DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Content, diagnostic, correlational, and genetic similarities between common measures of childhood aggressive behaviors and related psychiatric traits.

BACKGROUND: Given the role of childhood aggressive behavior (AGG) in everyday child development, precise and accurate measurement is critical in clinical practice and research. This study aims to quantify agreement among widely used measures of childhood AGG regarding item content, clinical concordance, correlation, and underlying genetic construct. METHODS: We analyzed data from 1254 Dutch twin pairs (age 8-10 years, 51.1% boys) from a general population sample for whom both parents completed the A-TAC, CBCL, and SDQ at the same occasion. RESULTS: There was substantial variation in item content among AGG measures, ranging from .00 (i.e., mutually exclusive) to .50 (moderate agreement). Clinical concordance (i.e., do the same children score above a clinical threshold among AGG measures) was very weak to moderate with estimates ranging between .01 and .43 for mother-reports and between .12 and .42 for father-reports. Correlations among scales were weak to strong, ranging from .32 to .70 for mother-reports and from .32 to .64 for father-reports. We found weak to very strong genetic correlations among the measures, with estimates between .65 and .84 for mother-reports and between .30 and .87 for father-reports. CONCLUSIONS: Our results demonstrated that degree of agreement between measures of AGG depends on the type (i.e., item content, clinical concordance, correlation, genetic correlation) of agreement considered. Because agreement was higher for correlations compared to clinical concordance (i.e., above or below a clinical cutoff), we propose the use of continuous scores to assess AGG, especially for combining data with different measures. Although item content can be different and agreement among observed measures may not be high, the genetic correlations indicate that the underlying genetic liability for childhood AGG is consistent across measures.

Genetic meta-analysis of obsessive-compulsive disorder and self-report compulsive symptoms.

We investigated whether obsessive-compulsive (OC) symptoms from a population-based sample could be analyzed to detect genetic variants influencing obsessive-compulsive disorder (OCD). We performed a genome-wide association studies (GWAS) on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N = 8,267 with genome-wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case-control GWAS (r G = 0.61, p = .017) previously published by the Psychiatric Genomics Consortium (PGC-OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (r G = -0.02 and r G = 0.42, respectively). A meta-analysis of the compulsive symptoms GWAS with the PGC-OCD revealed no genome-wide significant Single-Nucleotide Polymorphisms (SNPs combined N = 17,992, indicating that the power is still low for individual SNP effects). A gene-based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene-based test also showed a significant increase in enrichment for psychiatric and brain-expressed genes. S-Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta-analysis with compulsive symptoms compared to the original PGC-OCD GWAS. Thus, the inclusion of dimensional symptom data in genome-wide association on clinical case-control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP-level power increases were limited, but aggregate, gene-level analyses showed increased enrichment for brain-expressed genes related to psychiatric disorders, and increased association with gene expression in brain tissues with known emotional, reward processing, memory, and fear-formation functions.

Characterizing the Relation Between Expression QTLs and Complex Traits: Exploring the Role of Tissue Specificity.

Measurement of gene expression levels and detection of eQTLs (expression quantitative trait loci) are difficult in tissues with limited sample availability, such as the brain. However, eQTL overlap between tissues might be high, which would allow for inference of eQTL functioning in the brain via eQTLs detected in readily accessible tissues, e.g. whole blood. Applying Stratified Linkage Disequilibrium Score Regression (SLDSR), we quantified the enrichment in polygenic signal of blood and brain eQTLs in genome-wide association studies (GWAS) of 11 complex traits. We looked at eQTLs discovered in 44 tissues by the Genotype-Tissue Expression (GTEx) consortium and two other large representative studies, and found no tissue-specific eQTL effects. Next, we integrated the GTEx eQTLs with regions associated with tissue-specific histone modifiers, and interrogated their effect on rheumatoid arthritis and schizophrenia. We observed substantially enriched effects of eQTLs located inside regions bearing modification H3K4me1 on schizophrenia, but not rheumatoid arthritis, and not tissue-specific. Finally, we extracted eQTLs associated with tissue-specific differentially expressed genes and determined their effects on rheumatoid arthritis and schizophrenia, these analysis revealed limited enrichment of eQTLs associated with gene specifically expressed in specific tissues. Our results pointed to strong enrichment of eQTLs in their effect on complex traits, without evidence for tissue-specific effects. Lack of tissue-specificity can be either due to a lack of statistical power or due to the true absence of tissue-specific effects. We conclude that eQTLs are strongly enriched in GWAS signal and that the enrichment is not specific to the eQTL discovery tissue. Until sample sizes for eQTL discovery grow sufficiently large, working with relatively accessible tissues as proxy for eQTL discovery is sensible and restricting lookups for GWAS hits to a specific tissue for which limited samples are available might not be advisable.

