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BACKGROUND: Adverse health and social outcomes are known to occur more frequently following parental death during childhood, but evidence is lacking for comparing long-term risks of internalised v. externalised harm. METHODS: This national register-based cohort study consisted of Danish persons born 1970-2000. The Civil Registration System and National Causes of Death Register were linked to ascertain parental deaths by cause before cohort members' 15th birthdays. From age 15 years, hospital-treated self-harm episodes were ascertained through linkage to the National Patient Register and the Psychiatric Central Research Register, and violent crimes were identified via linkage to the National Crime Register. Hazard ratio and cumulative incidence values were estimated. RESULTS: Self-harm and violent criminality risks were elevated following parental death during childhood. Covariate adjustment for gender, birth year and first-degree relatives' mental illnesses attenuated these associations, although significantly heightened risks persisted. The estimated hazard ratios did not differ greatly according to which parent died, but losing both parents conferred particularly large risk increases. Risks for both adverse outcomes were higher in relation to unnatural v. natural parental death; violent criminality risk was especially raised among individuals exposed to parental death by unnatural causes other than suicide. The association was strongest when pre-school age children experienced parental death. CONCLUSIONS: Effective early intervention is needed to help youngsters who have experienced the death of one or both parents to develop immediate and sustained coping strategies. Enhanced cooperation between health and social services and criminal justice agencies may mitigate risks for these two destructive behaviours.
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Experiencias Adversas de la Infancia/estadística & datos numéricos , Conducta Criminal , Muerte Parental/estadística & datos numéricos , Conducta Autodestructiva/epidemiología , Violencia/estadística & datos numéricos , Adolescente , Adulto , Aflicción , Niño , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Suicidio/estadística & datos numéricos , Adulto JovenRESUMEN
The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.
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Ambiente , Predisposición Genética a la Enfermedad/genética , Trastornos Mentales/epidemiología , Trastornos Mentales/genética , Adolescente , Adulto , Factores de Edad , Niño , Estudios de Cohortes , Dinamarca , Femenino , Genotipo , Humanos , Masculino , Trastornos Mentales/clasificación , Trastornos Mentales/diagnóstico , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Studies have indicated that the association of urbanicity at birth and during upbringing with schizophrenia may be driven by familial factors such as genetic liability. We used a population-based nested case-control study to assess whether polygenic risk score (PRS) for schizophrenia was associated with urbanicity at birth and at age 15, and to assess whether PRS and parental history of mental disorder together explained the association between urbanicity and schizophrenia. METHODS: Data were drawn from Danish population registries. Cases born since 1981 and diagnosed with schizophrenia between 1994 and 2009 were matched to controls with the same sex and birthdate (1549 pairs). Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of a separate, large meta-analysis. RESULTS: Those with higher PRS were more likely reside in the capital compared with rural areas at age 15 [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], but not at birth (OR 1.09, 95% CI 0.95-1.26). Adjustment for PRS produced almost no change in relative risks of schizophrenia associated with urbanicity at birth, but slightly attenuated those for urban residence at age 15. Additional adjustment for parental history led to slight attenuation of relative risks for urbanicity at birth [incidence rate ratio (IRR) for birth in capital = 1.54, 95% CI 1.18-2.02; overall p = 0.016] and further attenuation of relative risks for urbanicity at age 15 (IRR for residence in capital = 1.32, 95% CI 0.97-1.78; overall p = 0.148). CONCLUSIONS: While results regarding urbanicity during upbringing were somewhat equivocal, genetic liability as measured here does not appear to explain the association between urbanicity at birth and schizophrenia.
