RESUMO
Sex differences in the epidemiology and clinical characteristics of schizophrenia are well-known; however, the molecular mechanisms underlying these differences remain unclear. Further, the potential advantages of sex-stratified meta-analyses of epigenome-wide association studies (EWAS) of schizophrenia have not been investigated. Here, we performed sex-stratified EWAS meta-analyses to investigate whether sex stratification improves discovery, and to identify differentially methylated regions (DMRs) in schizophrenia. Peripheral blood-derived DNA methylation data from 1519 cases of schizophrenia (male n = 989, female n = 530) and 1723 controls (male n = 997, female n = 726) from three publicly available datasets, and the TOP cohort were meta-analyzed to compare sex-specific, sex-stratified, and sex-adjusted EWAS. The predictive power of each model was assessed by polymethylation score (PMS). The number of schizophrenia-associated differentially methylated positions identified was higher for the sex-stratified model than for the sex-adjusted one. We identified 20 schizophrenia-associated DMRs in the sex-stratified analysis. PMS from sex-stratified analysis outperformed that from sex-adjusted analysis in predicting schizophrenia. Notably, PMSs from the sex-stratified and female-only analyses, but not those from sex-adjusted or the male-only analyses, significantly predicted schizophrenia in males. The findings suggest that sex-stratified EWAS meta-analyses improve the identification of schizophrenia-associated epigenetic changes and highlight an interaction between sex and schizophrenia status on DNA methylation. Sex-specific DNA methylation may have potential implications for precision psychiatry and the development of stratified treatments for schizophrenia.
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Suicide attempts (SA) are prevalent in substance use disorders (SUD). Epigenetic mechanisms may play a pivotal role in the molecular mechanisms of environmental effects eliciting suicidal behaviour in this population. Hypothalamic-pituitary-adrenal axis (HPA), oxytocin and neurotrophin pathways have been consistently involved in SA, yet , their interplay with childhood adversity remains unclear, particularly in SUD. In 24 outpatients with SUDs, we examined the relation between three parental dysfunctional styles and history of SA with methylation of 32 genes from these pathways, eventually analysing 823 methylation sites. Extensive phenotypic characterization was obtained using a semi-structured interview. Parental style was patient-reported using the Measure of Parental Style (MOPS) questionnaire, analysed with and without imputation of missing items. Linear regressions were performed to adjust for possible confounders, followed by multiple testing correction. We describe both differentially methylated probes (DMPs) and regions (DMRs) for each set of analyses (with and without imputation of MOPS items). Without imputation, five DMRs in OXTR, CRH and NTF3 significantly interacted with MOPS father abuse to increase the risk for lifetime SA, thus covering the three pathways. After imputation of missing MOPS items, two other DMPs from FKBP5 and SOCS3 significantly interacted with each of the three father styles to increase the risk for SA. Although our findings must be interpreted with caution due to small sample size, they suggest implications of stress reactivity genes in the suicidal risk of SUD patients and highlight the significance of father dysfunction as a potential marker of childhood adversity in SUD patients.
Assuntos
Transtornos Relacionados ao Uso de Substâncias , Tentativa de Suicídio , Humanos , Criança , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Pais , Transtornos Relacionados ao Uso de Substâncias/genética , Epigênese GenéticaRESUMO
Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits. Genetic variation is identified mainly by mapping short reads to the reference genome or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set of structural variants including many novel insertions and demonstrate how this variant catalogue enables further deciphering of known association mapping signals. We leverage the assemblies to provide 100 completely resolved major histocompatibility complex haplotypes and to resolve major parts of the Y chromosome. Our study provides a regional reference genome that we expect will improve the power of future association mapping studies and hence pave the way for precision medicine initiatives, which now are being launched in many countries including Denmark.