Appendiceal Duplication: A Comprehensive Review of Published Cases and Clinical Recommendations.

BACKGROUND: Duplex appendix is very rare (incidence 0.004%) but has clinical relevance given the frequency of appendicectomies performed. Failure to recognise duplication can result in failure of treatment and medico-legal consequences. A review of published cases was undertaken to identify factors that may help in managing this rare condition. METHODS: All English and non-English publications were identified in PubMed, Embase and Cochrane databases. Patient demographics, intraoperative findings, anatomical details and histopathology were analysed. RESULTS: A total of 141 cases were identified [male/female ratio 1.4:1, median age 20 years (range foetus to 69 years)]. Duplication of the appendix ranges from branching of the appendix trunk to a fully matured appendix located elsewhere along the colon. Most can be categorised by the Cave-Wallbridge classification. There were 22 Type A, 8 Type B1, 46 Type B2 and 10 Type C cases (Cave-Wallbridge). There were six cases of horseshoe and two cases of triple appendix. Six reports gave anatomical descriptions that could not be classified by Cave-Wallbridge categories and in 11 cases there were no anatomical descriptions. CONCLUSIONS: An anteriorly placed appendix, away from the convergence of the taenia, or a normal appendix in the presence of convincing clinical or radiological signs of appendicitis should instigate a careful examination of the caecal pole and possible exploration of the retrocaecal space for appendiceal duplication. If the patient had previous surgery for congenital abnormalities, Type B1 or Type C duplication should be considered.

High vitamin D3 diet administered during active colitis negatively affects bone metabolism in an adoptive T cell transfer model.

Decreased bone mineral density (BMD) represents an extraintestinal complication of inflammatory bowel disease (IBD). Vitamin D3 has been considered a viable adjunctive therapy in IBD. However, vitamin D3 plays a pleiotropic role in bone modeling and regulates the bone formation-resorption balance, depending on the physiological environment, and supplementation during active IBD may have unintended consequences. We evaluated the effects of vitamin D3 supplementation during the active phase of disease on colonic inflammation, BMD, and bone metabolism in an adoptive IL-10-/- CD4⁺ T cell transfer model of chronic colitis. High-dose vitamin D3 supplementation for 12 days during established disease had negligible effects on mucosal inflammation. Plasma vitamin D3 metabolites correlated with diet, but not disease, status. Colitis significantly reduced BMD. High-dose vitamin D3 supplementation did not affect cortical bone but led to a further deterioration of trabecular bone morphology. In mice fed a high vitamin D3 diet, colitis more severely impacted bone formation markers (osteocalcin and bone alkaline phosphatase) and increased bone resorption markers, ratio of receptor activator of NF-κB ligand to osteoprotegrin transcript, plasma osteoprotegrin level, and the osteoclast activation marker tartrate-resistant acid phosphatase (ACp5). Bone vitamin D receptor expression was increased in mice with chronic colitis, especially in the high vitamin D3 group. Our data suggest that vitamin D3, at a dose that does not improve inflammation, has no beneficial effects on bone metabolism and density during active colitis or may adversely affect BMD and bone turnover. These observations should be taken into consideration in the planning of further clinical studies with high-dose vitamin D3 supplementation in patients with active IBD.

An encyclopedia of mouse genes.

The laboratory mouse is the premier model system for studies of mammalian development due to the powerful classical genetic analysis possible (see also the Jackson Laboratory web site, http://www.jax.org/) and the ever-expanding collection of molecular tools. To enhance the utility of the mouse system, we initiated a program to generate a large database of expressed sequence tags (ESTs) that can provide rapid access to genes. Of particular significance was the possibility that cDNA libraries could be prepared from very early stages of development, a situation unrealized in human EST projects. We report here the development of a comprehensive database of ESTs for the mouse. The project, initiated in March 1996, has focused on 5' end sequences from directionally cloned, oligo-dT primed cDNA libraries. As of 23 October 1998, 352,040 sequences had been generated, annotated and deposited in dbEST, where they comprised 93% of the total ESTs available for mouse. EST data are versatile and have been applied to gene identification, comparative sequence analysis, comparative gene mapping and candidate disease gene identification, genome sequence annotation, microarray development and the development of gene-based map resources.

