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1.
Transl Psychiatry ; 9(1): 252, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591381

RESUMO

Mental disorders have for the majority of cases an unknown etiology, but several studies indicate that neurodevelopmental changes happen in utero or early after birth. We performed a nested case-control study of the relation between blood levels of neuro-developmental (S100B, BDNF, and VEGF-A) and inflammatory (MCP-1, TARC, IL-8, IL-18, CRP, and IgA) biomarkers in newborns, and later development of autism spectrum disorders (ASD, N = 751), attention deficit hyperactivity disorders (ADHD, N = 801), schizophrenia (N = 1969), affective (N = 641) or bipolar disorders (N = 641). Samples and controls were obtained as part of the iPSYCH Danish Case-Cohort Study using dried blood spot samples collected between 1981 and 2004, and stored frozen at the Danish National Biobank. In newborns lower blood level of BDNF was significantly associated with increased odds (OR 1.15) of developing ASD (p = 0.001). This difference could not be explained by genetic variation in the BDNF coding gene region. A tendency of decreased levels of all the neurotrophic markers and increased levels of all inflammatory markers was noted. The low newborn blood levels of BDNF in children developing ASD is an important finding, suggesting that lower BDNF levels in newborns contributes to the etiology of ASD and indicates new directions for further research. It may also help identifying a long-sought marker for high-ASD risk in, e.g., younger siblings of ASD children.

2.
Mol Psychiatry ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492941

RESUMO

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

3.
Nat Commun ; 10(1): 3927, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31456027

RESUMO

PURPOSE: Individuals with schizophrenia have been reported to have low employment rates. We examined the associations of schizophrenia with employment, income, and status of cohabitation from a work life course perspective. METHODS: Nationwide cohort study including all individuals (n = 2,390,127) born in Denmark between 1955 and 1991, who were alive at their 25th birthday. Diagnosis of schizophrenia (yes/no) between ages 15 and 25 was used as an exposure. Employment status, annual wage or self-employment earnings, level of education, and cohabitant status from the age of 25-61 (years 1980-2016) were used as outcomes. RESULTS: Schizophrenia diagnosis between ages 15 and 25 (n = 9448) was associated with higher odds of not being employed (at the age of 30: OR 39.4, 95% CI 36.5-42.6), having no secondary or higher education (7.4, 7.0-7.8), and living alone (7.6, 7.2-8.1). These odds ratios were two-to-three times lower and decreasing over time for those individuals who did not receive treatment in a psychiatric inpatient or outpatient clinic for schizophrenia after the age of 25. Between ages 25-61, individuals with schizophrenia have cumulative earning of $224,000, which is 14% of the amount that the individuals who have not been diagnosed with schizophrenia earn. CONCLUSIONS: Individuals with schizophrenia are at high risk of being outside the labour market and living alone throughout their entire life, resulting in an enormous societal loss in earnings. Individuals with less chronic course of schizophrenia had a gradual but substantial improvement throughout their work life.

5.
Psychoneuroendocrinology ; 108: 150-154, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31284079

RESUMO

Increasing evidence shows that latent infections and inflammation is associated with cognitive and behavioral changes in humans. This case-control study investigates the association between Herpes Simplex Virus Type 1 (HSV-1) infection and C-reactive Protein (CRP) levels, and psychiatric disorders and suicidal behavior. Public health register data from 81,912 participants in the Danish Blood Donor Study, were reviewed to identify individuals registered with an ICD-10 code of any psychiatric diagnosis, or who had attempted or committed suicide. We found 1,504 psychiatric cases and 353 suicidal cases; for all cases, controls were frequency-matched by age and sex, resulting in 5,336 participants. Plasma samples were analyzed for IgG-class antibodies against HSV-1 and CRP. HSV-1 infection was associated with suicidal behavior (odds-ratio, 1.40; 95% confidence interval [CI] 1.11-1.77). Accounting for temporality, HSV-1 infection was associated with having first psychiatric disorder after the date of blood collection (incidence rate ration, 1.44; 95% CI, 1.05-1.95). No association between CRP and psychiatric disorders or suicidal behavior was found. The finding that HSV-1 was associated with suicidal behavior and first psychiatric disorder indicates that infection may play a role in the etiology and pathogenesis of suicidal behavior and development of psychiatric disorders.

6.
Nat Commun ; 10(1): 3043, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292440

RESUMO

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.

7.
Brain Behav Immun ; 81: 341-347, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31247291

RESUMO

Childhood infection has been proposed as an important etiologic factor for schizophrenia. However, it is unclear to what extent the association between childhood infection and schizophrenia is confounded by parental socioeconomic status and mental illness, and childhood adversity, and whether the association is explained by familial liability for infections. We used a historical, population-based cohort design, selecting all singletons born in Denmark between 1981 and 1998 (n = 882,813). We identified exposure to infection as having been hospitalized with an infection in the Danish national registers. Data from a range of population-based registers were used to construct a childhood adversity index. The index included the following adversities: family disruption, parental incarceration, parental chronic somatic disease, death of a parent, parent permanently outside of workforce, childhood abuse and placement in out-of-home care. We also assessed parental socioeconomic status and mental illness. Multiple admissions with infections during childhood increased the risk of schizophrenia with an Incidence Rate Ratio (IRR) of 1.28 (95% CI: 1.19-1.38) for 1 infection to an IRR of 1.43 (95% CI: 1.30-1.58) for 2-3 infections and an IRR of 1.95 (95% CI: 1.66-2.29) for ≥4 infections. Parental socioeconomic status and mental illness, and childhood adversities increased the odds of acquiring childhood infections and was associated with schizophrenia, but did not explain the results. Similarly did familial liability for infection increase the risk of schizophrenia, but did not explain the association between infection and schizophrenia. Parental mental health modified the association between childhood infection and schizophrenia (p-value 0.02), and we found no significant effect of childhood infection in those with propensity for psychotic disorders.

