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Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are 'modern'. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, 'mya'), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are 'ancient', meaning their emergence dates back to cellular organisms and opisthokonta (3500-1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as 'medium-aged'. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.
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Oxitocina , Receptores de Oxitocina , Animales , Humanos , Anciano , Oxitocina/metabolismo , Receptores de Oxitocina/genética , Transducción de Señal , Encéfalo/metabolismoRESUMEN
Individuals with schizophrenia and bipolar disorder are at an increased risk of cardiovascular disease (CVD), and a range of biomarkers related to CVD risk have been found to be abnormal in these patients. Common genetic factors are a putative underlying mechanism, alongside lifestyle factors and antipsychotic medication. However, the extent to which the altered CVD biomarkers are related to genetic factors involved in schizophrenia and bipolar disorder is unknown. In a sample including 699 patients with schizophrenia, 391 with bipolar disorder, and 822 healthy controls, we evaluated 8 CVD risk biomarkers, including BMI, and fasting plasma levels of CVD biomarkers from a subsample. Polygenic risk scores (PGRS) were obtained from genome-wide associations studies (GWAS) of schizophrenia and bipolar disorder from the Psychiatric Genomics Consortium. The CVD biomarkers were used as outcome variables in linear regression models including schizophrenia and bipolar disorder PGRS as predictors, age, sex, diagnostic category, batch and 10 principal components as covariates, controlling for multiple testing by Bonferroni correction for the number of independent tests. Bipolar disorder PGRS was significantly (p = 0.03) negatively associated with BMI after multiple testing correction, and schizophrenia PGRS was nominally negatively associated with BMI. There were no other significant associations between bipolar or schizophrenia PGRS, and other investigated CVD biomarkers. Despite a range of abnormal CVD risk biomarkers in psychotic disorders, we only found a significant negative association between bipolar disorder PGRS and BMI. This has previously been shown for schizophrenia PGRS and BMI, and warrants further exploration.
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Introduction: Patients with predementia Alzheimer's disease (AD) and at-risk subjects are targets for promising disease-modifying treatments, and improved polygenic risk scores (PRSs) could improve early-stage case selection. Methods: Phenotype-informed PRSs were developed by selecting AD-associated variants conditional on relevant inflammatory or cardiovascular traits. The primary outcome was longitudinal changes in measures of AD pathology, namely development of pathological amyloid deposition, medial temporal lobe atrophy, and cognitive decline in a prospective cohort study including 394 adults without AD dementia. Results: High-risk groups defined by phenotype-informed AD PRSs had significantly steeper volume decline in medial temporal cortices, and the high-risk group defined by the cardiovascular-informed AD PRS had significantly increased hazard ratio of pathological amyloid deposition, compared to low-risk groups. Discussion: AD PRSs informed by inflammatory disorders or cardiovascular risk factors and diseases are associated with development of AD pathology markers and may improve identification of subjects at risk for progression of AD.
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Increasing evidence has shown adverse effects of loneliness on cardiometabolic health. The neuromodulator and hormone oxytocin has traditionally been linked with social cognition and behaviour. However, recent implications of the oxytocin system in energy metabolism and the overrepresentation of metabolic issues in psychiatric illness suggests that oxytocin may represent a mechanism bridging mental and somatic traits. To clarify the role of the oxytocin signalling system in the link between cardiometabolic risk factors and loneliness, we calculated the contribution of single nucleotide polymorphisms (SNPs) in the oxytocin signalling pathway gene-set (154 genes) to the polygenic architecture of loneliness and body mass index (BMI). We investigated the associations of these oxytocin signalling pathway polygenic scores with body composition measured using body magnetic resonance imaging (MRI), bone mineral density (BMD), haematological markers, and blood pressure in a sample of just under half a million adults from the UK Biobank (BMD subsample n = 274,457; body MRI subsample n = 9796). Our analysis revealed significant associations of the oxytocin signalling pathway polygenic score for BMI with abdominal subcutaneous fat tissue, HDL cholesterol, lipoprotein(a), triglycerides, and BMD. We also found an association between the oxytocin signalling pathway polygenic score for loneliness and apolipoprotein A1, the major protein component of HDL. Altogether, these results provide additional evidence for the oxytocin signalling pathway's role in energy metabolism, lipid homoeostasis, and bone density, and support oxytocin's complex pleiotropic effects.