Cochlear implantation in advanced otosclerosis: utility of pre-operative radiological assessment in predicting intra-operative difficulty and final electrode position.

OBJECTIVE: This study aimed to determine if pre-operative radiological scoring can reliably predict intra-operative difficulty and final cochlear electrode position in patients with advanced otosclerosis. METHOD: A retrospective cohort study of advanced otosclerosis patients who underwent cochlear implantation (n = 48, 52 ears) was compared with a larger cohort of post-lingually deaf adult patients (n = 1414) with bilateral hearing loss and normal cochlear anatomy. Pre-operative imaging for advanced otosclerosis patients and final electrode position were scored and correlated with intra-operative difficulty and speech outcomes. RESULTS: Advanced otosclerosis patients benefit significantly from cochlear implantation. Mean duration of deafness was longer in the advanced otosclerosis group (19.5 vs 14.3 years; p < 0.05). CONCLUSION: Anatomical changes in advanced otosclerosis can result in increased difficulty of surgery. Evidence of pre-operative cochlear luminal changes was associated with intra-operative difficult insertion and final non-scala tympani position. Nearly all electrodes implanted in the advanced otosclerosis cohort were peri-modiolar. No reports of facial nerve stimulation were observed.

Predictions of Gibbs free energies for the adsorption of polyaromatic and nitroaromatic environmental contaminants on carbonaceous materials: efficient computational approach.

The adsorption of benzene, polycyclic aromatic hydrocarbons (PAHs), and nitroaromatic compounds (NACs) on the carbonaceous surfaces from the gas phase and water solution was investigated. Several different levels of theory were applied, including DFT-, MP2-, and CCSD(T)-based methods, to find an approach that is computationally inexpensive and can provide accurate thermodynamic parameters for studied adsorption phenomena. The methods and techniques used (including cluster and periodic approximations) were evaluated on the basis of comparison with available experimental data. The optimized structures of calculated complexes are obtained, and the interaction energies and Gibbs free energies are predicted. Good agreement was revealed for the theoretical and experimental adsorption energies of benzene and PAHs adsorbed on the carbon surfaces. The adsorption of benzene, PAHs, and NACs on carbon is suggested to be effective from the gas phase for all studied compounds and for PAHs and NACs also from water solution at room temperature.

A computer based, automated analysis of process and outcomes of diabetic care in 23 GP practices.

The predicted prevalence of diabetes in Ireland by 2015 is 190,000. Structured diabetes care in general practice has outcomes equivalent to secondary care and good diabetes care has been shown to be associated with the use of electronic healthcare records (EHRs). This automated analysis of EHRs in 23 practices took 10 minutes per practice compared with 15 hours per practice for manual searches. Data was extracted for 1901 type II diabetics. There was valid data for >80% of patients for 6 of the 9 key indicators in the previous year. 543 (34%) had a Hba1c > 7.5%, 142 (9%) had a total cholesterol >6 mmol/l, 83 (6%) had an LDL cholesterol >4 mmol/l, 367 (22%) had Triglycerides > 2.2 mmol/l and 162 (10%) had Blood Pressure > 160/100 mmHg. Data quality and key indicators of care compare well with manual audits in Ireland and the U.K. electronic healthcare records and automated audits should be a feature of all chronic disease management programs.

Scedosporium apiospermum infections in the middle ear and mastoid: case series and review of the literature.

OBJECTIVES: To present our case series and management of Scedosporium apiospermum infections of the middle ear and mastoid, and review the current literature on this rare yet potentially life-threatening condition. METHODS: Medical records of patients treated at the Royal Victorian Eye and Ear Hospital for S apiospermum middle ear and mastoid infections between 2009 and 2019 were reviewed. A literature search was conducted using PubMed, Medline and Cochrane Library databases. RESULTS: Two patients were identified in our institution: a 62-year-old diabetic woman with otogenic skull base osteomyelitis, and a 12-year-old boy with unilateral chronic suppurative otitis media which developed after tympanostomy tube insertion. The persistence of otalgia and otorrhoea despite prolonged antibiotic treatment characterised these cases. Both patients received voriconazole, and achieved disease resolution without complications. Ten relevant cases were identified after review of the literature. Despite treatment, there were three patient deaths, and four patients with otological or neurological complications. CONCLUSION: The presence of a middle ear or mastoid infection refractory to appropriate topical and systemic antibiotics should prompt clinicians to consider a fungal infection. The role of surgical debridement in the treatment of S apiospermum infection of the middle ear and mastoid is equivocal.

