between ADHD, anxiety disorders and bipolar disorder in a birth cohort of 2 409 236 individuals born in Denmark between 1955 and 1991. Individuals were followed from their sixteenth birthday or from January 1995 to their first clinical contact for bipolar disorder or until December 2012. We calculated incidence rates per 10 000 person-years and tested the effects of prior diagnoses on the risk of bipolar disorder in survival models. RESULTS: Over 37 394 865 person-years follow-up, 9250 onsets of bipolar disorder occurred. The incidence rate of bipolar disorder was 2.17 (95% CI 2.12-2.19) in individuals with no prior diagnosis of ADHD or anxiety, 23.86 (95% CI 19.98-27.75) in individuals with a prior diagnosis of ADHD only, 26.05 (95% CI 24.47-27.62) in individuals with a prior diagnosis of anxiety only and 66.16 (95% CI 44.83-87.47) in those with prior diagnoses of both ADHD and anxiety. The combination of ADHD and anxiety increased the risk of bipolar disorder 30-fold (95% CI 21.66-41.40) compared with those with no prior ADHD or anxiety. CONCLUSIONS: Early manifestations of both internalising and externalising psychopathology indicate liability to bipolar disorder. The combination of ADHD and anxiety is associated with a very high risk of bipolar disorder.Declaration of interestNone.


Assuntos
Transtornos de Ansiedade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/etiologia , Adolescente , Adulto , Transtornos de Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Dinamarca/epidemiologia , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
14.
Schizophr Res Cogn ; 9: 18-22, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28868239

RESUMO

Results from twin, family, and adoption studies all suggest that general intelligence is highly heritable. Several studies have shown lower premorbid intelligence in individuals before the onset of both mood disorders and psychosis, as well as in children and adolescents at genetic high risk for developing schizophrenia. Based on these findings, we aim to investigate if the association between educational achievement in parents and intelligence in their offspring is influenced by schizophrenia or mood disorder in parents. In a large population-based sample of young adult male conscripts (n = 156,531) the presence of a mental disorder in the parents were associated with significantly lower offspring scores on a test of general intelligence, the Børge Priens Prøve (BPP), and higher educational attainment in parents was significantly associated with higher BPP test scores in offspring. A significant interaction suggested that the positive association between maternal education and offspring intelligence was stronger in offspring of mothers with schizophrenia compared to the control group (p = 0.03). The associations between parental education and offspring intelligence are also observed when restricting the sample to conscripts whose parents are diagnosed after 30 years of age. In conclusion, findings from this study show a more positive effect of education on offspring intelligence in mothers with schizophrenia compared to mothers from the control group. This effect could have both environmental and genetic explanations.

15.
Mov Disord ; 32(4): 605-609, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28339122

RESUMO

BACKGROUND: Few studies have investigated mortality risk in individuals with tic disorders. METHODS: We thus measured the risk of premature death in individuals with tic disorders and with Tourette syndrome in a prospective cohort study with 80 million person-years of follow-up. We estimated mortality rate ratios and adjusted for calendar year, age, sex, urbanicity, maternal and paternal age, and psychiatric disorders to compare individuals with and without tic disorders. RESULTS: The risk of premature death was higher among individuals with tic disorders (mortality rate ratio, 2.02; 95% CI, 1.49-2.66) and with Tourette syndrome (mortality rate ratio, 1.63; 95% CI, 1.11-2.28) compared with controls. After the exclusion of individuals with comorbid attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and substance abuse, tic disorder remained associated with increased mortality risk (mortality rate ratio, 2.30; 95% CI, 1.57-3.23), as did also Tourette Syndrome (mortality rate ratio, 1.81; 95% CI, 1.11-2.75). CONCLUSIONS: These results are of clinical significance for clinicians and advocacy organizations. Several factors may contribute to this increased risk of premature death, and more research mapping out these factors is needed. © 2017 International Parkinson and Movement Disorder Society.


Assuntos
Transtornos de Tique/epidemiologia , Transtornos de Tique/mortalidade , Síndrome de Tourette/epidemiologia , Síndrome de Tourette/mortalidade , Adulto , Distribuição por Idade , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Sistema de Registros , Distribuição por Sexo , Transtornos de Tique/complicações , Síndrome de Tourette/complicações , Adulto Jovem
16.
Schizophr Bull ; 43(5): 1064-1069, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28184875

RESUMO

Treatment-resistant schizophrenia (TRS) affects around one-third of individuals with schizophrenia. Although a number of sociodemographic and clinical predictors of TRS have been identified, data on the genetic risk of TRS are sparse. We aimed to investigate the association between a polygenic risk score for schizophrenia and treatment resistance in patients with schizophrenia. We conducted a nationwide, population-based follow-up study among all Danish individuals born after 1981 and with an incident diagnosis of schizophrenia between 1999 and 2007. Based on genome-wide data polygenic risk scores for schizophrenia were calculated in 862 individuals with schizophrenia. TRS was defined as either clozapine initiation or at least 2 periods of different antipsychotic monotherapies and still being hospitalized. We estimated hazard rate ratios (HRs) for TRS in relation to the polygenic risk score while adjusting for population stratification, age, sex, geographical area at birth, clinical treatment setting, psychiatric comorbidity, and calendar year. Among the 862 individuals with schizophrenia, 181 (21.0%) met criteria for TRS during 4674 person-years of follow-up. We found no significant association between the polygenic risk score and TRS, adjusted HR = 1.13 (95% CI: 0.95-1.35). Based on these results, the use of the polygenic risk score for schizophrenia to identify individuals with TRS is at present inadequate to be of clinical utility at the individual patient level. Future research should include larger genetic samples in combination with non-genetic markers. Moreover, a TRS-specific developed polygenic risk score would be of great interest towards early prediction of TRS.