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Enfermedades Cardiovasculares , Oxitocina , Adulto , Índice de Masa Corporal , Enfermedades Cardiovasculares/metabolismo , HDL-Colesterol , Humanos , Soledad , Oxitocina/genéticaRESUMEN
BACKGROUND: Brain-computer interfaces (BCIs) are systems capable of translating human brain patterns, measured through electroencephalography (EEG), into commands for an external device. Despite the great advances in machine learning solutions to enhance the performance of BCI decoders, the translational impact of this technology remains elusive. The reliability of BCIs is often unsatisfactory for end-users, limiting their application outside a laboratory environment. METHODS: We present the analysis on the data acquired from an end-user during the preparation for two Cybathlon competitions, where our pilot won the gold medal twice in a row. These data are of particular interest given the mutual learning approach adopted during the longitudinal training phase (8 months), the long training break in between the two events (1 year) and the demanding evaluation scenario. A multifaceted perspective on long-term user learning is proposed: we enriched the information gathered through conventional metrics (e.g., accuracy, application performances) by investigating novel neural correlates of learning in different neural domains. RESULTS: First, we showed that by focusing the training on user learning, the pilot was capable of significantly improving his performance over time even with infrequent decoder re-calibrations. Second, we revealed that the analysis of the within-class modifications of the pilot's neural patterns in the Riemannian domain is more effective in tracking the acquisition and the stabilization of BCI skills, especially after the 1-year break. These results further confirmed the key role of mutual learning in the acquisition of BCI skills, and particularly highlighted the importance of user learning as a key to enhance BCI reliability. CONCLUSION: We firmly believe that our work may open new perspectives and fuel discussions in the BCI field to shift the focus of future research: not only to the machine learning of the decoder, but also in investigating novel training procedures to boost the user learning and the stability of the BCI skills in the long-term. To this end, the analyses and the metrics proposed could be used to monitor the user learning during training and provide a marker guiding the decoder re-calibration to maximize the mutual adaptation of the user to the BCI system.
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Interfaces Cerebro-Computador , Encéfalo , Electroencefalografía/métodos , Humanos , Aprendizaje Automático , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Schizophrenia is a complex polygenic disorder with subtle, distributed abnormalities in brain morphology. There are indications of shared genetic architecture between schizophrenia and brain measures despite low genetic correlations. Through the use of analytical methods that allow for mixed directions of effects, this overlap may be leveraged to improve our understanding of underlying mechanisms of schizophrenia and enrich polygenic risk prediction outcome. METHODS: We ran a multivariate genome-wide analysis of 175 brain morphology measures using data from 33,735 participants of the UK Biobank and analyzed the results in a conditional false discovery rate together with schizophrenia genome-wide association study summary statistics of the Psychiatric Genomics Consortium (PGC) Wave 3. We subsequently created a pleiotropy-enriched polygenic score based on the loci identified through the conditional false discovery rate approach and used this to predict schizophrenia in a nonoverlapping sample of 743 individuals with schizophrenia and 1074 healthy controls. RESULTS: We found that 20% of the loci and 50% of the genes significantly associated with schizophrenia were also associated with brain morphology. The conditional false discovery rate analysis identified 428 loci, including 267 novel loci, significantly associated with brain-linked schizophrenia risk, with functional annotation indicating high relevance for brain tissue. The pleiotropy-enriched polygenic score explained more variance in liability than conventional polygenic scores across several scenarios. CONCLUSIONS: Our results indicate strong genetic overlap between schizophrenia and brain morphology with mixed directions of effect. The results also illustrate the potential of exploiting polygenetic overlap between brain morphology and mental disorders to boost discovery of brain tissue-specific genetic variants and its use in polygenic risk frameworks.
