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OBJECTIVES: To describe individual views, wishes, and preferences for end of life care and to report UK anaesthetists' personal perspectives. METHODS: The 'bigconversations' questionnaire was developed by modifying an existing framework for end of life discussions. An online cross-sectional survey of UK anaesthetists was then conducted using the questionnaire in January 2019. RESULTS: The bigconversations questionnaire was validated as measuring the important aspects of end of life care by an expert panel and was found to have moderate test-retest reliability. Responses were received from 760/1913 (40%) of those invited to take part. Overall, 698/760 (92%) of respondents wished to be well informed about their condition and prognosis and 518/760 (68%) wanted to be heavily involved in decision-making about their health. Meanwhile, 639/760 (84%) of respondents would choose to forego treatment aimed at prolonging life should that life be of poor quality. The desire to spend time with family was a theme which arose from the qualitative analysis. CONCLUSION: This study provides the first systematic description of UK doctors', specifically anaesthetists', personal preferences for end of life care. Broad trends were identified: to be well informed; to avoid high-intensity medical treatments if terminally unwell; to spend remaining time with family and friends; and to be symptom-free and well cared for. However, a substantial minority expressed different, indeed opposite, opinions. This variation highlights that good quality end of life care must be driven by discussion of an individual's values, wishes, and preferences.
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Anestesistas/psicología , Anestesistas/estadística & datos numéricos , Prioridad del Paciente/estadística & datos numéricos , Encuestas y Cuestionarios/estadística & datos numéricos , Cuidado Terminal/psicología , Cuidado Terminal/estadística & datos numéricos , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prioridad del Paciente/psicología , Reino UnidoRESUMEN
It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.
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Trastorno Depresivo Mayor/genética , Síndrome Metabólico/genética , Factores de Edad , Edad de Inicio , Índice de Masa Corporal , Factores de Riesgo Cardiometabólico , Estudios de Casos y Controles , Comorbilidad , Enfermedad de la Arteria Coronaria/genética , Bases de Datos Genéticas , Depresión/genética , Depresión/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Diabetes Mellitus Tipo 2/genética , Femenino , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Síndrome Metabólico/fisiopatología , Herencia Multifactorial/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Accidente Cerebrovascular/genéticaRESUMEN
BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.
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Trastorno Depresivo Mayor , Alelos , Depresión , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad , Antígenos HLA , Haplotipos , Humanos , Complejo Mayor de HistocompatibilidadRESUMEN
INTRODUCTION: Advance care planning is a means for patients to communicate their wishes, fears and desires for future health decisions should they lose the ability to consider or communicate these. Despite being supported by governments and healthcare leaders, uptake amongst the general population remains low. Nurses play a crucial role in promoting and engaging with these discussions given their close relationship with patients and families in a range of clinical settings. AIM: To describe the barriers that nurses and healthcare professionals believe prevent them from exploring advance care planning with their patients. METHOD: We carried out a systematic review of peer-reviewed journal articles from the databases MEDLINE, Embase, CINAHL Plus, Web of Science and ProQuest Central, guided by the PRISMA checklist. RESULTS: Eleven articles were identified: all were self-reporting surveys using a mix of open and closed questions. They originated in the USA, Canada, Australia and Ireland. The participants included various healthcare professionals, with the majority of studies focussing on nurses. The two most important barriers to advance care planning are lack of education and insufficient time. Advance care planning appears to be well supported, and nurses and healthcare professionals report themselves to be comfortable and confident to take on the responsibility. CONCLUSION: There is a need for greater education and training for nurses and healthcare professionals. In particular, there needs to be better understanding of professional and legal responsibilities. The need for sufficient time to be made available to allow these conversations, in often busy settings, will need institutional and financial support. RELEVANCE TO CLINICAL PRACTICE: Increased training and knowledge are likely to lead to more positive attitudes and greater confidence for nurses, and other healthcare professionals, which should help support and encourage patient engagement with advance care planning.
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Planificación Anticipada de Atención , Actitud del Personal de Salud , Educación en Enfermería , Femenino , Personal de Salud/educación , Humanos , Participación del Paciente/psicología , Encuestas y CuestionariosRESUMEN
Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.
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Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Translocación Genética/genética , Adulto , Animales , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 11/genética , Imagen de Difusión Tensora/métodos , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Trastornos Mentales/genética , Ratones , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Sustancia Blanca/metabolismo , Sustancia Blanca/fisiologíaRESUMEN
The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.
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Cromosomas Humanos Par 16/genética , Trastornos Mentales/genética , FN-kappa B/metabolismo , Anomalías Múltiples/genética , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Proliferación Celular , Duplicación Cromosómica/genética , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , FN-kappa B/genética , Neuroimagen/métodos , Neuronas , Organoides/fisiología , Transducción de Señal , Células Madre/fisiologíaRESUMEN
The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of the translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether, our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.
