RESUMO
Adverse environments are linked to elevated youth antisocial behavior. However, this relation is thought to depend, in part, on genetic susceptibility. The present study investigated whether polygenic risk for antisociality moderates relations between hostile environments and stable as well as dynamic antisocial behaviors across adolescence. We derived two antisocial-linked polygenic risk scores (PRS) (N = 721) based on previous genome-wide association studies. Forms of antisocial behavior (nonaggressive conduct problems, physical aggression, social aggression) and environmental hostility (harsh parenting and school violence) were assessed at age 13, 15, and 17 years. Relations to individual differences stable across adolescence (latent stability) vs. time-specific states (timepoint residual variance) of antisocial behavior were assessed via structural equation models. Higher antisocial PRS, harsh parenting, and school violence were linked to stable elevations in antisocial behaviors across adolescence. We identified a consistent polygenic-environment interaction suggestive of differential susceptibility in late adolescence. At age 17, harsher parenting was linked to higher social aggression in those with higher antisocial PRS, and lower social aggression in those with lower antisocial PRS. This suggests that genetics and environmental hostility relate to stable youth antisocial behaviors, and that genetic susceptibility moderates home environment-antisocial associations specifically in late adolescence.
RESUMO
Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene-environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.
Assuntos
Variações do Número de Cópias de DNA/genética , Transtorno Depressivo Maior , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Mapeamento Cromossômico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Loci Gênicos , Humanos , FenótipoRESUMO
BACKGROUND AND PURPOSE: Individuals with radiologically isolated syndrome (RIS) are at increased risk of converting to multiple sclerosis (MS). Early identification of later converters is crucial for optimal treatment decisions. The purpose of this study was to assess the predictive potential of optical coherence tomography (OCT) measures in individuals with RIS regarding conversion to MS. METHODS: This prospective observational cohort study included 36 individuals with RIS and 36 healthy controls recruited from two German MS centers. All individuals received baseline OCT and clinical examination and were longitudinally followed over up to 6 years. The primary outcome measure was the conversion to MS. RESULTS: During clinical follow-up of 46 (26-58) months (median, 25%-75% interquartile range), eight individuals with RIS converted to MS. Individuals converting to MS showed a thinning of the peripapillary retinal nerve fiber layer (pRNFL) and the common ganglion cell and inner plexiform layer (GCIP) at baseline and during follow-up. Individuals with a pRNFL of 99 µm or lower or a GCIP of 1.99 mm3 or lower were at a 7.5- and 8.0-fold risk for MS conversion, respectively, compared to individuals with higher measures. After correction for other known risk factors, Cox proportional hazards regression revealed a hazard ratio of 1.08 for conversion to MS for each 1 µm decline in pRNFL. CONCLUSIONS: Reduction of the pRNFL might be a novel and independent risk factor for conversion to MS in individuals with RIS. OCT might be useful for risk stratification and therapeutic decision-making in individuals with RIS.
Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Doenças Desmielinizantes/diagnóstico por imagem , Humanos , Esclerose Múltipla/diagnóstico por imagem , Estudos Prospectivos , Retina/diagnóstico por imagem , Tomografia de Coerência ÓpticaRESUMO
Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
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Povo Asiático/genética , Transtorno Depressivo Maior/genética , População Branca/genética , Teorema de Bayes , Estudos de Casos e Controles , China , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Few regional and seasonal Guillain-Barré syndrome (GBS) clusters have been reported so far. It is unknown whether patients suffering from sporadic GBS differ from GBS clusters with respect to clinical and paraclinical parameters, HLA association and antibody response to glycosphingolipids and Campylobacter jejuni (Cj). We examined 40 consecutive patients with GBS from the greater Munich area in Germany with 14 of those admitted within a period of 3 months in fall 2010 defining a cluster of GBS. Sequencing-based HLA typing of the HLA genes DRB1, DQB1, and DPB1 was performed, and ELISA for anti-glycosphingolipid antibodies was carried out. Clinical and paraclinical findings (Cj seroreactivity, cerebrospinal fluid parameters, and electrophysiology) were obtained and analyzed. GBS cluster patients were characterized by a more severe clinical phenotype with more patients requiring mechanical ventilation and higher frequencies of autoantibodies against sulfatide, GalC and certain ganglioside epitopes (54 %) as compared to sporadic GBS cases (13 %, p = 0.017). Cj seropositivity tended to be higher within GBS cluster patients (69 %) as compared to sporadic cases (46 %, p = 0.155). We noted higher frequencies of HLA class II allele DQB1*05:01 in the cluster cohort (23 %) as compared to sporadic GBS patients (3 %, p = 0.019). Cluster of severe GBS was defined by higher frequencies of autoantibodies against glycosphingolipids. HLA class II allele DQB1*05:01 might contribute to clinical worsening in the cluster patients.
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Autoanticorpos/líquido cefalorraquidiano , Glicoesfingolipídeos/imunologia , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/genética , Cadeias beta de HLA-DQ/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Infecções por Campylobacter/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Frequência do Gene , Predisposição Genética para Doença/genética , Alemanha , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa/genética , Índice de Gravidade de Doença , Adulto JovemRESUMO
Matrix metalloproteinase 9 (MMP9) plays an important role in the pathogenesis of multiple sclerosis (MS). However, the impact of genetic variants affecting MMP9 on MS susceptibility is still in debate. We could not detect an association of MMP9 SNPs with MS on a genome-wide significance level by SNP genotyping, followed by imputation of SNPs within a region stretching 2Mbp up- and down-stream of MMP9. Rs6073751, located within WFDC2, was found associated with MS most strongly. Rs3918242, associated with MS according to previous reports, showed nominal significance only. Meta-analysis of our own and published data did not confirm this effect.