Longevity of an immunocontraceptive vaccine effect on fecundity in rats.

•Increases in human-wildlife conflicts alongside cultural shifts against lethal control methods are driving the need for alternative wildlife management tools such as fertility control. Contraceptive formulations suitable for oral delivery would permit broader remote application in wildlife species.•This study evaluated the contraceptive effect and immune response to two novel injectable immunocontraceptive formulations targeting the Gonadotropin Releasing Hormone (GnRH): MAF-IMX294 and MAF-IMX294P conjugates, both identified as having potential as oral contraceptives. The study also explored whether in multiparous species immunocontraceptives may either totally prevent reproduction or also affect litter size.•Female rats, chosen as a model species, were given three doses of either MAF-IMX294 or MAF-IMX294P to compare anti-GnRH immune response and reproductive output up to 310 days post-treatment.•Both formulations induced anti-GnRH antibody titres in 100% of rats and significantly impaired fertility compared to control animals. Following treatment with MAF-IMX294 and MAF-IMX294P 0 of 9 and 1 of 10 females respectively produced litters following the first mating challenge 45 days post-treatment, compared to 9 of 9 control animals.•Across the whole 310 day study period 7 of 9 females from the MAF-IMX294 group and 10 of 10 females in the MAF-IMX294P group became fertile, producing at least one litter throughout six mating challenges.•No significant differences were found between the two formulations in antibody titre response or duration of contraceptive effect, with an average time to first pregnancy of 166 days for MAF-IMX294 and 177 days for MAF-IMX294P for all females that became fertile.•Following treatment with MAF-IMX294 and MAF-IMX294P the first litter produced post-infertility in treated females was significantly smaller than in control animals. This indicates treatment with immunocontraceptives may induce an overall suppression of fecundity extending past an initial infertility effect. This increases the potential long-term impact of these immunocontraceptives in multiparous species such as commensal rodents.

High frequency of cholecystitis in dogs with gallbladder mucocoele in Hong Kong.

The aims of this retrospective study were to characterise the epidemiological, clinical, histopathological, and microbiological findings as well as surgical outcomes in dogs admitted to a specialist veterinary hospital in Hong Kong for surgical management of gallbladder mucocoele (GBM). Inclusion criteria were cases with histopathological diagnosis of GBM and accompanying abdominal imaging, serum biochemistry, bile culture, and liver biopsy histology results. Fifty-six cases met the inclusion criteria. The median age at diagnosis was 12 years (range, 5-16 years). Miniature or toy pure-breed dogs were most commonly affected, including Poodles, Pomeranians, Schnauzers, Bichon frises and Chihuahuas. However, no breed was over-represented compared with their expected proportions among annual hospital admissions. Histological evidence of cholecystitis was present in 84% of cases, including acute cholecystitis in 18%, chronic cholecystitis in 37.5%, acute on chronic cholecystitis in 28% and acute with necrosis in 6%. The most common liver lesions were cholestasis in 64%, along with portal fibrosis in 55%, oedema in 50% and bile duct hyperplasia in 50%. Bile culture was positive in 29.6% of cases. Escherichia coli and Enterobacter species were most commonly isolated. Stentrophomonas maltophili was cultured from one case. Of the 16 cases where bacteria were isolated from bile culture, 94% had evidence of chronic cholecystitis and 81% had evidence of cholangiohepatitis. Fifty dogs (89.3%) survived to discharge including 5/5 dogs with ruptured gallbladders. Of 34 dogs with follow-up data, 21/34 (61.8%) were still alive 12 months later. Gallbladder mucocoeles were frequently associated with both acute and chronic inflammation. High survival rates to discharge were achieved.

Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis.

We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. We identify four broad factors (neurodevelopmental, compulsive, psychotic and internalizing) that underlie genetic correlations among the disorders and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce stratified genomic structural equation modeling, which we use to identify gene sets that disproportionately contribute to genetic risk sharing. This includes protein-truncating variant-intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for genetic overlap across disorders with psychotic features. Multivariate association analyses detect 152 (20 new) independent loci that act on the individual factors and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate-to-high genetic correlations across all 11 disorders, we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants.

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms.

OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. CONCLUSION: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

NHE3 modulates the severity of colitis in IL-10-deficient mice.