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Esquizofrenia , Encéfalo , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple , Esquizofrenia/genéticaRESUMEN
Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine's polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100-12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of 'pleiotropic' variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.
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Trastornos Mentales , Trastornos Migrañosos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Trastornos Mentales/genética , Trastornos Migrañosos/genética , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Lithium is the first-line treatment for bipolar disorder (BD), but there is a large variation in response rate and adverse effects. Although the molecular effects of lithium have been studied extensively, the specific mechanisms of action remain unclear. In particular, the molecular changes underlying lithium adverse effects are little known. Multiple linear regression analyses of lithium serum concentrations and global gene expression levels in whole blood were carried out using a large case-control sample (n = 1450). Self-reported adverse effects of lithium were assessed with the "Udvalg for Kliniske Undersøgelser" (UKU) adverse effect rating scale, and regression analysis was used to identify significant associations between lithium-related genes and six of the most common adverse effects. Serum concentrations of lithium were significantly associated with the expression levels of 52 genes (FDR < 0.01), largely replicating previous results. We found 32 up-regulated genes and 20 down-regulated genes in lithium users compared to non-users. The down-regulated gene set was enriched for several processes related to the translational machinery. Two adverse effects were significantly associated (p < 0.01) with three or more lithium-associated genes: tremor (FAM13A-AS1, FAR2, ITGAX, RWDD1, and STARD10) and xerostomia (ANKRD13A, FAR2, RPS8, and RWDD1). The adverse effect association with the largest effect was between CAMK1D expression and nausea/vomiting. These results suggest putative transcriptional mechanisms that may predict lithium adverse effects, and could thus have a large potential for informing clinical practice.
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Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Expresión Génica/efectos de los fármacos , Litio/efectos adversos , Litio/uso terapéutico , Antipsicóticos/sangre , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/genética , Estudios de Casos y Controles , Estudios de Cohortes , Proteínas Activadoras de GTPasa/genética , Humanos , Entrevistas como Asunto , Litio/sangreRESUMEN
The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.
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Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Imagen por Resonancia Magnética , Neuroimagen , Trastorno Bipolar/tratamiento farmacológico , Genética , Hipocampo/efectos de los fármacos , HumanosRESUMEN
Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterized by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing. To investigate whether the oxytocin system has a pleiotropic effect on the etiology of severe mental illness and cardiometabolic conditions, we explored oxytocin's role in the shared genetic liability of schizophrenia, bipolar disorder, type-2 diabetes, and several phenotypes linked with cardiovascular disease and type 2 diabetes risk using a polygenic pathway-specific approach. Analysis of a large sample with about 480,000 individuals (UK Biobank) revealed statistically significant associations across the range of phenotypes analyzed. By comparing these effects to those of polygenic scores calculated from 100 random gene sets, we also demonstrated the specificity of many of these significant results. Altogether, our results suggest that the shared effect of oxytocin-system dysfunction could help partially explain the co-occurrence of social and cardiometabolic dysfunction in severe mental illnesses.
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Diabetes Mellitus Tipo 2 , Trastornos Mentales , Bancos de Muestras Biológicas , Diabetes Mellitus Tipo 2/genética , Humanos , Trastornos Mentales/genética , Herencia Multifactorial , Oxitocina/genética , Fenotipo , Reino UnidoRESUMEN
BACKGROUND: A range of sleep disturbances are commonly experienced by patients with psychiatric disorders, and genome-wide genetic analyses have shown some significant genetic correlations between these traits. Here, we applied novel statistical genetic methodologies to better characterize the potential shared genetic architecture between sleep-related phenotypes and psychiatric disorders. METHODS: Using the MiXeR method, which can estimate polygenic overlap beyond genetic correlation, the shared genetic architecture between major psychiatric disorders (bipolar disorder [N = 51,710], depression [N = 480,359], and schizophrenia [N = 77,096]) and sleep-related phenotypes (chronotype [N = 449,734], insomnia [N = 386,533] and sleep duration [N = 446,118]) were quantified on the basis of genetic summary statistics. Furthermore, the conditional/conjunctional false discovery rate framework was used to identify specific shared loci between these phenotypes, for which positional and functional annotation were conducted with FUMA. RESULTS: Extensive genetic overlap between the sleep-related phenotypes and bipolar disorder (63%-77%), depression (76%-79%), and schizophrenia (64%-79%) was identified, with moderate levels of congruence between most investigated traits (47%-58%). Specific shared loci were identified for all bivariate analyses, and a subset of 70 credible genes were mapped to these shared loci. CONCLUSIONS: The current results provide evidence for substantial polygenic overlap between psychiatric disorders and sleep-related phenotypes, beyond genetic correlation (|rg| = 0.02 to 0.42). Moderate congruency within the shared genetic components suggests a complex genetic relationship and potential subgroups with higher or lower genetic concordance. This work provides new insights and understanding of the shared genetic etiology of sleep-related phenotypes and psychiatric disorders and highlights new opportunities and avenues for future investigation.
