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

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

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

Age-related change in retinal nerve fiber layer thickness measured with spectral domain optical coherence tomography

PubMed ID: 24194190PURPOSE. We investigated age-related change in peripapillary retinal nerve fiber layer thicknesses (RNFLT) measured with spectral domain optical coherence tomography (SDOCT) in healthy individuals. METHODS. In this cross-sectional study, peripapillary RNFL measurement was performed using a Cirrus SD-OCT device. Linear regression analysis and Spearman's correlation analysis were performed to investigate the level of difference in age-related change in the overall mean, 4 quadrants mean, and 12 clock-hour sectors mean RNFLT. RESULTS. Mean age of the 121 healthy participants was 39 years (range, 20-59 years). Mean 4 quadrant and mean 12 clock-hour sector RNFLT in the 121 randomly selected eyes in 121 healthy participants decreased significantly with age in the overall group (Spearman's correlation analysis, P < 0.05). Overall mean RNFLT decreased by 0.365 lm (95% confidence interval [CI], 0.47-0.26; linear regression analysis, P < 0.001) for every one year increase in age. Overall, the greatest decrease in mean RNFLT was in the lower quadrant (0.575 lm/y; 95% CI, 0.733-0.416), versus the least decrease in the nasal quadrant (0.141 lm/y; 95% CI, 0.272-0.010), and the greatest decrease in mean RNFLT was in the 6 clock-hour sector (0.656 lm/y; 95% CI, 0.939-0.374), versus the least decrease in the 3 clock-hour sector (0.119 lm/y; 95% CI, 0.266-0.029). CONCLUSIONS. Age-related decrease in RNFLT varied according to sector. Age-related change should be accounted for in any assessment of RNFLT. Regional age-related change is accounted for by Cirrus SD-OCT in its normative database.© 2013 The Association for Research in Vision and Ophthalmology, Inc

The efficacy of autologous serum eye drops for severe dry eye syndrome: A randomized double-blind crossover study

PubMed ID: 24566903Background: To evaluate the efficacy of autologous serum (AS) eye drops for the symptomatic relief of severe dry eye syndrome (DES), as compared to conventional preservative-free artificial tears (PFAT). Methods: This prospective double-blind randomized crossover study used the Ocular Surface Disease Index (OSDI), tear film break-up time (TBUT), Schirmer's Test, and OXFORD Scale at baseline and after each of two 1-month treatment periods to measure the effect of 20 % diluted AS eye drops vs. PFAT in 20 consecutive severe DES patients that were refractory to conventional treatment. Results: The study included 20 (18 female and two male) severe DES patients (40 eyes). Significantly higher TBUT (P??0.05 [Mann-Whitney U test]). Conclusions: AS eye drops were more effective than conventional eye drops for improving tear film stability and subjective comfort in patients with severe DES. © 2014 Springer-Verlag Berlin Heidelberg

The role of mast cells in vascularized recurrent pterygium

Objective: To determine and compare the mast cell count in primary and recurrent vascularized pterygium, and in normal bulbar conjunctiva. Methods: The study included 22 patients with primary pterygium (PP group) and 28 patients with vascularized recurrent pterygium (VRP group) that underwent excision via the limbal conjunctival autograft technique. Normal conjunctiva samples were collected from the superotemporal bulbar conjunctival region, just temporal to the site from which the autograft conjunctival tissue was harvested. The total number of mast cells in the pterygium (primary and recurrent) and control tissue samples was calculated microscopically using 1% toluidine blue stain under 400× magnification. Results: The mean mast cell count in primary and vascularized recurrent pterygium tissue was 7.45 ± 2.06 mm-2 and 16.11 ± 4.33 mm-2, respectively, and the difference was significant (independent samples t-test, P&lt;0.001). The mean mast cell count in pterygium tissue was significantly higher than that in normal conjunctiva tissue in both groups (Student's t-test, P&lt;0.001). Conclusion: An increase in the number of mast cells might play a role in the pathogenesis of recurrent pterygium. Determination of a mast cell count cut-off value could be of diagnostic significance for recurrent pterygium

Stress response of juvenile rainbow trout (Oncorhynchus mykiss)to chemical cues released from stressed conspecifics

The objective of this study was to determine whether exposure of rainbow trout (Oncorhynchus mykiss) to water containing a stressed trout or skin extract from stressed and non-stressed trout would elicit a stress response in conspecifics. Juvenile rainbow trout were exposed for 1 hour to water containing a stressed fish, homogenized skin extracts from a non-stressed fish, skin extract from a stressed fish and water with none of these factors. The stress response was measured over a 24-h period (1, 6, 12, 24 h after exposure). Plasma cortisol levels increased at 12 h in fish exposed to water from a stressed fish and skin extract from a stressed fish. Plasma glucose and hepatic hsp70 levels were not affected by treatments. The results suggest that rainbow trout elicit a stress response when exposed to stress-related alarm cues released from conspecifics