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Trastornos Mentales/epidemiología , Padres , Sistema de Registros/estadística & datos numéricos , Esquizofrenia/epidemiología , Población Urbana/estadística & datos numéricos , Adolescente , Bancos de Muestras Biológicas , Estudios de Casos y Controles , Dinamarca/epidemiología , Femenino , Humanos , Recién Nacido , Masculino , Trastornos Mentales/genética , Herencia Multifactorial , Población Rural/estadística & datos numéricos , Esquizofrenia/genéticaRESUMEN
BACKGROUND: Maternal smoking has consistently been associated with multiple adverse childhood outcomes including externalizing disorders. In contrast the association between maternal smoking during pregnancy (MSDP) and internalizing (anxiety and depressive) disorders in offspring has received less investigation. METHOD: We conducted a nationwide cohort study including 957635 individuals born in Denmark between 1991 and 2007. Data on MSDP and diagnoses of depression or anxiety disorders were derived from national registers and patients were followed up from the age of 5 years to the end of 2012. Hazard rate ratios (HRRs) were estimated using stratified Cox regression models. Sibling data were used to disentangle individual- and familial-level effects of MSDP and to control for unmeasured familial confounding. RESULTS: At the population level, offspring exposed to MSDP were at increased risk for both severe depression [HRR 1.29, 95% confidence interval (CI) 1.22-1.36] and severe anxiety disorders (HRR 1.26, 95% CI 1.20-1.32) even when controlling for maternal and paternal traits. However, there was no association between MSDP and internalizing disorders when controlling for the mother's propensity for MSDP (depression: HRR 1.11, 95% CI 0.94-1.30; anxiety disorders: HRR 0.94, 95% CI 0.80-1.11) or comparing differentially exposed siblings (depression: HRR 1.18, 95% CI 0.75-1.89; anxiety disorders: HRR 0.87, 95% CI 0.55-1.36). CONCLUSIONS: The results suggest that familial background factors account for the association between MSDP and severe internalizing disorders not the specific exposure to MSDP.
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Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R(2) and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R(2) values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (Ptarget=0.017, Preplication=0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvementtarget= 50%; improvementreplication= 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness.
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Estudio de Asociación del Genoma Completo/métodos , Esquizofrenia/genética , Adulto , Estudios de Casos y Controles , Dinamarca , Femenino , Predisposición Genética a la Enfermedad/genética , Alemania , Humanos , Masculino , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: The risk of certain psychiatric disorders is elevated among immigrants. To date, no population studies on immigrant health have addressed eating disorders. We examined whether risk of eating disorders in first- and second-generation immigrants differs from native-born Danes and Swedes. METHOD: All individuals born 1984-2002 (Danish cohort) and 1989-1999 (Swedish cohort) and residing in the respective country on their 10th birthday were included. They were followed up for the development of eating disorders based on out-patient and in-patient data. RESULTS: The risks of all eating disorder types were lower among first-generation immigrants compared to the native populations: Incidence-rate ratio (95% confidence interval) was 0.39 (0.29, 0.51) for anorexia nervosa, 0.60 (0.42, 0.83) for bulimia nervosa, and 0.62 (0.47, 0.79) for other eating disorders in Denmark and 0.27 (0.21, 0.34) for anorexia nervosa, 0.30 (0.18, 0.51) for bulimia nervosa, and 0.39 (0.32, 0.47) for other eating disorders in Sweden. Likewise, second-generation immigrants by both parents were at lower risk, whereas those with only one foreign-born parent were not. CONCLUSION: The decreased risk of eating disorders among immigrants is opposite to what has been observed for other psychiatric disorders, particularly schizophrenia. Possible explanations include buffering sociocultural factors and underdetection in health care.
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Emigrantes e Inmigrantes/estadística & datos numéricos , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Adulto , Dinamarca , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Características de la Residencia , Factores de Riesgo , SueciaRESUMEN
BACKGROUND: The post-pubertal association of female gender with emotional disorder is a robust finding. However, studies exploring the association of gender and emotional disorders before puberty are few and present diverging results. The aim of this study was to present gender-specific incidence rates of emotional disorders throughout childhood. METHOD: This is a population-based cohort study of 907,806 Danish 3- to 18-year-olds. The outcome was assignment of an emotional disorder diagnosis based on in-patient and out-patient data from The Danish Psychiatric Central Register. Outcome measures were incidence rates and cumulative incidences for unipolar depressive disorder (ICD-10: F32-F33), anxiety disorders (ICD-10: F40-F42), and emotional disorders with onset specific to childhood (ICD-10: F93). RESULTS: Pre-pubertal incidence rates for depressive and anxiety disorders were higher for boys than girls. At age 12 years the pattern reversed. The cumulative incidence for any emotional disorder (F32-F33, F40-F42, F93) on the 11th birthday was 0.52% (95% CI 0.50-0.55) for boys and 0.31% (95% CI 0.29-0.33) for girls. On the 19th birthday cumulative incidence was 2.33% (95% CI 2.24-2.43) for boys and 3.77% (95% CI 3.64-3.90) for girls. The pre-pubertal male preponderance was also significant for depressive disorders (F32-F33, p = 0.00144) and anxiety disorders (F40-F42, F93, p < 0.00001) separately. CONCLUSIONS: Emotional disorders seem to display a male preponderance before the age of 12 years and a female preponderance thereafter. Studies exploring this gender-age interaction are needed. Still, the results question the general assumption that females throughout the lifespan are more at risk for emotional disorders than males.
