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Nat Commun ; 10(1): 3043, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292440


There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.

Testes Genéticos , Modelos Genéticos , Idade Paterna , Adulto , Fatores Etários , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Criança , Dinamarca/epidemiologia , Epilepsia/epidemiologia , Epilepsia/genética , Feminino , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Incidência , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prevalência , Sistema de Registros/estatística & dados numéricos , Medição de Risco/métodos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Sequenciamento Completo do Exoma
Contemp Clin Trials ; 74: 61-69, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30287268


BACKGROUND: Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. METHODS: ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. RESULTS: Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. CONCLUSIONS: Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.govNCT01916538;

PLoS One ; 11(6): e0157352, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27355346


BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with early onset. ADHD is associated with significant morbidity and mortality, partly due to delayed diagnosis. Identification of children at high risk for developing ADHD could lead to earlier diagnosis and potentially change the negative trajectory of the illness for the better. Since early psychosocial adversity is considered to be a likely etiological risk factor for ADHD, markers of this construct may be useful for early identification of children at high risk. Therefore, we sought to investigate whether Rutter's indicators of adversity (low social class, severe marital discord, large family size, paternal criminality, maternal mental disorder, and placement in out-of-home care) assessed in infancy could serve as early predictors for the development of ADHD. METHODS AND FINDINGS: Using data from the Danish nationwide population-based registers, we established a cohort consisting of all 994,407 children born in Denmark between January 1st 1993 and December 31st 2011 and extracted dichotomous values for the six Rutter's indicators of adversity at age 0-12 months (infancy) for each cohort member. The cohort members were followed from their second birthday and the association between the sum of Rutter's indicators of adversity (RIA-score) in infancy and subsequent development of ADHD was estimated by means of Cox regression. Also, the number needed to screen (NNS) to detect one case of ADHD based on the RIA-scores in infancy was calculated. During follow-up (9.6 million person-years), 15,857 males and 5,663 females from the cohort developed ADHD. For both males and females, there was a marked dose-response relationship between RIA-scores assessed in infancy and the risk for developing ADHD. The hazard ratios for ADHD were 11.0 (95%CI: 8.2-14.7) and 11.4 (95%CI: 7.1-18.3) respectively, for males and females with RIA-scores of 5-6, compared to males and females with RIA-scores of 0. Among males with RIA-scores of 5-6, 37.6% (95%CI: 27.0-50.7) had been diagnosed with ADHD prior to the age of 20, corresponding to a NNS of 3.0 (95%CI: 2.2-4.0). CONCLUSIONS: Rutter's indicators of adversity assessed in infancy strongly predicted ADHD. This knowledge may be important for early identification of ADHD.

Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/psicologia , Criança , Dinamarca , Família , Características da Família , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento/métodos , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Classe Social
Br J Psychiatry ; 206(5): 401-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25657359


BACKGROUND: Clinical and population-based studies report increased prevalence of autism spectrum disorders (ASD) in individuals with anorexia nervosa and in their relatives. No nationwide study has yet been published on co-occurrence of these disorders. AIMS: To investigate comorbidity of ASD in individuals with anorexia nervosa, and aggregation of ASD and anorexia nervosa in their relatives. METHOD: In Danish registers we identified all individuals born in 1981-2008, their parents, and full and half siblings, and linked them to data on hospital admissions for psychiatric disorders. RESULTS: Risk of comorbidity of ASD in probands with anorexia nervosa and aggregation of ASD in families of anorexia nervosa probands were increased. However, the risk of comorbid and familial ASD did not differ significantly from comorbid and familial major depression or any psychiatric disorder in anorexia nervosa probands. CONCLUSIONS: We confirm aggregation of ASD in probands with anorexia nervosa and in their relatives; however, the relationship between anorexia nervosa and ASD appears to be non-specific.

Anorexia Nervosa/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Família/psicologia , Irmãos/psicologia , Adolescente , Estudos de Coortes , Comorbidade , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Análise de Regressão , Fatores de Risco , Distribuição por Sexo
Schizophr Res ; 162(1-3): 74-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25620118


Different case definitions of schizophrenia have been used in register based research. However, no previous study has externally validated two different case definitions of schizophrenia against a wide range of risk factors for schizophrenia. We investigated hazard ratios (HRs) for a wide range of risk factors for ICD-10 DCR schizophrenia using a nationwide Danish sample of 2,772,144 residents born in 1955-1997. We compared one contact only (OCO) (the case definition of schizophrenia used in Danish register based studies) with two or more contacts (TMC) (a case definition of at least 2 inpatient contacts with schizophrenia). During the follow-up, the OCO definition included 15,074 and the TMC 7562 cases; i.e. half as many. The TMC case definition appeared to select for a worse illness course. A wide range of risk factors were uniformly associated with both case definitions and only slightly higher risk estimates were found for the TMC definition. Choosing at least 2 inpatient contacts with schizophrenia (TMC) instead of the currently used case definition would result in almost similar risk estimates for many well-established risk factors. However, this would also introduce selection and include considerably fewer cases and reduce power of e.g. genetic studies based on register-diagnosed cases only.

Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Adulto , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Pacientes Internados , Masculino , Modelos de Riscos Proporcionais , Sistema de Registros , Medição de Risco , Fatores de Risco , Esquizofrenia/terapia , Índice de Gravidade de Doença , Fatores Socioeconômicos
J Child Psychol Psychiatry ; 56(5): 558-65, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25156482


BACKGROUND: Knowledge on the significance of childhood psychotic symptoms and experiences (PE) is still limited. This study aimed to investigate the prevalence and clinical significance of PE in preadolescent children from the general population by use of in-depth psychopathological interviews and comprehensive diagnostic assessments. METHODS: We investigated 1,632 children from the general population-based Copenhagen Child Cohort 2000. PE were measured by semistructured interviews using the K-SADS-PL-items on psychotic and affective symptoms, each symptom scored as not present versus likely or definitely present. The Development and Well-Being Assessment (DAWBA) was used independently to diagnose DSM-IV-mental disorders. Puberty development and sleep disturbance were self-reported. The associations between PE (any lifetime hallucination and/or delusion) and various mental problems and disorders were examined by multivariable binomial regression analyses, adjusting for gender and onset of puberty. RESULTS: The weighted life time prevalence of PE at age 11-12 years was 10.9% (CI 9.1-12.7). The majority of children with PE (n = 172) either had a diagnosable DSM-IV-mental disorder (31.4%) or self-reported mental health difficulties in absence of a diagnosis (31.4%). The risk of delusions increased with onset of puberty. The risk of PE increased with emotional and neurodevelopmental disorders, subthreshold depressive symptoms, sleep problems and lack of sleep, regardless of whether PE were expressed as hallucinations and/or delusions. The highest correlations were seen for emotional and multiple disorders. CONCLUSIONS: Psychotic experiences are particularly prevalent in the context of affective dysregulation and sleep disturbance, increase with onset of puberty and represent a trans-diagnostic marker of psychopathology.

Sintomas Afetivos/epidemiologia , Delusões/epidemiologia , Alucinações/epidemiologia , Transtornos Mentais/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Criança , Comorbidade , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Transtornos Psicóticos/epidemiologia