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Estudio de Asociación del Genoma Completo , Trastornos Mentales , Sitios Genéticos , Predisposición Genética a la Enfermedad , Humanos , Trastornos Mentales/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Sueño/genéticaRESUMEN
Increased risk-taking is a central component of bipolar disorder (BIP) and is implicated in schizophrenia (SCZ). Risky behaviours, including smoking and alcohol use, are overrepresented in both disorders and associated with poor health outcomes. Positive genetic correlations are reported but an improved understanding of the shared genetic architecture between risk phenotypes and psychiatric disorders may provide insights into underlying neurobiological mechanisms. We aimed to characterise the genetic overlap between risk phenotypes and SCZ, and BIP by estimating the total number of shared variants using the bivariate causal mixture model and identifying shared genomic loci using the conjunctional false discovery rate method. Summary statistics from genome wide association studies of SCZ, BIP, risk-taking and risky behaviours were acquired (n = 82,315-466,751). Genomic loci were functionally annotated using FUMA. Of 8.6-8.7 K variants predicted to influence BIP, 6.6 K and 7.4 K were predicted to influence risk-taking and risky behaviours, respectively. Similarly, of 10.2-10.3 K variants influencing SCZ, 9.6 and 8.8 K were predicted to influence risk-taking and risky behaviours, respectively. We identified 192 loci jointly associated with SCZ and risk phenotypes and 206 associated with BIP and risk phenotypes, of which 68 were common to both risk-taking and risky behaviours and 124 were novel to SCZ or BIP. Functional annotation implicated differential expression in multiple cortical and sub-cortical regions. In conclusion, we report extensive polygenic overlap between risk phenotypes and BIP and SCZ, identify specific loci contributing to this shared risk and highlight biologically plausible mechanisms that may underlie risk-taking in severe psychiatric disorders.
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Trastorno Bipolar , Esquizofrenia , Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Asunción de Riesgos , Esquizofrenia/genéticaRESUMEN
Major mental disorders are highly prevalent and make a substantial contribution to the global disease burden. It is known that mental disorders share clinical characteristics, and genome-wide association studies (GWASs) have recently provided evidence for shared genetic factors as well. Genetic overlaps are usually identified at the single-marker level. Here, we aimed to identify genetic overlaps at the gene level between 7 mental disorders (schizophrenia, autism spectrum disorder, major depressive disorder, anorexia nervosa, ADHD, bipolar disorder and anxiety), 8 brain morphometric traits, 2 cognitive traits (educational attainment and general cognitive function) and 9 personality traits (subjective well-being, depressive symptoms, neuroticism, extraversion, openness to experience, agreeableness and conscientiousness, children's aggressive behaviour, loneliness) based on publicly available GWASs. We performed systematic conditional regression analyses to identify independent signals and select loci associated with more than one trait. We identified 48 genes containing independent markers associated with several traits (pleiotropy at the gene level). We also report 9 genes with different markers that show independent associations with single traits (allelic heterogeneity). This study demonstrates that mental disorders and related traits do show pleiotropy at the gene level as well as the single-marker level. The identification of these genes might be important for prioritizing further deep genotyping, functional studies, or drug targeting.
