Distinct etiological influences on obsessive-compulsive symptoms dimensions: A multivariate twin study

Background Obsessive-compulsive disorder (OCD) is characterized by five major dimensions, including contamination/washing, harm/checking, symmetry/ordering, hoarding, and forbidden thoughts. How these dimensions may relate etiologically to the symptoms of other obsessive-compulsive related disorders (OCRDs) and anxiety disorders (ADs) is not well known. The aim of this study was to examine the genetic and environmental overlap between each major obsessive-compulsive dimension with the symptoms of other OCRDs and ADs. MethodsTwo thousand four hundred ninety-five twins of both sexes, aged between 18 and 45 years, were recruited from the Australian Twin Registry. Measures used scores on four dimensions (obsessing (forbidden thoughts), washing, checking, and ordering) of the Obsessive-Compulsive Inventory-Revised, Dysmorphic Concerns Questionnaire, Hoarding Rating Scale, Anxiety Sensitivity Index, Social Phobia Inventory, and Stress subscale of the Depression, Anxiety, and Stress Scale. Multivariate twin modeling methods using continuous and categorized variables were performed, also controlling for age and gender. ResultsOur findings suggested that forbidden thoughts and washing demonstrated the strongest genetic overlap with other AD symptoms, while ordering was genetically related to OCRD symptoms. Common genetic influences on checking symptoms were best estimated when modeling OCRDs together with AD symptoms. Common environmental factors of ordering and checking were shared with AD symptoms. ConclusionsImportant shared genetic and environmental risk factors exist between OCD, OCRDs, and ADs, but which vary alongside the expression of its major dimension

Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides

Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5' and 3' splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the two "essential" splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combinations. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript, compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the "splice region" and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies.Peer reviewe

Controlling the {111}/{110} Surface Ratio of Cuboidal Ceria Nanoparticles

The ability to control size and morphology is crucial in optimizing nanoceria catalytic activity as this is governed by the atomistic arrangement of species and structural features at the surfaces. Here, we show that cuboidal cerium oxide nanoparticles can be obtained via microwave-assisted hydrothermal synthesis in highly alkaline media. HRTEM revealed that the cube edges were truncated by CeO2{110} surfaces and the cube corners by CeO2{111} surfaces. When adjusting synthesis conditions by increasing NaOH concentration, the average particle size increased. Although this was accompanied by an increase of the cube faces, CeO2{100}, the cube edges, CeO2{110}, and cube corners, CeO2{111} remained of constant size. Molecular Dynamics (MD) was used to rationalise this behaviour and revealed that energetically, the corners and edges cannot be atomically sharp, rather they are truncated by {111} and {110} surfaces respectively to stabilise the nanocube; both experiment and simulation agreed a minimum size of ~1.6 nm associated with this truncation. Moreover, HRTEM and MD revealed {111}/{110} faceting of the {110} edges, which balances the surface energy associated with the exposed surfaces, which follows {111}>{110}>{100}, although only the {110} surface facets because of the ease of extracting oxygen from its surface, which follows {111}>{100}>{110}. Finally, MD revealed that the {100} surfaces are ‘liquid-like’ with a surface oxygen mobility 5 orders of magnitude higher than that on the {111} surfaces; this arises from the flexibility of the surface species network that can access many different surface arrangements due to very small energy differences. This finding has implications for understanding the surface chemistry of nanoceria and provides avenues to rationalize the design of catalytically active materials at the nanoscale

Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans but with limited evidence in other ancestries. Here, we present a multi-ancestry proteome-wide MR analysis based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the putative causal effects of 1,545 proteins on eight diseases in African (32,658) and European (1,219,993) ancestries and identified 45 and 7 protein-disease pairs with MR and genetic colocalization evidence in the two ancestries, respectively. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence in both ancestries and seven pairs with specific effects in the two ancestries separately. Integrating these MR signals with clinical trial evidence, we prioritized 16 pairs for investigation in future drug trials. Our results highlight the value of proteome-wide MR in informing the generalizability of drug targets for disease prevention across ancestries and illustrate the value of meta-analysis of biobanks in drug development

