RESUMEN
First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Asunto(s)
Trastorno Bipolar/patología , Disfunción Cognitiva/patología , Escolaridad , Predisposición Genética a la Enfermedad , Inteligencia/fisiología , Neuroimagen , Esquizofrenia/patología , Trastorno Bipolar/complicaciones , Trastorno Bipolar/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Familia , Humanos , Imagen por Resonancia Magnética , Esquizofrenia/complicaciones , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/etiologíaRESUMEN
Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.
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Trastorno Bipolar , Trastorno Bipolar/genética , Encéfalo/diagnóstico por imagen , Ligamiento Genético/genética , Humanos , Linaje , Fenotipo , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.
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Antidepresivos , Trastorno Depresivo Mayor , Interacciones Farmacológicas , Prescripción Inadecuada , Pruebas de Farmacogenómica , Antidepresivos/metabolismo , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Toma de Decisiones Clínicas , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Interacciones Farmacológicas/genética , Femenino , Humanos , Prescripción Inadecuada/prevención & control , Masculino , Persona de Mediana Edad , Farmacogenética , Inducción de Remisión , Resultado del Tratamiento , Estados Unidos , United States Department of Veterans AffairsRESUMEN
BACKGROUND: A national Department of Veterans Affairs (VA) mental health (MH) quality metric tracks engagement in outpatient MH care after discharge from residential and inpatient settings, with recommendations for 2 or more visits 30 days postdischarge. LOCAL PROBLEM: A gap in transitioning patients from residential to outpatient MH care was identified at this site. METHODS: A transition management process was developed and piloted, including a new MH Discharge Consult and an RN Transition Care Managers team. INTERVENTIONS: Transition Care Managers triaged Discharge Consults, communicated with schedulers and patients pre- and postdischarge, and tracked MH engagement for 30 days postdischarge. Process, outcome, and balancing measures were developed and iteratively adjusted using Plan-Do-Study-Act (PDSA) cycles. RESULTS: Over 55 weeks, 443 Discharge Consults were placed. There was an average 89% success rate in connecting patients with 2 or more MH visits versus 53% preintervention. CONCLUSIONS: This pilot showed promising results in improving postdischarge MH engagement with the use of PDSA cycles to collect data and refine processes.
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Salud Mental , Veteranos , Cuidados Posteriores , Atención Ambulatoria , Transición de la Salud , Humanos , Pacientes Ambulatorios , Alta del Paciente , Estados Unidos , United States Department of Veterans Affairs , Veteranos/psicologíaRESUMEN
BACKGROUND: Disturbed sleep and activity are prominent features of bipolar disorder type I (BP-I). However, the relationship of sleep and activity characteristics to brain structure and behavior in euthymic BP-I patients and their non-BP-I relatives is unknown. Additionally, underlying genetic relationships between these traits have not been investigated. METHODS: Relationships between sleep and activity phenotypes, assessed using actigraphy, with structural neuroimaging (brain) and cognitive and temperament (behavior) phenotypes were investigated in 558 euthymic individuals from multi-generational pedigrees including at least one member with BP-I. Genetic correlations between actigraphy-brain and actigraphy-behavior associations were assessed, and bivariate linkage analysis was conducted for trait pairs with evidence of shared genetic influences. RESULTS: More physical activity and longer awake time were significantly associated with increased brain volumes and cortical thickness, better performance on neurocognitive measures of long-term memory and executive function, and less extreme scores on measures of temperament (impulsivity, cyclothymia). These associations did not differ between BP-I patients and their non-BP-I relatives. For nine activity-brain or activity-behavior pairs there was evidence for shared genetic influence (genetic correlations); of these pairs, a suggestive bivariate quantitative trait locus on chromosome 7 for wake duration and verbal working memory was identified. CONCLUSIONS: Our findings indicate that increased physical activity and more adequate sleep are associated with increased brain size, better cognitive function and more stable temperament in BP-I patients and their non-BP-I relatives. Additionally, we found evidence for pleiotropy of several actigraphy-behavior and actigraphy-brain phenotypes, suggesting a shared genetic basis for these traits.
