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

ORNL rod-bundle heat-transfer test data. Volume 7. Thermal-Hydraulic Test Facility experimental data report for test series 3. 07. 9 - steady-state film boiling in upflow

Thermal-Hydraulic Test Facility (THTF) test series 3.07.9 was conducted by members of the Oak Ridge National Laboratory Pressurized-Water Reactor (ORNL-PWR) Blowdown Heat Transfer (BDHT) Separate-Effects Program on September 11, September 18, and October 1, 1980. The objective of the program is to investigate heat transfer phenomena believed to occur in PWRs during accidents, including small- and large-break loss-of-coolant accidents. Test series 3.07.9 was designed to provide steady-state film boiling data in rod bundle geometry under reactor accident-type conditions. This report presents the reduced instrument responses for THTF test series 3.07.9. Also included are uncertainties in the instrument responses, calculated mass flows, and calculated rod powers

ORNL rod-bundle heat-transfer test data. Volume 3. Thermal-hydraulic test facility experimental data report for test 3. 06. 6B - transient film boiling in upflow. [PWR]

Reduced instrument responses are presented for Thermal-Hyraulic Test Facility (THTF) Test 3.06.6B. This test was conducted by members of the Oak Ridge National Laboratory Pressurized-Water-Reactor (PWR) Blowdown Heat Transfer (BDHT) Separate-Effects Program on August 29, 1980. The objective of the program was to investigate heat transfer phenomena believed to occur in PWR's during accidents, including small and large break loss-of-coolant accidents. Test 3.06.6B was conducted to obtain transient film boiling data in rod bundle geometry under reactor accident-type conditions. The primary purpose of this report is to make the reduced instrument responses for THTF Test 3.06.6B available. Included in the report are uncertainties in the instrument responses, calculated mass flows, and calculated rod powers

ORNL rod-bundle heat-transfer test data. Volume 6. Thermal-hydraulic test facility experimental data report for test 3. 05. 5B - double-ended cold-leg break simulation

Thermal-Hydraulic Test Facility (THTF) Test 3.05.5B was conducted by members of the ORNL PWR Blowdown Heat Transfer Separate-Effects Program on July 3, 1980. The objective of the program is to investigate heat transfer phenomena believed to occur in PWRs during accidents, including small and large break loss-of-coolant accidents. Test 3.05.5B was designed to provide transient thermal-hydraulics data in rod bundle geometry under reactor accident-type conditions. Reduced instrument responses are presented. Also included are uncertainties in the instrument responses, calculated mass flows, and calculated rod powers

Two linear beetle-type scanning tunneling microscopes

Two beetle-type scanning tunneling microscopes are described. Both designs have the thermal stability of the Besocke beetle and the simplicity of the Wilms beetle. Moreover, sample holders were designed that also allow both semiconductor wafers and metal single crystals to be studied. The coarse approach is a linear motion of the beetle towards the sample using inertial slip–stick motion. Ten wires are required to control the position of the beetle and scanner and measure the tunneling current. The two beetles were built with different sized piezolegs, and the vibrational properties of both beetles were studied in detail. It was found, in agreement with previous work, that the beetle bending mode is the lowest principal eigenmode. However, in contrast to previous vibrational studies of beetle-type scanning tunneling microscopes, we found that the beetles did not have the “rattling” modes that are thought to arise from the beetle sliding or rocking between surface asperities on the raceway. The mass of our beetles is 3–4 times larger than the mass of beetles where rattling modes have been observed. We conjecture that the mass of our beetles is above a “critical beetle mass.” This is defined to be the beetle mass that attenuates the rattling modes by elastically deforming the contact region to the extent that the rattling modes cannot be identified as distinct modes in cross-coupling measurements

Fabrication of metal matrix composites of

Fine fibrous titanium carbide (TiC) was processed through the self-propagating high-temperature synthesis (SHS) method and employed to fabricate aluminum matrix composites. Two consol-idation methods were investigated: (1) combustion synthesis of TiC fiber/Al composites directly using titanium powders and carbon fibers ignited simultaneously with varying amounts of the matrix metal powder and (2) combustion synthesis of TiC using titanium powders and carbon fibers followed by consolidation into different amounts of the metal matrix powder, Al, via hot isostatic pressing (HIP). In the former method, when the amount of the Al in the matrix was increased, the maximum temperature obtained by the combustion reaction decreased and the propagation of the synthesis reactions became difficult to maintain. Preheating was required for the mixture of reactants with more than approximately 5 mole pct aluminum matrix powders in order to ignite and maintain the propagation rate. Microstructural analysis of the products from the Al/C/Ti reaction without preheating shows that small amounts of an aluminum carbide phase (AI4C3) are present. In the second method, following separation of the individual fibers in the TiC product, dense composites containing the SHS products were obtained by HIP of a mixture of the TiC fibers and Al powders. No ternary phase was formed during this procedure. © 1992 The Minerals, Metals and Materials Society, and ASM International