8.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
10.
Eur J Hum Genet ; 27(9): 1445-1455, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30976114

RESUMO

Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.

12.
Philos Trans R Soc Lond B Biol Sci ; 374(1770): 20180120, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30966880

RESUMO

There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10-7. Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.

13.
Proc Natl Acad Sci U S A ; 116(11): 5188-5193, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30804178

RESUMO

Urban residence is associated with a higher risk of some psychiatric disorders, but the underlying drivers remain unknown. There is increasing evidence that the level of exposure to natural environments impacts mental health, but few large-scale epidemiological studies have assessed the general existence and importance of such associations. Here, we investigate the prospective association between green space and mental health in the Danish population. Green space presence was assessed at the individual level using high-resolution satellite data to calculate the normalized difference vegetation index within a 210 × 210 m square around each person's place of residence (∼1 million people) from birth to the age of 10. We show that high levels of green space presence during childhood are associated with lower risk of a wide spectrum of psychiatric disorders later in life. Risk for subsequent mental illness for those who lived with the lowest level of green space during childhood was up to 55% higher across various disorders compared with those who lived with the highest level of green space. The association remained even after adjusting for urbanization, socioeconomic factors, parental history of mental illness, and parental age. Stronger association of cumulative green space presence during childhood compared with single-year green space presence suggests that presence throughout childhood is important. Our results show that green space during childhood is associated with better mental health, supporting efforts to better integrate natural environments into urban planning and childhood life.


Assuntos
Meio Ambiente , Transtornos Mentais/epidemiologia , Adolescente , Adulto , Criança , Dinamarca , Humanos , Fatores de Risco , Urbanização
14.
JAMA Psychiatry ; 76(3): 259-270, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649197

RESUMO

Importance: Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity. Objectives: To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice. Design, Setting, and Participants: This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018. Main Outcomes and Measures: Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated. Results: A total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years). Conclusions and Relevance: Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.

15.
Brain Behav Immun ; 79: 152-158, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30685531

RESUMO

BACKGROUND: Common infectious pathogens have been associated with psychiatric disorders, self-violence and risk-taking behavior. METHODS: This case-control study reviews register data on 81,912 individuals from the Danish Blood Donor Study to identify individuals who have a psychiatric diagnosis (N = 2591), have attempted or committed suicide (N = 655), or have had traffic accidents (N = 2724). For all cases, controls were frequency matched by age and sex, resulting in 11,546 participants. Plasma samples were analyzed for immunoglobulin G (IgG) antibodies against Toxoplasma gondii and cytomegalovirus (CMV). RESULTS: T. gondii was detected in 25·9% of the population and was associated with schizophrenia (odds ratio [OR], 1·47; 95% confidence interval [CI], 1·03-2·09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (IRR, 2·78; 95% CI, 1·27-6·09). A very weak association between traffic accident and toxoplasmosis (OR, 1·11; 95% CI, 1·00-1·23, p = 0.054) was found. CMV was detected in 60·8% of the studied population and was associated with any psychiatric disorder (OR, 1·17; 95% CI, 1·06-1·29), but also with a smaller group of neurotic, stress-related, and somatoform disorders (OR, 1·27; 95% CI, 1·12-1·44), and with attempting or committing suicide (OR, 1·31; 95% CI, 1·10-1·56). Accounting for temporality, any psychiatric disorder (IRR, 1·37; 95% CI, 1·08-1·74) and mood disorders (IRR, 1·43; 95% CI, 1·01-2·04) were associated with exposure to CMV. No association between traffic accident and CMV (OR, 1·06; 95% CI, 0·97-1·17) was found. CONCLUSIONS: This large-scale serological study is the first study to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia, and between CMV and any psychiatric disorder.

16.
Nat Commun ; 9(1): 5296, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30546018

RESUMO

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122%. Individuals living in a high gene-by-environmental risk locale have a 78% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.


Assuntos
Meio Ambiente , Predisposição Genética para Doença/genética , Geografia , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Mapeamento Cromossômico/métodos , Dinamarca/epidemiologia , Humanos , Estudo de Prova de Conceito , Fatores de Risco
18.
Contemp Clin Trials ; 74: 61-69, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30287268

RESUMO

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; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

19.
Lancet Psychiatry ; 5(7): 573-580, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29886042

RESUMO

BACKGROUND: Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort. METHODS: This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders. FINDINGS: Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012-0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040-0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy. INTERPRETATION: The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry. FUNDING: Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.

20.
Am J Hum Genet ; 102(6): 1204-1211, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861106

RESUMO

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

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