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Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Trastorno Bipolar/psicología , Encéfalo/patología , Sueño , Actigrafía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cognición , Familia , Femenino , Humanos , Patrón de Herencia/genética , Modelos Lineales , Masculino , Memoria a Corto Plazo , Persona de Mediana Edad , Linaje , Fenotipo , Temperamento , Adulto JovenRESUMEN
Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes.
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Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Ritmo Circadiano , Sueño , Actigrafía , Cromosomas Humanos Par 1/genética , Familia , Femenino , Humanos , Patrón de Herencia/genética , Escala de Lod , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Carácter Cuantitativo HeredableRESUMEN
Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.
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Trastorno Bipolar/genética , Trastorno Bipolar/patología , Encéfalo/patología , Predisposición Genética a la Enfermedad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Adulto JovenRESUMEN
The central sulcus (CS) divides the pre- and postcentral gyri along the dorsal-ventral plane of which all motor and sensory functions are topographically organized. The motor-hand area of the precentral gyrus or KNOB has been described as the anatomical substrate of the hand in humans. Given the importance of the hand in primate evolution, here we examine the evolution of the motor-hand area by comparing the relative size and pattern of cortical folding of the CS surface area from magnetic resonance images in 131 primates, including Old World monkeys, apes and humans. We found that humans and great apes have a well-formed motor-hand area that can be seen in the variation in depth of the CS along the dorsal-ventral plane. We further found that great apes have relatively large CS surface areas compared to Old World monkeys. However, relative to great apes, humans have a small motor-hand area in terms of both adjusted and absolute surface areas.
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Evolución Biológica , Mano/fisiología , Corteza Sensoriomotora/anatomía & histología , Animales , Encéfalo/anatomía & histología , Chlorocebus aethiops , Femenino , Gorilla gorilla , Humanos , Hylobates , Macaca radiata , Imagen por Resonancia Magnética , Masculino , Pan paniscus , Pan troglodytes , Papio anubis , Pongo pygmaeus , Especificidad de la EspecieRESUMEN
Perinatal depression (PND) affects up to 20% of women and is associated with significant impairment and disability in affected women. In addition, perinatal depression is associated with broader public health and multigenerational consequences. Innovative approaches are needed to reduce the burden of perinatal depression through identification, tracking, and treatment of depressive symptoms during the perinatal period. This study is a randomized clinical trial comparing the relative efficacy of a multi-tiered system of care, Screening and Treatment of Anxiety and Depression (STAND) to perinatal care delivered by a reproductive psychiatrist in reducing symptoms of depression and anxiety. A sample of 167 individuals was randomized between week 28 of pregnancy and 6 months postpartum. A secondary aim compares the original online therapy intervention used in the first half of the study to a newer online therapy program used in the second half of the study for individuals assigned to the STAND treatment. The study measures, intervention groups, and analysis methods are described, as well as expected implications. The findings from this study may improve the methods for tracking symptom changes over time, monitoring treatment response, and providing personalized care for individuals with PND. As such, this study may improve the lives of patients with PND and their families and lower the related health care costs to society.Trial registration NCT: 9/24/2021NCT direct link: https://www.clinicaltrials.gov/study/NCT05056454?term=NCT05056454&rank=1&a=1 .
