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1.
Cell ; 157(2): 486-498, 2014 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-24725413

RESUMEN

Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of ß-amyloid (Aß)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aß-associated neurotoxicity and AD-like pathology.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Calpaína/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cognición , Quinasa 5 Dependiente de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Endocitosis , Técnicas de Sustitución del Gen , Hipocampo/metabolismo , Humanos , Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Ratones , Proteínas del Tejido Nervioso/genética , Fosfotransferasas , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis
2.
Mol Cell ; 79(3): 521-534.e15, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32592681

RESUMEN

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input "easy Hi-C" protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.


Asunto(s)
Cromatina/metabolismo , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Genoma Humano , Neurogénesis/genética , Regiones Promotoras Genéticas , Adulto , Línea Celular , Cerebro/citología , Cerebro/crecimiento & desarrollo , Cerebro/metabolismo , Cromatina/ultraestructura , Mapeo Cromosómico , Feto , Histonas/genética , Histonas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas del Tejido Nervioso/clasificación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/citología , Neuronas/metabolismo , Lóbulo Temporal/citología , Lóbulo Temporal/crecimiento & desarrollo , Lóbulo Temporal/metabolismo , Factores de Transcripción/clasificación , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
Brief Bioinform ; 25(5)2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39222061

RESUMEN

Harnessing the power of single-cell genomics technologies, single-cell Hi-C (scHi-C) and its derived technologies provide powerful tools to measure spatial proximity between regulatory elements and their target genes in individual cells. Using a global background model, we propose SnapHiC-G, a computational method, to identify long-range enhancer-promoter interactions from scHi-C data. We applied SnapHiC-G to scHi-C datasets generated from mouse embryonic stem cells and human brain cortical cells. SnapHiC-G achieved high sensitivity in identifying long-range enhancer-promoter interactions. Moreover, SnapHiC-G can identify putative target genes for noncoding genome-wide association study (GWAS) variants, and the genetic heritability of neuropsychiatric diseases is enriched for single-nucleotide polymorphisms (SNPs) within SnapHiC-G-identified interactions in a cell-type-specific manner. In sum, SnapHiC-G is a powerful tool for characterizing cell-type-specific enhancer-promoter interactions from complex tissues and can facilitate the discovery of chromatin interactions important for gene regulation in biologically relevant cell types.


Asunto(s)
Elementos de Facilitación Genéticos , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Análisis de la Célula Individual , Animales , Humanos , Ratones , Análisis de la Célula Individual/métodos , Estudio de Asociación del Genoma Completo/métodos , Genómica/métodos , Biología Computacional/métodos
4.
PLoS Genet ; 18(3): e1010102, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35259165

RESUMEN

Hi-C data provide population averaged estimates of three-dimensional chromatin contacts across cell types and states in bulk samples. Effective analysis of Hi-C data entails controlling for the potential confounding factor of differential cell type proportions across heterogeneous bulk samples. We propose a novel unsupervised deconvolution method for inferring cell type composition from bulk Hi-C data, the Two-step Hi-c UNsupervised DEconvolution appRoach (THUNDER). We conducted extensive simulations to test THUNDER based on combining two published single-cell Hi-C (scHi-C) datasets. THUNDER more accurately estimates the underlying cell type proportions compared to reference-free methods (e.g., TOAST, and NMF) and is more robust than reference-dependent methods (e.g. MuSiC). We further demonstrate the practical utility of THUNDER to estimate cell type proportions and identify cell-type-specific interactions in Hi-C data from adult human cortex tissue samples. THUNDER will be a useful tool in adjusting for varying cell type composition in population samples, facilitating valid and more powerful downstream analysis such as differential chromatin organization studies. Additionally, THUNDER estimated contact profiles provide a useful exploratory framework to investigate cell-type-specificity of the chromatin interactome while experimental data is still rare.


Asunto(s)
Cromatina , Cromatina/genética , Humanos
5.
Mol Psychiatry ; 28(1): 475-482, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36380236

RESUMEN

Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.


Asunto(s)
Trastorno del Espectro Autista , Esquizofrenia , Humanos , Esquizofrenia/genética , Estudio de Asociación del Genoma Completo , Canadá , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética
6.
Mol Psychiatry ; 27(6): 2803-2812, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35322200

RESUMEN

Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell transcriptomics, and pharmacological studies suggest an important, but untested, overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics. To directly compare genes with antipsychotic-induced differential expression to genes involved in schizophrenia, we applied single-cell RNA-sequencing to striatal samples from male C57BL/6 J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We identified differentially expressed genes in three cell populations identified from the single-cell RNA-sequencing (medium spiny neurons [MSNs], microglia, and astrocytes) and applied multiple analysis pipelines to contextualize these findings, including comparison to GWAS results for schizophrenia. In MSNs in particular, differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) from mice treated with olanzapine compared with haloperidol. DEGs were enriched in loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses of gene expression in MSNs highlighted neuron/synapse development, alternative splicing, and mitochondrial function as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. In conclusion, single-cell RNA sequencing may provide important insights into antipsychotic mechanisms of action and links to findings from psychiatric genomic studies.


