Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

Genome-wide by Environment Interaction Studies of Depressive Symptoms and Psychosocial Stress in UK Biobank and Generation Scotland

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 x 10(-6)). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 x 10(-9); total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 x 10(-8); dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 x 10(-8); dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 x 10(-6)). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 x 10(-3)). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

Geoprocessamento aplicado à observação da sazonalidade das larvas da mosca Dermatobia hominis no município de Seropédica - RJ Geoprocessing applied to the seasonality of Dermatobia hominis larvae in the municipality of Seropédica, Rio de Janeiro

Associações espaço-temporais entre os fatores envolvidos na distribuição sazonal das larvas da mosca do berne - Dermatobia hominis (Linnaeus Jr., 1781) (Diptera: Cuterebridae) - em bovinos foram analisadas por geoprocessamento, utilizando-se o sistema de análise geoambiental da Universidade Federal do Rio de Janeiro, no município de Seropédica, RJ. Na primavera, 50% da área do município foi muito favorável ao desenvolvimento dessa miíase. Esse grau de favorabilidade reduziu-se para 35%, 23% e 12% no verão, outono e inverno, respectivamente.Space-temporal associations between factors involved in the seasonal distribution of Dermatobia hominis (Linnaeus Jr., 1781) (Diptera: Cuterebridae) fly larvae in cattle were analyzed by geoprocessing using the geo-environment system of the Universidade Federal do Rio de Janeiro, in the municipality of Seropédica, RJ. In the spring, 50% of the area was favorable, reducing its extension to 35% in the summer, to 23% in the fall and to 12% in the winter

Genome-wide association of mood-incongruent psychotic bipolar disorder

Mood-incongruent psychotic features (MICP) are familial symptoms of bipolar disorder (BP) that also occur in schizophrenia (SZ), and may represent manifestations of shared etiology between the major psychoses. In this study we have analyzed three large samples of BP with imputed genome-wide association data and have performed a meta-analysis of 2196 cases with MICP and 8148 controls. We found several regions with suggestive evidence of association (P<10(-6)), although no marker met genome-wide significance criteria. The top associations were on chromosomes: 6q14.2 within the PRSS35/SNAP91 gene complex (rs1171113, P=9.67 × 10(-8)); 3p22.2 downstream of TRANK/LBA1 (rs9834970, P=9.71 × 10(-8)); and 14q24.2 in an intron of NUMB (rs2333194, P=7.03 × 10(-7)). These associations were present in all three samples, and both rs1171113 and rs2333194 were found to be overrepresented in an analysis of MICP cases compared with all other BP cases. To test the relationship of MICP with SZ, we performed polygenic analysis using the Psychiatric GWAS Consortium SZ results and found evidence of association between SZ polygenes and the presence of MICP in BP cases (meta-analysis P=0.003). In summary, our analysis of the MICP phenotype in BP has provided suggestive evidence for association of common variants in several genes expressed in the nervous system. The results of our polygenic analysis provides support for a modest degree of genetic overlap between BP with MICP and SZ, highlighting that phenotypic correlations across syndromes may be due to the influence of polygenic risk factors

Erratum: Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review

<b><i>Background:</i></b> Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. CMT is classified into 2 main subgroups: CMT type 1 (CMT1; demyelinating form) and CMT type 2 (CMT2; axonal form). The objectives of this study were to systematically review and assess the quality of studies reporting the incidence and/or prevalence of CMT worldwide. <b><i>Summary:</i></b> A total of 802 studies were initially identified, with only 12 meeting the inclusion criteria. CMT prevalence was reported in 10 studies and ranged from 9.7/100,000 in Serbia to 82.3/100,000 in Norway. The frequency of the main subtypes varied from 37.6 to 84% for CMT1 and from 12 to 35.9% for CMT2; the country with the lowest prevalence of CMT1 was Norway, and the country with the highest prevalence of CMT1 was Iceland; on the other hand, CMT2 was least prevalent in the United Kingdom and most prevalent in Norway. <b><i>Key Messages:</i></b> This review reveals the gaps that still exist in the epidemiological knowledge of CMT around the world. Published studies are of varying quality and utilise different methodologies, thus precluding a robust conclusion. Additional research focusing on epidemiological features of CMT in different nations and different ethnic groups is needed