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Trastorno del Espectro Autista , Trastorno Depresivo Mayor , Trastornos de Ansiedad , Niño , Trastorno Depresivo Mayor/genética , Extraversión Psicológica , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Selective serotonin reuptake inhibitors (SSRIs) are prescribed both to patients with schizophrenia and bipolar disorder. Previous studies have shown associations between SSRI treatment and cardiometabolic alterations. The aim of the present study was to investigate genetic variants associated with cardiometabolic adverse effects in patients treated with SSRIs in a naturalistic setting, using a genome-wide cross-sectional approach in a genetically homogeneous sample. We included and genotyped 1981 individuals with schizophrenia or bipolar disorder, of whom 1180 had information available on the outcomes low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), triglycerides, and body mass index (BMI) and investigated interactions between SNPs and SSRI use (N = 246) by conducting a genome-wide GxE analysis. We report 13 genome-wide significant interaction effects of SNPs and SSRI serum concentrations on LDL-cholesterol, HDL-cholesterol, and BMI, located in four distinct genomic loci. This study provides new insight into the pharmacogenetics of SSRI but warrants replication in independent populations.
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Síndrome Metabólico/inducido químicamente , Polimorfismo de Nucleótido Simple/genética , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Adulto , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Estudios Transversales , Femenino , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Masculino , Síndrome Metabólico/genética , Noruega , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Triglicéridos/sangreRESUMEN
This study examined the relationship between proximal arm strength and mobility performance in wheelchair rugby (WR) athletes and examined whether a valid structure for classifying proximal arm strength impairment could be determined. Fifty-seven trained WR athletes with strength impaired arms and no trunk function performed six upper body isometric strength tests and three 10 m sprints in their rugby wheelchair. All strength measures correlated with 2 m and 10 m sprint times (r ≥ -0.43; p ≤ 0.0005) and were entered into k-means cluster analyses with 4-clusters (to mirror the current International Wheelchair Rugby Federation [IWRF] system) and 3-clusters. The 3-cluster structure provided a more valid structure than both the 4-cluster and existing IWRF system, as evidenced by clearer differences in strength (Effect sizes [ES] ≥ 1.0) and performance (ES ≥ 1.1) between adjacent clusters and stronger mean silhouette coefficient (0.64). Subsequently, the 3-cluster structure for classifying proximal arm strength impairment would result in less overlap between athletes from adjacent classes and reduce the likelihood of athletes being disadvantaged due to their impairment. This study demonstrated that the current battery of isometric strength tests and cluster analyses could facilitate the evidence-based development of classifying proximal arm strength impairment in WR.
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Brazo/fisiología , Fútbol Americano/fisiología , Movimiento/fisiología , Fuerza Muscular/fisiología , Paratletas , Prueba de Estudio Conceptual , Adulto , Ataxia/clasificación , Ataxia/fisiopatología , Rendimiento Atlético/fisiología , Análisis por Conglomerados , Femenino , Fútbol Americano/clasificación , Humanos , Contracción Isométrica/fisiología , Masculino , Paratletas/clasificación , Valores de Referencia , Traumatismos de la Médula Espinal/complicaciones , Deportes para Personas con Discapacidad/fisiología , Silla de RuedasRESUMEN
Genome-wide association studies (GWAS) have identified several common genetic variants influencing major depression and general cognitive abilities, but little is known about whether the two share any of their genetic aetiology. Here we investigate shared genomic architectures between major depression (MD) and general intelligence (INT) with the MiXeR statistical tool and their overlapping susceptibility loci with conjunctional false discovery rate (conjFDR), which evaluate the level of overlap in genetic variants and improve the power for gene discovery between two phenotypes. We analysed GWAS data on MD (n = 480,359) and INT (n = 269,867) to characterize polygenic architecture and identify genetic loci shared between these phenotypes. Despite non-significant genetic correlation (rg = -0.0148, P = 0.50), we observed large polygenic overlap and identified 92 loci shared between MD and INT at conjFDR < 0.05. Among the shared loci, 69 and 64 are new for MD and INT, respectively. Our study demonstrates polygenic overlap between these phenotypes with a balanced mixture of effect.