Asunto(s)
Antipsicóticos , Animales , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Expresión Génica , Haloperidol/farmacología , Haloperidol/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Olanzapina , ARN
7.
Artículo en Inglés | MEDLINE | ID: mdl-37946624

RESUMEN

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity.

8.
Am J Med Genet B Neuropsychiatr Genet ; 189(5): 163-173, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35785430

RESUMEN

We present innovative research practices in psychiatric genetic studies to ensure representation of individuals from diverse ancestry, sex assigned at birth, gender identity, age, body shape and size, and socioeconomic backgrounds. Due to histories of inappropriate and harmful practices against marginalized groups in both psychiatry and genetics, people of certain identities may be hesitant to participate in research studies. Yet their participation is essential to ensure diverse representation, as it is incorrect to assume that the same genetic and environmental factors influence the risk for various psychiatric disorders across all demographic groups. We present approaches developed as part of the Eating Disorders Genetics Initiative (EDGI), a study that required tailored approaches to recruit diverse populations across many countries. Considerations include research priorities and design, recruitment and study branding, transparency, and community investment and ownership. Ensuring representation in participants is costly and funders need to provide adequate support to achieve diversity in recruitment in prime awards, not just as supplemental afterthoughts. The need for diverse samples in genetic studies is critical to minimize the risk of perpetuating health disparities in psychiatry and other health research. Although the EDGI strategies were designed specifically to attract and enroll individuals with eating disorders, our approach is broadly applicable across psychiatry and other fields.


Asunto(s)
Identidad de Género , Investigación , Femenino , Humanos , Recién Nacido , Masculino
9.
10.
Addict Biol ; 26(1): e12880, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32064741

RESUMEN

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.


Asunto(s)
Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Trastornos Relacionados con Sustancias/genética , Alcoholismo/genética , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Esquizofrenia/genética , Tabaquismo/genética
11.
Mol Psychiatry ; 24(3): 338-344, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30531935

RESUMEN

Fragile X syndrome is rare but a prominent cause of intellectual disability. It is usually caused by a de novo mutation that occurs on multiple haplotypes and thus would not be expected to be detectible using genome-wide association (GWA). We conducted GWA in 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio = 8.10, P = 2.5 × 10-10). These findings withstood robust attempts at falsification. Fine-mapping yielded a minimum P = 1.13 × 10-14, but did not narrow the interval. Comprehensive functional genomic integration did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer FMR1 CGG repeats than controls with the protective haplotype (P = 4.75 × 10-5), which may predispose toward increases in CGG number to the premutation range over many generations. This is a salutary reminder of the complexity of even "simple" monogenetic disorders.


Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Adulto , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Haplotipos/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación , Factores de Riesgo
12.
EBioMedicine ; 103: 105086, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38580523

RESUMEN

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).


Asunto(s)
Consumo de Bebidas Alcohólicas , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Fenotipo , Polimorfismo de Nucleótido Simple , Humanos , Consumo de Bebidas Alcohólicas/genética , Femenino , Estudios de Cohortes , Masculino , Fenómica , Predisposición Genética a la Enfermedad , Alcohol Deshidrogenasa/genética , Genotipo , Alelos
13.
Complex Psychiatry ; 9(1-4): 100-118, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37404872

RESUMEN

Introduction: Posttraumatic stress disorder (PTSD) is a complex multifactorial disorder influenced by the interaction of genetic and environmental factors. Analyses of epigenomic and transcriptomic modifications may help to dissect the biological factors underlying the gene-environment interplay in PTSD. To date, most human PTSD epigenetics studies have used peripheral tissue, and these findings have complex and poorly understood relationships to brain alterations. Studies examining brain tissue may help characterize the brain-specific transcriptomic and epigenomic profiles of PTSD. In this review, we compiled and integrated brain-specific molecular findings of PTSD from humans and animals. Methods: A systematic literature search according to the PRISMA criteria was performed to identify transcriptomic and epigenomic studies of PTSD, focusing on brain tissue from human postmortem samples or animal-stress paradigms. Results: Gene- and pathway-level convergence analyses revealed PTSD-dysregulated genes and biological pathways across brain regions and species. A total of 243 genes converged across species, with 17 of them significantly enriched for PTSD. Chemical synaptic transmission and signaling by G-protein-coupled receptors were consistently enriched across omics and species. Discussion: Our findings point out dysregulated genes highly replicated across PTSD studies in humans and animal models and suggest a potential role for the corticotropin-releasing hormone/orexin pathway in PTSD's pathophysiology. Further, we highlight current knowledge gaps and limitations and recommend future directions to address them.