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Variação Genética/genética , Genética Populacional/normas , Genoma Humano/genética , Genômica/normas , Análise de Sequência de DNA/normas , Adulto , Alelos , Criança , Cromossomos Humanos Y/genética , Dinamarca , Feminino , Haplótipos/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Idade Materna , Taxa de Mutação , Idade Paterna , Mutação Puntual/genética , Padrões de ReferênciaRESUMO
BACKGROUND: Noninvasive neurostimulation treatments are increasingly being used to treat major depression, which is a common cause of disability worldwide. While electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are both effective in treating depressive episodes, their mechanisms of action are, however, not completely understood. ECT is given under general anesthesia, where an electrical pulse is administered through electrodes placed on the patient's head to trigger a seizure. ECT is used for the most severe cases of depression and is usually not prescribed before other options have failed. With TMS, brain stimulation is achieved through rapidly changing magnetic fields that induce electric currents underneath a ferromagnetic coil. Its efficacy in depressive episodes has been well documented. This project aims to identify the neurobiological underpinnings of both the effects and side effects of the neurostimulation techniques ECT and TMS. METHODS: The study will utilize a pre-post case control longitudinal design. The sample will consist of 150 subjects: 100 patients (bipolar and major depressive disorder) who are treated with either ECT (N = 50) or TMS (N = 50) and matched healthy controls (N = 50) not receiving any treatment. All participants will undergo multimodal magnetic resonance imaging (MRI) as well as neuropsychological and clinical assessments at multiple time points before, during and after treatment. Arterial spin labeling MRI at baseline will be used to test whether brain perfusion can predict outcomes. Signs of brain disruption, potentiation and rewiring will be explored with resting-state functional MRI, magnetic resonance spectroscopy and multishell diffusion weighted imaging (DWI). Clinical outcome will be measured by clinician assessed and patient reported outcome measures. Memory-related side effects will be investigated, and specific tests of spatial navigation to test hippocampal function will be administered both before and after treatment. Blood samples will be stored in a biobank for future analyses. The observation time is 6 months. Data will be explored in light of the recently proposed disrupt, potentiate and rewire (DPR) hypothesis. DISCUSSION: The study will contribute data and novel analyses important for our understanding of neurostimulation as well as for the development of enhanced and more personalized treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05135897.
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Transtorno Bipolar , Transtorno Depressivo Maior , Eletroconvulsoterapia , Estimulação Magnética Transcraniana , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia/efeitos adversos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Estimulação Magnética Transcraniana/efeitos adversos , Resultado do Tratamento , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/terapiaRESUMO
Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.
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Estudo de Associação Genômica Ampla , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Putamen , TálamoRESUMO
BACKGROUND: Several risk factors for anxious-depressive symptomatology during the COVID-19 pandemic have been established. However, few studies have examined the relationship between personality traits, hardiness, and such symptomatology during the pandemic. These constructs might serve as risk- and/or protective factors for such mental distress through the pandemic. METHODS: A sample of 5783 Norwegians responded to a survey at two time points within the first year of the pandemic. The first data collection was in April 2020 (T1) and the second in December 2020 (T2). Measures included the Ten-Item Personality-Inventory, the Revised Norwegian Dispositional Resilience Scale, and the Patient Health Questionnaire Anxiety and Depression Scale. Analyses were performed using Pearson's correlations, multiple linear regression, and a moderation analysis. RESULTS: Anxious-depressive symptomatology in early phases (T1) of the pandemic was the strongest predictor for the presence of such symptomatology 9 months after the outbreak (T2). Personality and hardiness correlated significantly with mental distress at T1 and T2. Personality traits explained 5% variance in symptoms when controlling for age, gender, solitary living, negative economic impact, and mental distress at baseline. Higher neuroticism predicted higher mental distress, whereas higher conscientiousness and extraversion predicted less mental distress. Hardiness did not explain variance in outcome beyond personality traits. Hardiness did not significantly moderate the relationship between neuroticism and mental distress. CONCLUSION: Individuals with high levels of neuroticism had greater difficulties adapting to the circumstances of the COVID-19 pandemic and were more prone to mental distress. Contrastingly, higher conscientiousness and extraversion may have served as protective factors for mental distress during the pandemic. The current findings might aid identification of vulnerable individuals and groups. Consequently, preventive interventions could be offered to those who need it the most.
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COVID-19 , Pandemias , Humanos , Noruega/epidemiologia , Personalidade , Fatores de ProteçãoRESUMO
The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer's disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields' genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10-16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.