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Trastorno Depresivo Mayor/genética , Inteligencia/genética , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Sitios Genéticos , Predisposición Genética a la Enfermedad , Genoma , Estudio de Asociación del Genoma Completo , Humanos , Inteligencia/fisiología , Herencia Multifactorial , Polimorfismo de Nucleótido SimpleRESUMEN
Differential diagnosis between childhood onset attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) remains a challenge, mainly due to overlapping symptoms and high rates of comorbidity. Despite this, genetic correlation reported for these disorders is low and non-significant. Here we aimed to better characterize the genetic architecture of these disorders utilizing recent large genome-wide association studies (GWAS). We analyzed independent GWAS summary statistics for ADHD (19,099 cases and 34,194 controls) and BD (20,352 cases and 31,358 controls) applying the conditional/conjunctional false discovery rate (condFDR/conjFDR) statistical framework that increases the power to detect novel phenotype-specific and shared loci by leveraging the combined power of two GWAS. We observed cross-trait polygenic enrichment for ADHD conditioned on associations with BD, and vice versa. Leveraging this enrichment, we identified 19 novel ADHD risk loci and 40 novel BD risk loci at condFDR <0.05. Further, we identified five loci jointly associated with ADHD and BD (conjFDR < 0.05). Interestingly, these five loci show concordant directions of effect for ADHD and BD. These results highlight a shared underlying genetic risk for ADHD and BD which may help to explain the high comorbidity rates and difficulties in differentiating between ADHD and BD in the clinic. Improving our understanding of the underlying genetic architecture of these disorders may aid in the development of novel stratification tools to help reduce these diagnostic difficulties.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno Bipolar , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno Bipolar/genética , Niño , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
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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Estudio de Asociación del Genoma Completo , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Humanos , Persona de Mediana Edad , Putamen , TálamoRESUMEN
BACKGROUND: Parkinson's disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders. METHODS: We analyzed recent large genome-wide association studies on patients with SCZ (N = 77,096) and PD (N = 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci. RESULTS: We observed genetic enrichment in PD conditional on associations with SCZ and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PD risk loci and 1 novel SCZ locus at conditional FDR < .01. Furthermore, we identified 9 genomic loci jointly associated with PD and SCZ at conjunctional FDR < .05. There was an even distribution of antagonistic and agonistic effect directions among the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to the shared loci, 65 are expressed in the human brain and show cell type-specific expression profiles. CONCLUSIONS: Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD, indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinical features between the disorders.
Asunto(s)
Enfermedad de Parkinson , Esquizofrenia , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Esquizofrenia/genéticaRESUMEN
Cognitive impairments are considered core features in schizophrenia and other psychotic disorders. Cognitive impairments are, to a lesser degree, also documented in healthy first-degree relatives. Although recent studies have shown (negative) genetic correlations between schizophrenia and general cognitive ability, the association between polygenic risk for schizophrenia and individual cognitive phenotypes remains unclear. We here investigated the association between a polygenic score for schizophrenia (SCZPGS) and six well-defined cognitive domains, in addition to a composite measure of cognitive ability and a measure of premorbid intellectual ability in 731 participants with a psychotic disorder and 851 healthy controls. We also investigated the association between a PGS for general cognitive ability (COGPGS) and the same cognitive domains in the same sample. We found no significant associations between the SCZPGS and any cognitive phenotypes, in either patients with a psychotic disorder or healthy controls. For COGPGS we observed stronger associations with cognitive phenotypes in healthy controls than in participants with psychotic disorders. In healthy controls, the association between COGPGS (at the p value threshold of ≥0.01) and working memory remained significant after Bonferroni correction (ß = 0.12, p = 8.6 × 10-5). Altogether, the lack of associations between SCZPGS and COGPGS with cognitive performance in participants with psychotic disorders suggests that either environmental factors or unassessed genetic factors play a role in the development of cognitive impairments in psychotic disorders. Working memory should be further studied as an important cognitive phenotype.