Asunto(s)
Ansiedad , Depresión , Atención Perinatal , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Femenino , Embarazo , Depresión/terapia , Depresión/diagnóstico , Depresión/psicología , Atención Perinatal/métodos , Ansiedad/terapia , Ansiedad/psicología , Resultado del Tratamiento , Adulto , Afecto , Intervención basada en la Internet , Complicaciones del Embarazo/terapia , Complicaciones del Embarazo/psicología , Factores de Tiempo , Depresión Posparto/terapia , Depresión Posparto/diagnóstico , Depresión Posparto/psicologíaRESUMEN
BACKGROUND: The global burden of anxiety and depression has created an urgent need for scalable approaches to increase access to evidence-based mental health care. The Screening and Treatment for Anxiety and Depression (STAND) system of care was developed to meet this need through the use of internet-connected devices for assessment and provision of treatment. STAND triages to level of care (monitoring only, digital therapy with coaches, digital therapy assisted by clinicians in training, and clinical care) and then continuously monitors symptoms to adapt level of care. Triaging and adaptation are based on symptom severity and suicide risk scores obtained from computerized adaptive testing administered remotely. OBJECTIVE: This article discusses how the STAND system of care improves upon current clinical paradigms, and presents preliminary data on feasibility, acceptability, and effectiveness of STAND in a sample of US-based university students. METHODS: US-based university students were recruited and enrolled in an open trial of the STAND system of care. Participants were triaged based on initial symptom severity derived from a computerized adaptive test and monitored over 40 weeks on anxiety, depression, and suicide risk to inform treatment adaptation and evaluate preliminary effectiveness. RESULTS: Nearly 5000 students were screened and 516 received care. Depression and anxiety severity scores improved across all tiers (P<.001 in all cases). Suicide risk severity improved in the highest tier (ie, clinical care; P<.001). Acceptability and feasibility were demonstrated. CONCLUSIONS: STAND is a feasible and acceptable model of care that can reach large numbers of individuals. STAND showed preliminary effectiveness on all primary outcome measures. Current directions to improve STAND are described.
RESUMEN
Vervet monkeys are a frequently studied animal model in neuroscience research. Although equally distantly related to humans, the ancestors of vervets diverged from those of macaques and baboons more than 11 million years ago, antedating the divergence of the ancestors of humans, chimpanzees and gorillas. To facilitate anatomic localization in the vervet brain, two linked on-line electronic atlases are described, one based on registered MRI scans from hundreds of vervets (http://www.loni.ucla.edu/Research/Atlases/Data/vervet/vervetmratlas/vervetmratlas.html) and the other based on a high-resolution cryomacrotome study of a single vervet (http://www.loni.ucla.edu/Research/Atlases/Data/vervet/vervetatlas/vervetatlas.html). The averaged MRI atlas is also available as a volume in Neuroimaging Informatics Technology Initiative format. In the cryomacrotome atlas, various sulcal and subcortical structures have been anatomically labeled and surface rendered views are provided along the primary planes of section. Both atlases simultaneously provide views in all three primary planes of section, rapid navigation by clicking on the displayed images, and stereotaxic coordinates in the averaged MRI atlas space. Despite the extended time period since their divergence, the major sulcal and subcortical landmarks in vervets are highly conserved relative to those described in macaques.
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Atlas como Asunto , Encéfalo/anatomía & histología , Chlorocebus aethiops/anatomía & histología , Internet , Animales , Mapeo Encefálico , Gráficos por Computador , Interpretación Estadística de Datos , Procesamiento de Imagen Asistido por Computador , Informática , Macaca mulatta , Imagen por Resonancia Magnética , Especificidad de la Especie , Técnicas EstereotáxicasRESUMEN
The area and volume of brain structural features, as assessed by high-resolution three-dimensional magnetic resonance imaging (MRI), are among the most heritable measures relating to the human CNS. We have conducted MRI scanning of all available monkeys >2 years of age (n = 357) from the extended multigenerational pedigree of the Vervet Research Colony (VRC). Using a combination of automated and manual segmentation we have quantified several correlated but distinct brain structural phenotypes. The estimated heritabilities (h(2)) for these measures in the VRC are higher than those reported previously for such features in humans or in other nonhuman primates: total brain volume (h(2) = 0.99, SE = 0.06), cerebral volume (h(2) = 0.98, SE = 0.06), cerebellar volume (h(2) = 0.86, SE = 0.09), hippocampal volume (h(2) = 0.95, SE = 0.07) and corpus callosum cross-sectional areas (h(2) = 0.87, SE = 0.07). These findings indicate that, in the controlled environment and with the inbreeding structure of the VRC, additive genetic factors account for almost all of the observed variance in brain structure, and suggest the potential of the VRC for genetic mapping of quantitative trait loci underlying such variance.