Assuntos
Antipsicóticos/farmacologia , Resistência a Medicamentos/genética , Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Sistema de Registros/estatística & dados numéricos , Esquizofrenia/genética , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Dinamarca , Feminino , Seguimentos , Humanos , Masculino , Risco , Esquizofrenia/tratamento farmacológico , Adulto Jovem
18.
PLoS One ; 12(2): e0171595, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28166306

RESUMO

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Predisposição Genética para Doença , Locos de Características Quantitativas , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transdução de Sinais , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Risco
19.
Schizophr Res ; 184: 122-127, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27939829

RESUMO

BACKGROUND: It is unknown whether an increased genetic liability to schizophrenia influences the risk of dying early. The aim of the study was to determine whether the genetic predisposition to schizophrenia is associated with the risk of dying early and experience a suicide attempt. METHOD: Case control study, Denmark. The main measure was the mortality rate ratios (MRR) for deaths and odds ratios (OR) for multiple suicide attempts, associated with one standard deviations increase of the polygenic risk-score for schizophrenia (PRS). RESULTS: We replicated the high mortality MRR=9.01 (95% CI: 3.56-22.80), and high risk of multiple suicide attempts OR=33.16 (95% CI: 20.97-52.43) associated with schizophrenia compared to the general population. However, there was no effect of the PRS on mortality MRR=1.00 (95% CI 0.71-1.40) in the case-control setup or in cases only, MRR=1.05 (95% CI 0.73-1.51). Similar, no association between the PRS and multiple suicide attempts was found in the adjusted models, but in contrast, family history of mental disorders was associated with both outcomes. CONCLUSIONS: A genetic predisposition for schizophrenia, measured by PRS, has little influence on the excess mortality or the risk of suicide attempts. In contrast there is a strong significant effect of family history of mental disorders. Our findings could reflect that the common variants detected by recent PRS only explain a small proportion of risk of schizophrenia, and that future, more powerful PRS instruments may be able to predict excess mortality within this disorder.


Assuntos
Predisposição Genética para Doença , Mortalidade Prematura , Herança Multifatorial , Sistema de Registros , Esquizofrenia/genética , Esquizofrenia/mortalidade , Tentativa de Suicídio/estatística & dados numéricos , Adolescente , Adulto , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Risco , Adulto Jovem
20.
Biol Psychiatry ; 80(8): 609-16, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27364036

RESUMO

BACKGROUND: Several studies have suggested an important role of infections in the etiology of schizophrenia; however, shared genetic liability toward infections and schizophrenia could influence the association. We therefore investigated the possible effect of polygenic risk scores (PRSs) for schizophrenia on the association between infections and the risk of schizophrenia. METHODS: We conducted a nested case-control study on a Danish population-based sample born after 1981 comprising of 1692 cases diagnosed with schizophrenia between 1994 and 2008 and 1724 matched controls. All individuals were linked utilizing nationwide population-based registers with virtually complete registration of all hospital contacts for infections. PRSs were calculated using discovery effect size estimates weights from an independent meta-analysis (34,600 cases and 45,968 control individuals). RESULTS: A prior hospital contact with infection had occurred in 41% of the individuals with schizophrenia and increased the incidence rate ratio (IRR) of schizophrenia by 1.43 (95% confidence interval [CI] = 1.22-1.67). Adding PRS, which was robustly associated with schizophrenia (by an IRR of 1.46 [95% CI = 1.34-1.60] per standard deviation of the score), did not alter the association with infections and the increased risk of schizophrenia remained (IRR = 1.41; 95% CI = 1.20-1.66). Furthermore, there were no interactions between PRS and infections on the risk of developing schizophrenia (p = .554). Neither did PRS affect the risk of acquiring infections among patients with schizophrenia (odds ratio = 1.00; 95% CI = 0.89-1.12) nor among controls (odds ratio = 1.09; 95% CI: 0.96-1.24). CONCLUSIONS: PRS and a history of infections have independent effects on the risk for schizophrenia, and the common genetic risk measured by PRS did not account for the association with infection in this sample.


Assuntos
Predisposição Genética para Doença , Infecções/genética , Herança Multifatorial/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Dinamarca/epidemiologia , Saúde da Família/estatística & dados numéricos , Feminino , Humanos , Incidência , Infecções/complicações , Infecções/epidemiologia , Masculino , Sistema de Registros , Fatores de Risco , Esquizofrenia/complicações , Esquizofrenia/epidemiologia
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