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Síntomas Afectivos/epidemiología , Trastornos de Ansiedad/epidemiología , Trastorno Depresivo/epidemiología , Pubertad , Adolescente , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Incidencia , Masculino , Factores SexualesRESUMEN
BACKGROUND: There is growing interest in the role of childhood adversities, including parental death and separation, in the etiology of psychotic disorders. However, few studies have used prospectively collected data to specifically investigate parental separation across development, or assessed the importance of duration of separation, and family characteristics. METHOD: We measured three types of separation not due to death: maternal, paternal, and from both parents, across the ages of 1-15 years among a cohort of 985 058 individuals born in Denmark 1971-1991 and followed to 2011. Associations with narrowly and broadly defined schizophrenia and bipolar disorder in the psychiatric register were assessed in terms of separation occurrence, age of separation, and number of years separated. Interactions with parental history of mental disorder were assessed. RESULTS: Each type of separation was associated with all three outcomes, adjusting for age, sex, birth period, calendar year, family history of mental disorder, urbanicity at birth and parental age. Number of years of paternal separation was positively associated with both schizophrenia and bipolar disorder. Associations between separation from both parents and schizophrenia were stronger when separation occurred at later ages, while those with bipolar disorder remained stable across development. The first occurrence of paternal separation appeared to increase risk more when it occurred earlier in childhood. Associations differed according to parental history of mental disorder, although in no situation was separation protective. CONCLUSIONS: Effects of parental separation may differ by type, developmental timing and family characteristics. These findings highlight the importance of considering such factors in studies of childhood adversity.
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Trastorno Bipolar/epidemiología , Hijo de Padres Discapacitados/psicología , Padres/psicología , Trastornos Psicóticos/etiología , Riesgo , Esquizofrenia/epidemiología , Adolescente , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Lactante , Masculino , Relaciones Padres-HijoRESUMEN
Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.
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Factores de Transcripción ARNTL/genética , Cadherinas/genética , Infecciones por Citomegalovirus/complicaciones , Interacción Gen-Ambiente , Proteínas de Homeodominio/genética , Esquizofrenia/genética , Nexinas de Clasificación/genética , Factores de Transcripción/genética , alfa Catenina/genética , Estudios de Casos y Controles , Infecciones por Citomegalovirus/genética , Dinamarca , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Alemania , Humanos , Exposición Materna , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/complicaciones , Población Blanca/genética , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
BACKGROUND: Persons discharged from inpatient psychiatric services are at greatly elevated risk of harming themselves or inflicting violence on others, but no studies have reported gender-specific absolute risks for these two outcomes across the spectrum of psychiatric diagnoses. We aimed to estimate absolute risks for self-harm and interpersonal violence post-discharge according to gender and diagnostic category. METHODS: Danish national registry data were utilized to investigate 62,922 discharged inpatients, born 1967-2000. An age and gender matched cohort study was conducted to examine risks for self-harm and interpersonal violence at 1 year and at 10 years post-discharge. Absolute risks were estimated as cumulative incidence percentage values. RESULTS: Patients diagnosed with substance misuse disorders were at especially elevated risk, with the absolute risks for either self-harm or interpersonal violence being 15.6% (95% CI 14.9, 16.3%) of males and 16.8% (15.6, 18.1%) of females at 1 year post-discharge, rising to 45.7% (44.5, 46.8%) and 39.0% (37.1, 40.8%), respectively, within 10 years. Diagnoses of personality disorders and early onset behavioral and emotional disorders were also associated with particularly high absolute risks, whilst risks linked with schizophrenia and related disorders, mood disorders, and anxiety/somatoform disorders, were considerably lower. CONCLUSIONS: Patients diagnosed with substance misuse disorders, personality disorders and early onset behavioral and emotional disorders are at especially high risk for internally and externally directed violence. It is crucial, however, that these already marginalized individuals are not further stigmatized. Enhanced care at discharge and during the challenging transition back to life in the community is needed.
