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1.
Biol Psychiatry ; 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38821194

RESUMO

Suicide is the second leading cause of death in U.S. adolescents and young adults, and generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This paper is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that, while bulk tissue studies provide comprehensive information, single-nucleus approaches identifying cell-type specific changes are needed. While single nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches combining cell-type specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression, and how these interact with epigenetic marks, single nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole genome sequencing and genome-wide association databases. The workshop concluded with the recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarkers discovery, to guide suicide prevention.

2.
Nat Commun ; 14(1): 2613, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37188697

RESUMO

Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes. We performed TWAS in healthy term placentae (N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain (N = 166) and additional placenta TWAS for other disorders/traits. The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness. These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies. Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone.


Assuntos
COVID-19 , Esquizofrenia , Gravidez , Feminino , Humanos , Placenta/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , COVID-19/metabolismo , SARS-CoV-2 , Trofoblastos/metabolismo
3.
Am J Psychiatry ; 179(3): 226-241, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35236118

RESUMO

OBJECTIVE: The authors sought to study the transcriptomic and genomic features of completed suicide by parsing the method chosen, to capture molecular correlates of the distinctive frame of mind of individuals who die by suicide, while reducing heterogeneity. METHODS: The authors analyzed gene expression (RNA sequencing) from postmortem dorsolateral prefrontal cortex of patients who died by suicide with violent compared with nonviolent means, nonsuicide patients with the same psychiatric disorders, and a neurotypical group (total N=329). They then examined genomic risk scores (GRSs) for each psychiatric disorder included, and GRSs for cognition (IQ) and for suicide attempt, testing how they predict diagnosis or traits (total N=888). RESULTS: Patients who died by suicide by violent means showed a transcriptomic pattern remarkably divergent from each of the other patient groups but less from the neurotypical group; consistently, their genomic profile of risk was relatively low for their diagnosed illness as well as for suicide attempt, and relatively high for IQ: they were more similar to the neurotypical group than to other patients. Differentially expressed genes (DEGs) associated with patients who died by suicide by violent means pointed to purinergic signaling in microglia, showing similarities to a genome-wide association study of Drosophila aggression. Weighted gene coexpression network analysis revealed that these DEGs were coexpressed in a context of mitochondrial metabolic activation unique to suicide by violent means. CONCLUSIONS: These findings suggest that patients who die by suicide by violent means are in part biologically separable from other patients with the same diagnoses, and their behavioral outcome may be less dependent on genetic risk for conventional psychiatric disorders and be associated with an alteration of purinergic signaling and mitochondrial metabolism.


Assuntos
Suicídio Consumado , Encéfalo , Estudo de Associação Genômica Ampla , Humanos , Transcriptoma/genética , Violência/psicologia
6.
Proc Natl Acad Sci U S A ; 118(7)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33558239

RESUMO

Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.


Assuntos
Encéfalo/anatomia & histologia , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Placenta/metabolismo , Esquizofrenia/genética , Transcriptoma , Encéfalo/fisiologia , Cognição , Feminino , Loci Gênicos , Humanos , Lactente , Recém-Nascido , Masculino , Tamanho do Órgão/genética , Gravidez
7.
Psychiatr Genet ; 29(5): 200-210, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31465000

RESUMO

The brain-derived neurotrophic factor (BDNF) is a secretory growth factor that promotes neuronal proliferation and survival, synaptic plasticity and long-term potentiation in the central nervous system. Brain-derived neurotrophic factor biosynthesis and secretion are chrono-topically regulated processes at the cellular level, accounting for specific localizations and functions. Given its role in regulating brain development and activity, BDNF represents a potentially relevant gene for schizophrenia, and indeed BDNF and its non-synonymous functional variant, rs6265 (C → T, Val → Met) have been widely studied in psychiatric genetics. Human and animal studies have indicated that brain-derived neurotrophic factor is relevant for schizophrenia-related phenotypes, and that: (1) fine-tuned regulation of brain-derived neurotrophic factor secretion and activity is necessary to guarantee brain optimal development and functioning; (2) the Val → Met substitution is associated with impaired activity-dependent secretion of brain-derived neurotrophic factor; (3) disruption of brain-derived neurotrophic factor signaling is associated with altered synaptic plasticity and neurodevelopment. However, genome-wide association studies failed to associate the BDNF locus with schizophrenia, even though a sub-threshold association exists. Here, we will review studies focused on the relationship between the genetic variation of BDNF and schizophrenia, trying to fill the gap between genetic risk per se and insights from molecular biology. A deeper understanding of brain-derived neurotrophic factor biology and of the epigenetic regulation of brain-derived neurotrophic factor and its interactome during development may help clarifying the potential role of this gene in schizophrenia, thus informing development of brain-derived neurotrophic factor-based strategies of prevention and treatment of this disorder.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Esquizofrenia/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epigênese Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
8.
Forensic Sci Int ; 298: 402-407, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30953975

RESUMO

The term overkill usually indicates the infliction of massive injuries by far exceeding the extent necessary to kill the victim. Only few articles or textbooks report this term that is mostly associated with sex-motivated homicides where injuries, generally stabbing, are directed to significant sexual parts of the body. The aim of this study is to shed light on the phenomenon of overkill by reviewing some cases personally analyzed by the authors from both a forensic pathology rather than forensic psychiatry views. The reported results coupled with the literature revision confirmed the importance of a complete analysis of all criminological elements for better defining overkill cases.