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Encéfalo/anatomía & histología , Envejecimiento/fisiología , Animales , Atlas como Asunto , Encéfalo/crecimiento & desarrollo , Mapeo Encefálico , Cerebelo/anatomía & histología , Cerebelo/crecimiento & desarrollo , Chlorocebus aethiops , Cuerpo Calloso/anatomía & histología , Cuerpo Calloso/crecimiento & desarrollo , Femenino , Variación Genética , Hipocampo/anatomía & histología , Hipocampo/crecimiento & desarrollo , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Linaje , Fenotipo , Predominio SocialRESUMEN
Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.
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Trastorno Bipolar , Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
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Trastorno Bipolar , Encéfalo/patología , Predisposición Genética a la Enfermedad , Esquizofrenia , Adulto , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/genética , Esquizofrenia/patología , Adulto JovenRESUMEN
Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Aß1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aß1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aß1-40 and p-tau181 as potentially valuable biomarkers of these processes.
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Envejecimiento , Péptidos beta-Amiloides , Encéfalo/patología , Angiopatía Amiloide Cerebral , Chlorocebus aethiops , Enfermedades de los Monos , Fragmentos de Péptidos , Proteínas tau , Envejecimiento/líquido cefalorraquídeo , Envejecimiento/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/genética , Animales , Biomarcadores/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/genética , Cromosomas de los Mamíferos , Femenino , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Masculino , Modelos Animales , Enfermedades de los Monos/líquido cefalorraquídeo , Enfermedades de los Monos/genética , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/genética , Neuroimagen/métodos , Tamaño de los Órganos , Linaje , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/genética , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genéticaRESUMEN
By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.
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Chlorocebus aethiops/genética , Perfilación de la Expresión Génica , Variación Genética , Sitios de Carácter Cuantitativo/genética , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Chlorocebus aethiops/crecimiento & desarrollo , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Redes Reguladoras de Genes/fisiología , Biosíntesis de Proteínas/fisiología , Proteínas de Unión al ARN/fisiología , Sinapsis/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/fisiología , Proteómica/métodosRESUMEN
IMPORTANCE: Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes. OBJECTIVE: To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN, SETTING, AND PARTICIPANTS: Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I. MAIN OUTCOMES AND MEASURES: Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes. RESULTS: Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.
Asunto(s)
Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad/genética , Fenotipo , Adulto , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/psicología , Encéfalo/patología , Corteza Cerebral/patología , Femenino , Ligamiento Genético , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Tamaño de los Órganos/fisiología , Linaje , Estadística como Asunto , TemperamentoRESUMEN
Brain asymmetries, particularly asymmetries within regions associated with language, have been suggested as a key difference between humans and our nearest ancestors. These regions include the planum temporale (PT) - the bank of tissue that lies posterior to Heschl's gyrus and encompasses Wernicke's area, an important brain region involved in language and speech in the human brain. In the human brain, both the surface area and the grey matter volume of the PT are larger in the left compared to right hemisphere, particularly among right-handed individuals. Here we compared the grey matter volume and asymmetry of the PT in chimpanzees and three other species of nonhuman primate in two Genera including vervet monkeys (Chlorocebus aethiops sabaeus), rhesus macaques (Macaca mulatta) and bonnet macaques (Macaca radiata). We show that the three monkey species do not show population-level asymmetries in this region whereas the chimpanzees do, suggesting that the evolutionary brain development that gave rise to PT asymmetry occurred after our split with the monkey species, but before our split with the chimpanzees.