NHE3, the major intestinal Na(+)/H(+) exchanger, was shown to be downregulated and/or inhibited in patients with inflammatory bowel disease (IBD), a phenomenon believed to contribute to inflammation-associated diarrhea. NHE3(-/-) mice spontaneously develop colitis and demonstrate high susceptibility to dextran sulfate-induced mucosal injury. We investigated the effects of NHE3 deficiency on the development of chronic colitis in an IL-10 knockout (KO) mouse model of Crohn's disease. NHE3(-/-) mice were first backcrossed to 129/SvEv mice for >10 generations, with no apparent changes in their survival or phenotype. These mice were crossed with IL-10(-/-) mice on the same genetic background, and the phenotypes of 10-wk-old wild-type (WT), IL-10(-/-), NHE3(-/-), and IL-10(-/-)/NHE3(-/-) (double-KO) mice were studied. Histological and immunohistochemical examination of the colon established important architectural alterations, including increased neutrophilic and mononuclear cell infiltration in double- compared with single-KO mice. Double-KO mice demonstrated increased colonic expression of neutrophil collagenase matrix metalloproteinase-8 and the chemokines macrophage inflammatory protein-2, CXCL1, CXCL10, and CXCL11. Colonic IFNγ, IL-17, and IL-12/23 p40 protein secretion was significantly increased in double- compared with single-KO mice. IL-10(-/-)/NHE3(-/-) mouse colonic epithelium exhibited increased hallmarks of apoptosis, including a significantly increased number of cleaved caspase-3-positive surface epithelial cells. These results highlight the importance of NHE3 in the maintenance of intestinal barrier integrity and in modulating the inflammatory process in IL-10-deficient mice. Chronic NHE3 inhibition or underexpression observed in IBD may therefore contribute to the pathogenesis of IBD by influencing the extent of the epithelial barrier defect and affect the ultimate degree of inflammation.

The risk of variant Creutzfeldt-Jakob disease among UK patients with bleeding disorders, known to have received potentially contaminated plasma products.

The risk of variant Creutzfeldt-Jakob disease (vCJD) from potentially infected plasma products remains unquantified. This risk has been assessed for 787 UK patients with an inherited bleeding disorder prospectively followed-up for 10-20 years through the UK Haemophilia Centre Doctors' Organisation (UKHCDO) Surveillance Study. These patients had been treated with any of 25 'implicated' clotting factor batches from 1987 to 1999, which included in their manufacture, plasma from eight donors who subsequently developed clinical vCJD. Variant CJD infectivity of these batches was estimated using plasma fraction infectivity estimates and batch-manufacturing data. Total potential vCJD infectivity received by each patient has been estimated by cumulating estimated infectivity from all doses received during their lifetime. Of 787 patients, 604 (77%) were followed-up for over 13 years following exposure to an implicated batch. For these 604 patients, the estimated vCJD risk is ≥ 1% for 595, ≥ 50% for 164 and 100% for 51. This is additional to background UK population risk due to dietary exposure. Of 604 patients, 94 (16%) received implicated batches linked to donors who developed clinical vCJD within 6 months of their donations. One hundred and fifty-one (25%) had received their first dose when under 10 years of age. By 1st January 2009, none of these patients had developed clinical vCJD. The absence of clinical vCJD cases in this cohort to date suggests that either plasma fraction infectivity estimates are overly precautionary, or the incubation period is longer for this cohort than for implicated cellular blood product recipients. Further follow-up of this cohort is needed.

Can the Gibbs free energy of adsorption be predicted efficiently and accurately: an M05-2X DFT study.

This study presents new insight into the prediction of partitioning of organic compounds between a carbon surface (soot) and water, and it also sheds light on the sluggish desorption of interacting molecules from activated and nonactivated carbon surfaces. This paper provides details about the structure and interactions of benzene, polycyclic aromatic hydrocarbons, and aromatic nitrocompounds with a carbon surface modeled by coronene using a density functional theory approach along with the M05-2X functional. The adsorption was studied in vacuum and from water solution. The molecules studied are physisorbed on the carbon surface. While the intermolecular interactions of benzene and hydrocarbons are governed by dispersion forces, nitrocompounds are adsorbed also due to quite strong electrostatic interactions with all types of carbon surfaces. On the basis of these results, we conclude that the method of prediction presented in this study allows one to approach the experimental level of accuracy in predicting thermodynamic parameters of adsorption on a carbon surface from the gas phase. The empirical modification of the polarized continuum model leads also to a quantitative agreement with the experimental data for the Gibbs free energy values of the adsorption from water solution.

Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction.

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.

Genetic association study of childhood aggression across raters, instruments, and age.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.