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Proteínas Portadoras/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Translocación Genética , Proteínas Adaptadoras del Transporte Vesicular , Animales , Proteínas Portadoras/genética , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Modelos Animales , Trastornos del Humor/genética , Mutación , Proteínas del Tejido Nervioso/genética , Plasticidad Neuronal , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Análisis de Secuencia de ARN , Sinapsis/metabolismoRESUMEN
Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes.
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Trastornos Mentales/genética , Análisis de Secuencia de ADN/métodos , Adulto , Alelos , Contactinas/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Familia/psicología , Femenino , Frecuencia de los Genes/genética , Ligamiento Genético/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Genómica , Genotipo , Humanos , Escala de Lod , Masculino , Trastornos Mentales/fisiopatología , Persona de Mediana Edad , Trastornos del Humor/genética , Herencia Multifactorial , Proteínas del Tejido Nervioso/genética , Linaje , Fenotipo , ARN Largo no Codificante , ARN Mensajero/genética , Receptor del Glutamato Metabotropico 5/genética , Proteínas Recombinantes de Fusión/genética , Translocación GenéticaRESUMEN
Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.
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BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10-9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10-9). CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.
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Depresión/genética , Trastorno Depresivo/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Ácido Anhídrido Hidrolasas/genética , Estudio de Asociación del Genoma Completo , Humanos , Proteínas de Neoplasias/genética , Fenotipo , Población Blanca/genéticaRESUMEN
Rare genetic variants of large effect can help elucidate the pathophysiology of brain disorders. Here we expand the clinical and genetic analyses of a family with a (1;11)(q42;q14.3) translocation multiply affected by major psychiatric illness and test the effect of the translocation on the structure and function of prefrontal, and temporal brain regions. The translocation showed significant linkage (LOD score 6.1) with a clinical phenotype that included schizophrenia, schizoaffective disorder, bipolar disorder, and recurrent major depressive disorder. Translocation carriers showed reduced cortical thickness in the left temporal lobe, which correlated with general psychopathology and positive psychotic symptom severity. They showed reduced gyrification in prefrontal cortex, which correlated with general psychopathology severity. Translocation carriers also showed significantly increased activation in the caudate nucleus on increasing verbal working memory load, as well as statistically significant reductions in the right dorsolateral prefrontal cortex glutamate concentrations. These findings confirm that the t(1;11) translocation is associated with a significantly increased risk of major psychiatric disorder and suggest a general vulnerability to psychopathology through altered cortical structure and function, and decreased glutamate levels.
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BACKGROUND: Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI. RESULTS: Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes. CONCLUSIONS: Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on neurologically important pathways. Further work is required to investigate the underlying mechanisms and functional consequences of the observed differences in methylation.
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Trastorno Bipolar/genética , Metilación de ADN , Trastorno Depresivo Mayor/genética , Familia , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Femenino , Ontología de Genes , Estudio de Asociación del Genoma Completo , Haplotipos , Heterocigoto , Humanos , Masculino , EscociaRESUMEN
Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Herencia Multifactorial/genética , Esquizofrenia/genética , Trastorno Bipolar/genética , Estudios de Casos y Controles , Trastorno Depresivo Mayor/genética , Familia , Humanos , Patrón de Herencia/genética , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.
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Edad de Inicio , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad , Adolescente , Adulto , Anciano , Estudios de Cohortes , Salud de la Familia , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Prevalencia , Sistema de Registros , Factores de Riesgo , Escocia/epidemiología , Factores Sexuales , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVE: Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3). METHOD: Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33). RESULTS: We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity. CONCLUSIONS: We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis.
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Trastorno Bipolar/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 1/genética , Trastorno Ciclotímico/genética , Trastorno Depresivo Mayor/genética , Imagen de Difusión Tensora , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Translocación Genética , Sustancia Blanca/patología , Adolescente , Adulto , Trastorno Bipolar/patología , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 11/ultraestructura , Cuerpo Calloso/patología , Trastorno Ciclotímico/patología , Trastorno Depresivo Mayor/patología , Exones/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/fisiología , Esquizofrenia/patología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.
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Although many pathogenic copy number variations (CNVs) are associated with neuropsychiatric diseases, few of them have been functionally characterised. Here we report multiple schizophrenia cases with CNV abnormalities specific to unc-51-like kinase 4 (ULK4), a serine/threonine kinase gene. Deletions spanning exons 21-34 of ULK4 were present in 4 out of 3391 schizophrenia patients from the International Schizophrenia Consortium, but absent in 3181 controls. Deletions removing exons 33 and 34 of the large splice variant of ULK4 also were enriched in Icelandic schizophrenia and bipolar patients compared with 98,022 controls (Pâ=â0.0007 for schizophrenia plus bipolar disorder). Combining the two cohorts gives a P-value less than 0.0001 for schizophrenia, or for schizophrenia plus bipolar disorder. The expression of ULK4 is neuron-specific and developmentally regulated. ULK4 modulates multiple signalling pathways that include ERK, p38, PKC and JNK, which are involved in stress responses and implicated in schizophrenia. Knockdown of ULK4 disrupts the composition of microtubules and compromises neuritogenesis and cell motility. Targeted Ulk4 deletion causes corpus callosum agenesis in mice. Our findings indicate that ULK4 is a rare susceptibility gene for schizophrenia.