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Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Hipocampo/anatomia & histologia , Hipocampo/patologia , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico por imagem , Adulto JovemRESUMO
The many subcomponents of the human cortex are known to follow an anatomical pattern and functional relationship that appears to be highly conserved between individuals. This suggests that this pattern and the relationship among cortical regions are important for cortical function and likely shaped by genetic factors, although the degree to which genetic factors contribute to this pattern is unknown. We assessed the genetic relationships among 12 cortical surface areas using brain images and genotype information on 2,364 unrelated individuals, brain images on 466 twin pairs, and transcriptome data on 6 postmortem brains in order to determine whether a consistent and biologically meaningful pattern could be identified from these very different data sets. We find that the patterns revealed by each data set are highly consistent (p<10-3), and are biologically meaningful on several fronts. For example, close genetic relationships are seen in cortical regions within the same lobes and, the frontal lobe, a region showing great evolutionary expansion and functional complexity, has the most distant genetic relationship with other lobes. The frontal lobe also exhibits the most distinct expression pattern relative to the other regions, implicating a number of genes with known functions mediating immune and related processes. Our analyses reflect one of the first attempts to provide an assessment of the biological consistency of a genetic phenomenon involving the brain that leverages very different types of data, and therefore is not just statistical replication which purposefully use very similar data sets.
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Córtex Cerebral/metabolismo , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/genética , Transcriptoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Encefálico , Cadáver , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Lobo Frontal/anatomia & histologia , Lobo Frontal/diagnóstico por imagem , Perfilação da Expressão Gênica , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Fenótipo , Gêmeos/genéticaRESUMO
BACKGROUND: One explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants. RESULTS: Schizophrenia was the only trait in which DMR SNPs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. The enrichment survives multiple testing performed through permutation (n = 10,000) and bootstrapping (n = 5000) in INRICH (p < 0.01). Some enrichment of association with height was observed at the gene level. CONCLUSIONS: Regions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.
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Metilação de DNA/genética , Evolução Molecular , Esquizofrenia/genética , Adulto , Transtorno Bipolar/genética , Estatura/genética , Índice de Massa Corporal , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Anotação de Sequência Molecular , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
OBJECTIVE: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients. METHODS: (1) A set of 27 genes from the guanylate cyclase C pathway was tested for enrichment of association with IBD by Gene Set Enrichment Analysis, using genome-wide association summary statistics from 12,882 IBD patients and 21,770 controls. (2) We genotyped 163 known IBD risk loci and sequenced NOD2 in 22 patients with FGDS. Eight of them had concomitant Crohn's disease. (3) Global gene expression analysis was performed in ileal tissue from patients with FGDS, Crohn's disease and healthy individuals. RESULTS: The guanylate cyclase C gene set showed a significant enrichment of association in IBD genome-wide association data. Risk variants in NOD2 were found in 7/8 FGDS patients with concomitant Crohn's disease and in 2/14 FDGS patients without Crohn's disease. In ileal tissue, downregulation of metallothioneins characterized FGDS patients compared to healthy controls. CONCLUSIONS: Our results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of FGDS patients may contribute to IBD development, possibly alongside effects from NOD2 risk variants.
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Diarreia/genética , Doenças Inflamatórias Intestinais/genética , Receptores de Enterotoxina/genética , Adulto , Idoso , Estudos de Casos e Controles , Diarreia/metabolismo , Regulação para Baixo , Saúde da Família , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Íleo/patologia , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Proteína Adaptadora de Sinalização NOD2/genética , Noruega , Plasma/química , Medição de Risco , Síndrome , Adulto JovemRESUMO
The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n=670). Replication testing of SNPs with p-value<0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n=1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n=1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMD1 SNP rs2740931 and performance in immediate episodic memory (p-value=5×10-6, minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p⩽1.2×10-5). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n=3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease.
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Cognição/fisiologia , Proteínas de Membrana/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Proteínas Supressoras de TumorRESUMO
Genome-wide association studies (GWASs) are critically dependent on detailed knowledge of the pattern of linkage disequilibrium (LD) in the human genome. GWASs generate lists of variants, usually SNPs, ranked according to the significance of their association to a trait. Downstream analyses generally focus on the gene or genes that are physically closest to these SNPs and ignore their LD profile with other SNPs. We have developed a flexible R package (LDsnpR) that efficiently assigns SNPs to genes on the basis of both their physical position and their pairwise LD with other SNPs. We used the positional-binning and LD-based-binning approaches to investigate whether including these "LD-based" SNPs would affect the interpretation of three published GWASs on bipolar affective disorder (BP) and of the imputed versions of two of these GWASs. We show how including LD can be important for interpreting and comparing GWASs. In the published, unimputed GWASs, LD-based binning effectively "recovered" 6.1%-8.3% of Ensembl-defined genes. It altered the ranks of the genes and resulted in nonnegligible differences between the lists of the top 2,000 genes emerging from the two binning approaches. It also improved the overall gene-based concordance between independent BP studies. In the imputed datasets, although the increases in coverage (>0.4%) and rank changes were more modest, even greater concordance between the studies was observed, attesting to the potential of LD-based binning on imputed data as well. Thus, ignoring LD can result in the misinterpretation of the GWAS findings and have an impact on subsequent genetic and functional studies.