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Servicios de Salud Mental , Conducta Autodestructiva , Trastornos Relacionados con Sustancias , Masculino , Femenino , Humanos , Alta del Paciente , Pacientes Internos/psicología , Estudios de Cohortes , Cuidados Posteriores , Conducta Autodestructiva/diagnóstico , Conducta Autodestructiva/epidemiología , Violencia/psicología , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/complicaciones , Factores de RiesgoRESUMEN
Estrogen receptor (ER) and human epidermal growth factor 2 (HER2) expression guide the use of neoadjuvant chemotherapy (NACT) in patients with early breast cancer. We evaluate the independent predictive value of adding a multigene profile (CIT256 and PAM50) to immunohistochemical (IHC) profile regarding pathological complete response (pCR) and conversion of positive to negative axillary lymph node status. The cohort includes 458 patients who had genomic profiling performed as standard of care. Using logistic regression, higher pCR and node conversion rates among patients with Non-luminal subtypes are shown, and importantly the predictive value is independent of IHC profile. In patients with ER-positive and HER2-negative breast cancer an odds ratio of 9.78 (95% CI 2.60;36.8), P < 0.001 is found for pCR among CIT256 Non-luminal vs. Luminal subtypes. The results suggest a role for integrated use of up-front multigene subtyping for selection of a neoadjuvant approach in ER-positive HER2-negative breast cancer.
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BACKGROUND: Second-generation immigrants have an increased risk of schizophrenia, a finding that still lacks a satisfactory explanation. Various operational definitions of second-generation immigrants have been used, including foreign parental country of birth. However, with increasing global migration, it is not clear that parental country of birth necessarily is informative with regard to ethnicity. We compare two independently collected measures of parental foreign ethnicity, parental foreign country of birth versus genetic divergence, based on genome-wide genotypic data, to access which measure most efficiently captures the increased risk of schizophrenia among second-generation immigrants residing in Denmark. METHOD: A case-control study covering all children born in Denmark since 1981 included 892 cases of schizophrenia and 883 matched controls. Genetic divergence was assessed using principal component analyses of the genotypic data. Independently, parental foreign country of birth was assessed using information recorded prospectively in the Danish Civil Registration System. We compared incidence rate ratios of schizophrenia associated with these two independently collected measures of parental foreign ethnicity. RESULTS: People with foreign-born parents had a significantly increased risk of schizophrenia [relative risk (RR) 1.94 (95% confidence intervals (CI) 1.41-2.65)]. Genetically divergent persons also had a significant increased risk [RR 2.43 (95% CI 1.55-3.82)]. Mutual adjustment of parental foreign country of birth and genetic divergence showed no difference between these measures with regard to their potential impact on the results. CONCLUSIONS: In terms of RR of schizophrenia, genetic divergence and parental foreign country of birth are interchangeable entities, and both entities have validity with regard to identifying second-generation immigrants.
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Emigrantes e Inmigrantes/estadística & datos numéricos , Variación Genética , Padres , Sistema de Registros , Esquizofrenia/epidemiología , Estudios de Casos y Controles , Niño , Dinamarca/epidemiología , Emigrantes e Inmigrantes/psicología , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Análisis de Componente Principal , Factores de Riesgo , Esquizofrenia/etnología , Esquizofrenia/genéticaRESUMEN
SSX proteins are normally restricted to spermatogenic cells, but ectopic expression can be observed in many types of human cancer. We recently demonstrated that SSX family members may contribute to tumorigenesis by modifying chromatin structure and, in specific settings, compromise chromatin stability. Here, we used normal and tumorigenic breast epithelial cell line models to further study the effect of ectopic expression of SSX2 on nuclear organization. We show that SSX2 induces the formation of a novel type of nucleoplasmic lamin bodies. Ectopic expression of SSX2 in various breast epithelial cell lines led to the formation of a previously undescribed type of intranuclear bodies containing both A and B type lamins but no other components of the nuclear lamina. SSX2-expressing cells contained a highly variable number of lamin bodies distributed throughout the nuclear space. SSX2-mediated establishment of intranuclear lamin bodies could not be linked to previous molecular interactions of SSX proteins, including polycomb proteins and the Mediator complex, but was, however, dependent on S-phase progression. These results reveal a novel interaction between SSX2 and lamins in the nucleoplasmic space. They further suggest that SSX2 promotes the formation of chromatin neighborhoods supporting the organization of lamins into nuclear bodies. We speculate that this may have implications for the organization and functional regulation of chromatin in cancer cells. Our study contributes to the further understanding of the biology of SSX proteins in tumorigenesis.