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Variaciones en el Número de Copia de ADN/genética , Neuritas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Esquizofrenia/genética , Animales , Movimiento Celular/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Neuritas/patología , Neuronas/metabolismo , Neuronas/patología , Esquizofrenia/etiología , Esquizofrenia/patología , Eliminación de SecuenciaRESUMEN
BACKGROUND: Copy number variants (CNVs) have been shown to play a role in schizophrenia and intellectual disability. METHODS: We compared the CNV burden in 66 patients with intellectual disability and no symptoms of psychosis (ID-only) with the burden in 64 patients with intellectual disability and schizophrenia (ID + SCZ). Samples were genotyped on three plates by the Broad Institute using the Affymetrix 6.0 array. RESULTS: For CNVs larger than 100 kb, there was no difference in the CNV burden of ID-only and ID + SCZ. In contrast, the number of duplications larger than 1 Mb was increased in ID + SCZ compared to ID-only. We detected seven large duplications and two large deletions at chromosome 15q11.2 (18.5-20.1 Mb) which were all present in patients with ID + SCZ. The involvement of this region in schizophrenia was confirmed in Scottish samples from the ISC study (N = 2,114; 1,130 cases and 984 controls). Finally, one of the patients with schizophrenia and low IQ carrying a duplication at 15q11.2, is a member of a previously described pedigree with multiple cases of mild intellectual disability, schizophrenia, hearing impairment, retinitis pigmentosa and cataracts. DNA samples were available for 11 members of this family and the duplication was present in all 10 affected individuals and was absent in an unaffected individual. CONCLUSIONS: Duplications at 15q11.2 (18.5-20.1 Mb) are highly prevalent in a severe group of patients characterized by intellectual disability and comorbid schizophrenia. It is also associated with a phenotype that includes schizophrenia, low IQ, hearing and visual impairments resembling the spectrum of symptoms described in "ciliopathies."
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Estudio de Asociación del Genoma Completo , Encuestas Epidemiológicas , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Esquizofrenia/complicaciones , Esquizofrenia/genética , Duplicación Cromosómica/genética , Segregación Cromosómica/genética , Cromosomas Humanos Par 15/genética , Femenino , Reordenamiento Génico/genética , Humanos , Masculino , Linaje , EscociaRESUMEN
Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Trastornos Mentales/genética , Polimorfismo de Nucleótido Simple , Adulto , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno Bipolar/genética , Niño , Trastornos Generalizados del Desarrollo Infantil/genética , Enfermedad de Crohn/genética , Trastorno Depresivo Mayor/genética , Heterogeneidad Genética , Genoma Humano , Humanos , Patrón de Herencia , Esquizofrenia/genéticaRESUMEN
Disrupted-in-Schizophrenia 1 (DISC1) is a well researched candidate gene for schizophrenia and affective disorders with a range of functions relating to neurodevelopment. Several human brain imaging studies investigating correlations between common and rare variants in DISC1 and brain structure and function have shown conflicting results. A meta-analysis of case/control data showed no association between schizophrenia and any common SNP in DISC1. Therefore it is timely to review the literature to plan the direction of future studies. Twenty-two human brain imaging studies have examined the influence of DISC1 variants in health, schizophrenia, bipolar disorder or depression. The most studied common SNPs are Ser704Cys (rs821616) and Leu607Phe (rs6675281). Some imaging-genomic studies report effects on frontal, temporal and hippocampal structural indices in health and illness and a volumetric longitudinal study supports a putative role for these common SNPs in neurodevelopment. Callosal agenesis is described in association with rare deletions at 1q42 which include DISC1 and rare sequence variants at DISC1 itself. DISC1 interactions with translin-associated factor X (TRAX) and neuregulin have been shown to influence several regional volumes. In the first study involving neonates, a role for Ser704Cys (rs821616) has been highlighted in prenatal brain development with large clusters of reduced grey matter reported in the frontal lobes. Functional MRI studies examining associations between Ser704Cys (rs821616) and Leu607Phe (rs6675281) with prefrontal and hippocampal activation have also given inconsistent results. Prefrontal function was reported to be associated with interaction between DISC1 and CITRON (CIT) in health. Preliminary magnetic resonance spectroscopy and diffusion tensor data support the influence of Ser704Cys (rs821616) status on grey and white matter integrity. The glutamate system remains uninvestigated. Associations between rare sequence variants and structural changes in brain regions including the corpus callosum and effects of gene-gene interactions on brain structure and function are promising areas for future study.