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Estudo de Associação Genômica Ampla/estatística & dados numéricos , Desequilíbrio de Ligação/genética , Transtorno Bipolar/genética , Interpretação Estatística de Dados , Humanos , Polimorfismo de Nucleotídeo Único , Software/estatística & dados numéricosRESUMO
Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.
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Transtornos Cognitivos/genética , Cognição/fisiologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Fatigue is prevalent and disabling in primary Sjögren's syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue. The aim of this study was to investigate single nucleotide polymorphism (SNP) variations in pSS patients with high and low fatigue. A panel of 85 SNPs in 12 genes was selected based on previous studies in CFS. A total of 207 pSS patients and 376 healthy controls were genotyped. One-hundred and ninety-three patients and 70 SNPs in 11 genes were available for analysis after quality control. Patients were dichotomized based on fatigue visual analogue scale (VAS) scores, with VAS <50 denominated "low fatigue" (n = 53) and VAS ≥50 denominated "high fatigue" (n = 140). We detected signals of association with pSS for one SNP in SLC25A40 (unadjusted p = 0.007) and two SNPs in PKN1 (both p = 0.03) in our pSS case versus control analysis. The association with SLC25A40 was stronger when only pSS high fatigue patients were analysed versus controls (p = 0.002). One SNP in PKN1 displayed an association in the case-only analysis of pSS high fatigue versus pSS low fatigue (p = 0.005). This candidate gene study in pSS did reveal a trend for associations between genetic variation in candidate genes and fatigue. The results will need to be replicated. More research on genetic associations with fatigue is warranted, and future trials should include larger cohorts and multicentre collaborations with sharing of genetic material to increase the statistical power.
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Fadiga/genética , Polimorfismo de Nucleotídeo Único , Síndrome de Sjogren/genética , Adulto , Idoso , Estudos de Casos e Controles , Doença Crônica , Fadiga/diagnóstico , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte da Membrana Mitocondrial/genética , Noruega , Fenótipo , Proteína Quinase C/genética , Fatores de Risco , Índice de Gravidade de Doença , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnósticoRESUMO
The last decade has seen the development of large-scale genetics studies which have advanced our understanding of the genetic architecture of many complex heritable traits. In this review, we examine what progress has been made in understanding the genetics of cognitive traits. We cover the whole spectrum of distribution in cognitive abilities, from studies that have identified single genes implicated in intellectual disabilities, through studies investigating the missing and hidden heritability of cognitive abilities in the general population, and finally to studies looking at "high intelligence" samples.
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Aptidão/fisiologia , Cognição/fisiologia , Padrões de Herança/genética , Deficiência Intelectual/genética , Inteligência/genética , HumanosRESUMO
Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced perinatal asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of perinatal asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of perinatal asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with perinatal asphyxia. We found an interaction between methylation and exposure to perinatal asphyxia on case-control status, wherein having a history of perinatal asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to perinatal asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.
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Transtorno Bipolar , Transtornos Mentais , Recém-Nascido , Feminino , Gravidez , Humanos , Asfixia , Estudos Prospectivos , Transtorno Bipolar/genética , Epigênese GenéticaRESUMO
Cases with schizophrenia (SCZ) and healthy controls show differences in white blood cell (WBC) counts and blood inflammation markers. Here, we investigate whether time of blood draw and treatment with psychiatric medications are related to differences in estimated WBC proportions between SCZ cases and controls. DNA methylation data from whole blood was used to estimate proportions of six subtypes of WBCs in SCZ patients (n = 333) and healthy controls (n = 396). We tested the association of case-control status with estimated cell-type proportions and the neutrophil-to-lymphocyte ratio (NLR) in 4 models: with/without adjusting for time of blood draw, and then compared results from blood samples drawn during a 12-h (07:00-19:00) or 7-h (07:00-14:00) period. We also investigated WBC proportions in a subgroup of medication-free patients (n = 51). Neutrophil proportions were significantly higher in SCZ cases (mean=54.1%) vs. controls (mean=51.1%; p = <0.001), and CD8+T lymphocyte proportions were lower in SCZ cases (mean=12.1%) vs. controls (mean=13.2%; p = 0.001). The effect sizes in the 12-h sample (07:00-19:00) showed a significant difference between SCZ vs. controls for neutrophils, CD4+T, CD8+T, and B-cells, which remained significant after adjusting for time of blood draw. In the samples matched for time of blood draw during 07.00-14.00, we also observed an association with neutrophils, CD4+T, CD8+T, and B-cells that was unaffected by further adjustment for time of blood draw. In the medication-free patients, we observed differences that remained significant in neutrophils (p = 0.01) and CD4+T (p = 0.01) after adjusting for time of day. The association of SCZ with NLR was significant in all models (range: p < 0.001 to p = 0.03) in both medicated and unmedicated patients. In conclusion, controlling for pharmacological treatment and circadian cycling of WBC is necessary for unbiased estimates in case-control studies. Nevertheless, the association of WBC with SCZ remains, even after adjusting for the time of day.