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Cuerpos NuclearesRESUMEN
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare inherited disorder of the mitochondrial beta-oxidation of fatty acids. Patients with SCADD present mainly with symptoms of neuromuscular character. In order to investigate factors involved in the pathogenesis, we studied a disease-associated variant of the SCAD protein (p.Arg83Cys, c.319C>T), which is known to compromise SCAD protein folding. We investigated the consequences of overexpressing the misfolded mitochondrial protein, and thus determined whether the misfolded p.Arg83Cys SCAD proteins can elicit a toxic reaction. Human astrocytes were transiently transfected with either wild-type or p.Arg83Cys encoding cDNA, and analyzed for insoluble proteins/aggregate-formation, alterations in mitochondrial morphology, and for the presence of reactive oxygen species (ROS) in the mitochondria. The majority of cells overexpressing the p.Arg83Cys SCAD variant protein presented with an altered mitochondrial morphology of a grain-like structure, whereas the majority of the cells overexpressing wild-type SCAD presented with a normal thread-like mitochondrial reticulum. We found this grain-like structure to be associated with an increased amount of ROS. The mitochondrial morphology change was partly alleviated by addition of the mitochondrial targeted antioxidant MitoQ, indicating a ROS-induced mitochondrial fission. We therefore propose that SCAD misfolding leads to production of ROS, which in turn leads to fission and a grain-like structure of the mitochondrial reticulum. This finding indicates a toxic response elicited by misfolded p.Arg83Cys SCAD proteins.
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Butiril-CoA Deshidrogenasa/química , Errores Innatos del Metabolismo Lipídico/genética , Mitocondrias/genética , Estrés Oxidativo/genética , Pliegue de Proteína , Deficiencias en la Proteostasis/genética , Astrocitos/enzimología , Butiril-CoA Deshidrogenasa/deficiencia , Butiril-CoA Deshidrogenasa/genética , Línea Celular , Humanos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Especies Reactivas de Oxígeno/metabolismo , TransfecciónRESUMEN
BACKGROUND: A family history of schizophrenia is the strongest single indicator of individual schizophrenia risk. Bipolar affective disorder and schizo-affective disorders have been documented to occur more frequently in parents and siblings of schizophrenia patients, but the familial occurrence of the broader range of mental illnesses and their role as confounders have not been studied in large population-based samples. METHOD: All people born in Denmark between 1955 and 1991 (1.74 million) were followed for the development of schizophrenia (9324 cases) during 28 million person-years at risk. Information of schizophrenia in cohort members and psychiatric history in parents and siblings was established through linkage with the Danish Psychiatric Central Register. Data were analysed using log-linear Poisson regression. RESULTS: Schizophrenia was, as expected, strongly associated with schizophrenia and related disorders among first-degree relatives. However, almost any other psychiatric disorder among first-degree relatives increased the individual's risk of schizophrenia. The population attributable risk associated with psychiatric family history in general was 27.1% whereas family histories including schizophrenia only accounted for 6.0%. The general psychiatric family history was a confounder of the association between schizophrenia and urbanization of place of birth. CONCLUSIONS: Clinically diagnosed schizophrenia is associated with a much broader range of mental disorders in first-degree relatives than previously reported. This may suggest risk haplotypes shared across many disorders and/or shared environmental factors clustering in families. Failure to take the broad range of psychiatric family history into account may bias results of all risk-factor studies of schizophrenia.
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Trastornos Mentales/genética , Estudios de Cohortes , Dinamarca/epidemiología , Padre/estadística & datos numéricos , Ligamiento Genético , Humanos , Trastornos Mentales/diagnóstico , Trastornos Mentales/epidemiología , Madres/estadística & datos numéricos , Factores de Riesgo , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiología , Esquizofrenia/genéticaAsunto(s)
Edad Paterna , Esquizofrenia/epidemiología , Adolescente , Adulto , Orden de Nacimiento , Dinamarca/epidemiología , Padre , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Persona de Mediana Edad , Sistema de Registros , Riesgo , Esquizofrenia/genética , Adulto JovenRESUMEN
AIMS: Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys. METHODS: The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women. RESULTS: Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2-110.8, interquartile range = 6.0-19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1-2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs. CONCLUSIONS: Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.