Assuntos
Homicídio/psicologia , Adolescente , Adulto , Feminino , Psiquiatria Legal , Humanos , Defesa por Insanidade , Inteligência , Masculino , Transtornos Mentais/psicologia , Motivação , Traumatismo Múltiplo/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Armas , Ferimentos Perfurantes/psicologia
9.
Biol Psychiatry ; 85(5): 417-424, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30600091

RESUMO

BACKGROUND: Previous findings suggest that differences in brain expression of a human-specific long intergenic noncoding RNA (LINC01268; GRCh37/hg19: LOC285758) may be linked to suicide by violent methods. We sought to replicate and extend these findings in a new sample and translate the results to the behavioral level in living healthy subjects. METHODS: We examined RNA sequencing data in human brains to confirm the prior postmortem association of the long intergenic noncoding RNA specifically with suicide by violent means. In addition, we used a genetic variant associated with LINC01268 expression to detect association in healthy subjects with trait aggression and with in vivo prefrontal physiology related to behavioral control. Finally, we performed weighted gene coexpression network analysis and gene ontology analysis to identify biological processes associated with a LINC01268 coexpression network. RESULTS: In the replication sample, prefrontal expression of LINC01268 was again higher in suicides by violent means (n = 65) than in both nonsuicides (n = 78; p = 1.29 × 10-6) and suicides by nonviolent means (n = 46; p = 1.4 × 10-6). In the living cohort, carriers of the minor allele of a single nucleotide polymorphism associated with increased LINC01268 expression in brain scored higher on a lifetime aggression questionnaire and show diminished engagement of prefrontal cortex (Brodmann area 10) when viewing angry faces during functional magnetic resonance imaging. Weighted gene coexpression network analysis highlighted the immune response. CONCLUSIONS: These results suggest that LINC01268 influences emotional regulation, aggressive behavior, and suicide by violent means; the underlying biological dynamics may include modulation of genes potentially engaged in the immune response.


Assuntos
Agressão/fisiologia , Encéfalo/metabolismo , Córtex Pré-Frontal/fisiologia , RNA não Traduzido/biossíntese , RNA não Traduzido/fisiologia , Suicídio/psicologia , Violência , Adulto , Causas de Morte , Feminino , Neuroimagem Funcional , Redes Reguladoras de Genes/genética , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Fenótipo , Análise de Sequência de RNA
10.
Prog Mol Biol Transl Sci ; 158: 195-226, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30072054

RESUMO

Schizophrenia is a complex disorder of the brain, where genetic variants explain only a portion of risk. Neuroepigenetic mechanisms may explain the remaining share of risk, as well as the transition from susceptibility to the actual disease. Here, we discuss the most recent findings in the field of brain epigenetics applied to the study of schizophrenia. Methylome studies have found several candidates exhibiting methylation modifications in association with the disorder, but genes affected do not always overlap. Notably, these studies converge in that genes within the schizophrenia risk loci or genes differentially methylated in patients affected with the disorder are dynamically regulated during early life. They also imply that schizophrenia-associated genetic variation may affect DNA methylation in fetal and adult brains. Histone modifications may help mediating the effect of genetic risk variants associated with schizophrenia, and regulating chromatin higher-order structure. The 3D-organization of chromatin in the brain creates physical interactions within chromosomes, so that schizophrenia-associated genetic variants can be linked with genes distant from their loci; this suggests that chromatin conformation matters in the mechanism of risk for the disorder. Non-coding RNAs provide a novel and complex mechanism of gene regulation potentially significant for schizophrenia, as proposed by research on specific microRNAs and long non-coding RNAs (lncRNAs). Finally, a recent study in epitranscriptomics identifies RNA methylation as a further epigenetic mechanism active in human brain and specifically in a portion of the transcriptome associated with schizophrenia susceptibility. These findings indicate that, as expected from the complexity of the brain and its development, several epigenetic mechanisms may intervene in the etiopathogenesis of schizophrenia. An understanding of their roles calls for research approaches integrating the investigation of different epigenetic mechanisms and of environmental and genetic risk, in the context of development.


Assuntos
Epigênese Genética , Esquizofrenia/genética , Animais , Biomarcadores/sangue , Cromatina/metabolismo , Metilação de DNA/genética , Predisposição Genética para Doença , Humanos , Esquizofrenia/sangue
11.
Nat Med ; 24(6): 792-801, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29808008

RESUMO

Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study-derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.


Assuntos
Predisposição Genética para Doença , Placenta/patologia , Esquizofrenia/genética , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Acontecimentos que Mudam a Vida , Masculino , Herança Multifatorial/genética , Placenta/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Fatores de Risco , Caracteres Sexuais
12.
Epigenetics ; 11(1): 11-23, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26889735

RESUMO

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val(66)Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Metilação de DNA , Epigênese Genética , Genótipo , Esquizofrenia/genética , Alelos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Interação Gene-Ambiente , Proteínas de Homeodomínio/metabolismo , Humanos , Hipóxia/fisiopatologia , Memória de Curto Prazo , Metionina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/genética , Ligação Proteica , Fatores de Risco , Valina
13.
J Forensic Sci ; 59(1): 274-80, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24020455

RESUMO

Folie à deux is a rare clinical syndrome characterized by the transference of delusional ideas from one person to one or more other people in close association with the primary affected patient. Mummification indicates the preservation of the corpse of a person for a variable period of time. A brief review of the literature in this field is presented, and an exceptional case is described, characterized by the association of both these rare phenomena. The case is an example of folie à fammille which developed out of a condition of extreme religiousness and seclusion of an entire family. The shared psychosis led to the horrible death of some of the family members, while the last surviving member of the family lived for more than a year and a half with their mummified remains. The Judge commissioned a forensic psychiatry assessment to verify the survivor's ability to bear witness. The development of the psychiatric syndrome and its consequences are extensively discussed.


Assuntos
Múmias , Religião , Transtorno Paranoide Compartilhado/psicologia , Idoso , Família , Feminino , Psiquiatria Legal , Humanos , Itália , Masculino , Isolamento Social
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