Assuntos
Esquizofrenia , Humanos , Esquizofrenia/genética , Leucócitos , Linfócitos , Neutrófilos , Estudos de Casos e ControlesRESUMO
OBJECTIVES: Lymphotoxin ß (LTB) has been found to be upregulated in salivary glands of patients with primary Sjögren's syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin α (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS. METHODS: 527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing. RESULTS: Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS. CONCLUSIONS: A strong association was found between several SNP in the LTA/LTB/TNFα locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.
Assuntos
Linfotoxina-alfa/genética , Linfotoxina-beta/genética , Síndrome de Sjogren/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Linfotoxina-alfa/imunologia , Linfotoxina-beta/imunologia , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Glândulas Salivares/imunologia , Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/imunologia , Suécia/epidemiologia , Fator de Necrose Tumoral alfa/imunologia , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
Data collection for the Norwegian Cognitive NeuroGenetics sample (NCNG) was initiated in 2003 with a research grant (to Ivar Reinvang) to study cognitive aging, brain function, and genetic risk factors. The original focus was on the effects of aging (from middle age and up) and candidate genes (e.g., APOE, CHRNA4) in cross-sectional and longitudinal designs, with the cognitive and MRI-based data primarily being used for this purpose. However, as the main topic of the project broadened from cognitive aging to imaging and cognitive genetics more generally, the sample size, age range of the participants, and scope of available phenotypes and genotypes, have developed beyond the initial project. In 2009, a genome-wide association (GWA) study was undertaken, and the NCNG proper was established to study the genetics of cognitive and brain function more comprehensively. The NCNG is now controlled by the NCNG Study Group, which consists of the present authors. Prominent features of the NCNG are the adult life-span coverage of healthy participants with high-dimensional imaging, and cognitive data from a genetically homogenous sample. Another unique property is the large-scale (sample size 300-700) use of experimental cognitive tasks focusing on attention and working memory. The NCNG data is now used in numerous ongoing GWA-based studies and has contributed to several international consortia on imaging and cognitive genetics. The objective of the following presentation is to give other researchers the information necessary to evaluate possible contributions from the NCNG to various multi-sample data analyses.
Assuntos
Cognição , Estudo de Associação Genômica Ampla , Imageamento por Ressonância Magnética , Adulto , Envelhecimento/genética , Atenção , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Testes PsicológicosRESUMO
Background: Early stages of the COVID-19 pandemic have been associated with increasing obsessive-compulsive symptoms (OCS), but less is known regarding these symptoms' long-term trajectories. The aim of this study was to examine changes in contamination-related OCS in the Norwegian public during early and late stages of the pandemic, as well as characteristics that might be associated with these changes. Methods: In a longitudinal online survey, 12 580 participants completed self-report questionnaires in April 2020, including a retrospective assessment of contamination-related OCS severity (DOCS-SF) prior to COVID-19. In December 2020, 3405 (27.1%) of the participants completed the survey again. Results: In April, participants retrospectively recalled that their contamination-related OCS were lower prior to COVID-19 (d = 1.09). From April to December, symptoms slightly decreased (d = -0.16). The proportion of participants scoring above the clinical cut-off on DOCS-SF (≥16) changed accordingly from 2.4% pre-COVID to 27.8% in April and 24.0% in December. Previous severity of contamination-related OCS and symptoms of distress related to COVID-19 were the most powerful predictors of contamination-related OCS severity during the pandemic. Conclusions: Elevated levels of contamination-related OCS were detected at both early and late stages of the pandemic, but the long-term symptom trend seems to be slightly declining.