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Trastornos Mentales/epidemiología , Adolescente , Adulto , Anciano , Comorbilidad , Estudios Transversales , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Trastornos Mentales/clasificación , Persona de Mediana Edad , Prevalencia , Modelos de Riesgos Proporcionales , Trastornos Psicóticos/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: The hypothesis was that groin hernias are hereditary. This study was undertaken to establish the degree of familial clustering of groin hernias on a nationwide scale. METHODS: A register-based cohort was created consisting of all children in Denmark whose parents were born in 1970 or later by the use of the Danish Civil Registration System. Within this cohort, all groin hernia operations were identified. To establish the risk estimates associated with a positive family history of groin hernia operation, information on groin hernia operations in fathers, mothers and siblings was also assessed. RESULTS: In the cohort of 408 381 persons, a total of 4966 were operated on for groin hernia (incidence rate 2·12 per 1000 person-years at risk). A person with a mother who had undergone surgery for a groin hernia had an increased risk of 2·89 (95 per cent c.i. 2·48 to 3·34) of having a groin hernia operation; a person with a father operated on for a groin hernia had an increased risk of 1·75 (1·58 to 1·94); and a person with a sibling operated on for a groin hernia had an increased risk of 2·54 (2·17 to 2·96). The strongest association was seen between mothers who had been operated on for groin hernia and their daughters (increased risk 6·01, 95 per cent c.i. 4·53 to 7·80), compared with the risk in girls who did not have a mother who had undergone surgery for groin hernia. CONCLUSION: Groin hernias are clustered in families, with the strongest relationship seen between mothers and their daughters.
RESUMEN
AIM: Calcium channel blockers are widely used in cardiovascular diseases. Besides L-type channels, T- and P/Q-type calcium channels are involved in the contraction of human renal blood vessels. It was hypothesized that T- and P/Q-type channels are involved in the contraction of human brain and mammary blood vessels. METHODS: Internal mammary arteries from bypass surgery patients and cerebral arterioles from patients with brain tumours with and without hypertension were tested in a myograph and perfusion set-up. PCR and immunohistochemistry were performed on isolated blood vessels. RESULTS: The P/Q-type antagonist ω-agatoxin IVA (10-8 mol L-1 ) and the T-type calcium blocker mibefradil (10-7 mol L-1 ) inhibited KCl depolarization-induced contraction in mammary arteries from hypertensive patients with no effect on blood vessels from normotensive patients. ω-Agatoxin IVA decreased contraction in cerebral arterioles from hypertensive patients. L-type blocker nifedipine abolished the contraction in mammary arteries. PCR analysis showed expression of P/Q-type (Cav 2.1), T-type (Cav 3.1 and Cav 3.2) and L-type (Cav 1.2) calcium channels in mammary and cerebral arteries. Immunohistochemical labelling of mammary and cerebral arteries revealed the presence of Cav 2.1 in endothelial and smooth muscle cells. Cav 3.1 was also detected in mammary arteries. CONCLUSION: P/Q- and T-type Cav are present in human internal mammary arteries and in cerebral penetrating arterioles. P/Q- and T-type calcium channels are involved in the contraction of mammary arteries from hypertensive patients but not from normotensive patients. Furthermore, in cerebral arterioles P/Q-type channels importance was restricted to hypertensive patients might lead to that T- and P/Q-type channels could be a new target in hypertensive patients.
Asunto(s)
Canales de Calcio/metabolismo , Arterias Cerebrales/metabolismo , Hipertensión/metabolismo , Arterias Mamarias/metabolismo , Vasoconstricción/fisiología , Anciano , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Arterias Cerebrales/efectos de los fármacos , Femenino , Humanos , Inmunohistoquímica , Masculino , Arterias Mamarias/efectos de los fármacos , Persona de Mediana Edad , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Reacción en Cadena de la Polimerasa , Vasoconstricción/efectos de los fármacosRESUMEN
Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate with mental disorder later in life. DNA methylation was measured genome-wide from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 individuals diagnosed with a psychiatric disorder. Among several CpG sites with P-value<10-6, we identified cg23546855 (P-value=2.15 × 10-7) mapping to STK32C to be associated with a later psychiatric diagnosis. Pathway analysis of the top findings resulted in the identification of several Gene Ontology pathways to be significantly enriched (P-value<0.05 after Benjamini-Hochberg correction); among them are the following: neurogenesis, neuron development, neuron projection development, astrocyte development, axonogenesis and axon guidance. In addition, we identified differentially methylated CpG sites in LRP2BP (P-value=5.37 × 10-8) to be associated with intellectual disability (F70-79), in TOP1 (P-value=1.86 × 10-7) with behavioral disorders (F90-98), in NOSIP (P-value=5.12 × 10-8) with disorders of psychological development (F80-89) and in SEMA4B (P-value=4.02 × 10-7) with schizophrenia spectrum disorders (F20-29). In conclusion, our study suggests an association of DNA methylation differences at birth with development of mental disorder later in life in 22q11.2DS individuals.