14.
medRxiv ; 2023 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-37131804

RESUMEN

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5,000 richly-phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity.

15.
J Neurosci ; 31(44): 15751-6, 2011 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-22049418

RESUMEN

Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid ß (Aß) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aß, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aß, as well as the APP processing enzyme, ß-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aß plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aß levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aß-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aß levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aß-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aß production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/deficiencia , Ácido Aspártico Endopeptidasas/deficiencia , Quinasa 5 Dependiente de la Ciclina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Enfermedades Neurodegenerativas/patología , Sinapsis/fisiología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Análisis de Varianza , Animales , Reacción de Prevención/fisiología , Biofisica , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Muerte Celular/genética , Modelos Animales de Enfermedad , Estimulación Eléctrica/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Reacción Cataléptica de Congelación/fisiología , Lateralidad Funcional , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Hipocampo/patología , Técnicas In Vitro , Potenciación a Largo Plazo/genética , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/terapia , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Enfermedades Neurodegenerativas/complicaciones , Técnicas de Placa-Clamp , Fragmentos de Péptidos/metabolismo , Fosforilación/genética , Fosfotransferasas , Prosencéfalo/metabolismo , Prosencéfalo/patología , Sinapsis/genética , Sinaptofisina/metabolismo , Proteínas tau/metabolismo
16.
Genetics ; 218(1)2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-33693696

RESUMEN

Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176-kb candidate interval. A series of functional Xce alleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function structure basis and location of the Xce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross (CC) strains. Using published sequence data and applying a Bayesian "Pólya urn" model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20-30 cells contributing to brain. Second, CC founder strain NOD/ShiLtJ has a novel and unique functional allele, Xceg, that is the weakest in the Xce allelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xceb), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within the Xce. Copy number variation is common at the Xce locus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weak Xce alleles.


Asunto(s)
Compensación de Dosificación (Genética) , Inactivación del Cromosoma X/genética , Cromosoma X/genética , Alelos , Animales , Teorema de Bayes , Mapeo Cromosómico/métodos , Variaciones en el Número de Copia de ADN/genética , Genes Ligados a X/genética , Haplotipos , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Filogenia , ARN Largo no Codificante/genética
17.
G3 (Bethesda) ; 10(9): 3165-3177, 2020 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-32694196

RESUMEN

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (P < 0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.


Asunto(s)
Antipsicóticos , Discinesia Inducida por Medicamentos , Animales , Antipsicóticos/efectos adversos , Haloperidol/efectos adversos , Humanos , Masticación , Ratones , Fenotipo
18.
Nat Commun ; 11(1): 1842, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-32296054

RESUMEN

Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.


Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Esquizofrenia/genética , Encéfalo/metabolismo , Exoma/genética , Genoma Humano/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Sistema Nervioso/metabolismo , Control de Calidad , Análisis de Secuencia de ADN
19.
North Carol Law Rev ; 97(5): 1359-1398, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31871365

RESUMEN

Gene-environment interactions play a key role in how psychiatric disorders manifest and develop. Psychiatric genetics researchers are making progress in identifying genomic correlates of many disorders. And recently, the field of genetics has given rise to a technology that many claim will revolutionize the biological sciences and propel the field into a transformative phase: the powerful gene-editing tool known as CRISPR-Cas9. This Article illustrates which psychiatric conditions are likely to make an attractive target for CRISPR as the technology evolves and CRISPR therapies becomes a viable tool to manage or prevent disorders in a clinical setting. We examine the potential scientific and clinical challenges of applying CRISPR in the mental health context, along with the regulatory, ethical, and legal issues that might arise as a consequence of these applications.

20.
Nat Commun ; 10(1): 3310, 2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31346172

RESUMEN

Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.


Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Apolipoproteínas C/genética , Apolipoproteínas C/metabolismo , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Estudios de Casos y Controles , Cognición , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Nectinas/genética , Nectinas/metabolismo , Polimorfismo de Nucleótido Simple
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