Reaction time performance in ADHD: improvement under fast-incentive condition and familial effects

ABSTRACT Background Reaction time (RT) variability is one of the strongest findings to emerge in cognitive-experimental research of attention deficit hyperactivity disorder (ADHD). We set out to confirm the association between ADHD and slow and variable RTs and investigate the degree to which RT performance improves under fast event rate and incentives. Using a group familial correlation approach, we tested the hypothesis that there are shared familial effects on RT performance and ADHD. Method A total of 144 ADHD combined-type probands, 125 siblings of the ADHD probands and 60 control participants, ages 6-18, performed a four-choice RT task with baseline and fast-incentive conditions. Results ADHD was associated with slow and variable RTs, and with greater improvement in speed and RT variability from baseline to fast-incentive condition. RT performance showed shared familial influences with ADHD. Under the assumption that the familial effects represent genetic influences, the proportion of the phenotypic correlation due to shared familial influences was estimated as 60-70%. Conclusions The data are inconsistent with models that consider RT variability as reflecting a stable cognitive deficit in ADHD, but instead emphasize the extent to which energetic or motivational factors can have a greater effect on RT performance in ADHD. The findings support the role of RT variability as an endophenotype mediating the link between genes and ADH

ACCESS & LRG-BEASTS: a precise new optical transmission spectrum of the ultrahot Jupiter WASP-103b

We present a new ground-based optical transmission spectrum of the ultrahot Jupiter WASP-103b ($T_{eq} = 2484$K). Our transmission spectrum is the result of combining five new transits from the ACCESS survey and two new transits from the LRG-BEASTS survey with a reanalysis of three archival Gemini/GMOS transits and one VLT/FORS2 transit. Our combined 11-transit transmission spectrum covers a wavelength range of 3900--9450A with a median uncertainty in the transit depth of 148 parts-per-million, which is less than one atmospheric scale height of the planet. In our retrieval analysis of WASP-103b's combined optical and infrared transmission spectrum, we find strong evidence for unocculted bright regions ($4.3\sigma$) and weak evidence for H$_2$O ($1.9\sigma$), HCN ($1.7\sigma$), and TiO ($2.1\sigma$), which could be responsible for WASP-103b's observed temperature inversion. Our optical transmission spectrum shows significant structure that is in excellent agreement with the extensively studied ultrahot Jupiter WASP-121b, for which the presence of VO has been inferred. For WASP-103b, we find that VO can only provide a reasonable fit to the data if its abundance is implausibly high and we do not account for stellar activity. Our results highlight the precision that can be achieved by ground-based observations and the impacts that stellar activity from F-type stars can have on the interpretation of exoplanet transmission spectra.Comment: 33 pages, 17 figures, 7 tables. Accepted for publication in A

Runs of Homozygosity Implicate Autozygosity as a Schizophrenia Risk Factor

Autozygosity occurs when two chromosomal segments that are identical from a common ancestor are inherited from each parent. This occurs at high rates in the offspring of mates who are closely related (inbreeding), but also occurs at lower levels among the offspring of distantly related mates. Here, we use runs of homozygosity in genome-wide SNP data to estimate the proportion of the autosome that exists in autozygous tracts in 9,388 cases with schizophrenia and 12,456 controls. We estimate that the odds of schizophrenia increase by ∼17% for every 1% increase in genome-wide autozygosity. This association is not due to one or a few regions, but results from many autozygous segments spread throughout the genome, and is consistent with a role for multiple recessive or partially recessive alleles in the etiology of schizophrenia. Such a bias towards recessivity suggests that alleles that increase the risk of schizophrenia have been selected against over evolutionary time

HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

HIF1α induction by mTOR represents a metabolic checkpoint for the differentiation of TH17 and Treg cells