Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Cardiometabolic Pregnancy Complications in Association With Autism-Related Traits as Measured by the Social Responsiveness Scale in ECHO

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Inf luences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998–2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (β = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (β = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may inf luence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Person-centered/experiential psychotherapy for anxiety difficulties : theory, research and practice

Anxiety difficulties are an increasingly important focus for person-centered/experiential (PCE) psychotherapies. I begin by reviewing person-centered, focusing-oriented, and emotion-focused therapy (EFT) theories of anxiety. Next, I summarize a meta-analysis of 19 outcome studies of PCE therapies for adults with anxiety, most commonly supportive or person-centered therapies (PCT) carried out by cognitive behavior therapy (CBT) researchers. The results indicate large pre-post change but a clear inferiority to CBT. I then summarize promising early results from an ongoing study of PCT and EFT for social anxiety, which show large amounts of pre-post change for both forms of PCE therapy but substantially more change for clients in the EFT condition. I conclude with a discussion of the implications for PCE therapy practice, including the value of process differentiation and the possibility of developing more effective PCE approaches for anxiety

Physical separation of soil organic matter

The distribution of organic matter within physical fractions of the soil can be assessed by disruption of the soil structure, followed by the separation of physical fractions based on particle size or density. Disruption of the soil structure can be accomplished by physical or chemical methods, or some combination of the two. The most commonly used methods of physical disruption are shaking and sonication. Shaking is the more gentle method with the advantage of being able to obtain a wide range of disrupting energies relatively easily. Sonication can impart more energy to the soil in a shorter period of time. The greatest potential problem associated with the use of sonication is the redistribution of organic matter among size/density fractions. Chemical extraction methods are commonly used prior to disruption of soil for particle size analysis. Some chemical dispersants can selectively solubilize organic matter. This specificity can be used to determine the kinds and amounts of organic matter that bind particles into aggregates. Three methods of physical separation of soil have been used, sieving, sedimentation and densitometry. Sieving separates soil particles based strictly on size and is used primarily for aggregate separations of non-disrupted soil samples. Sedimentation separates particles based on an equivalent spherical diameter, which may vary in size, shape and density. It is most often used in conjunction with a disruption pretreatment to obtain fine fractions. Densitometry separates particles based on the weight per unit volume, independent of size and shape, and is used to separate lighter from heavier fractions. It is possible to combine any or all of these separation methods in order to isolate, for instance, organic matter from a particular size fraction that has a specific density

Platform drowning leading to cool-water carbonate deposition: Evolution of a late ordovician (Turinian-Chatfieldian) mixed-sediment platform within the taconic orogen (Long Point Group, Newfoundland Appalachians)

Late Ordovician (Turinian–Chatfieldian) drowning of a mixed carbonate–siliciclastic platform within the Taconic Orogen (Newfoundland Appalachians) is recorded by net deepening of an initial warm, shallow-water platform succession (Lourdes Formation) culminating in a metre-scale thick condensed interval that characterizes a drowning succession punctuated by storm deposits. Composition of transported material suggests that seaward drowning was coupled with back-stepping of a high-energy carbonate factory related to hinterland uplift and erosion that would eventually lead to drowning of the outer platform beneath marine-transported siliciclastic sediments (Winterhouse Formation). In the new offshore shelf setting, a sparse reciprocal stratigraphy of fine- to very coarse-grained phosphatic carbonate and mixed sediment is interpreted to document gravity-flow deposition downgradient from either a sustained or episodically developed high-energy cool-water carbonate source along the inner shelf. Transported carbonate was cemented rapidly at temperatures no warmer than 16 °C– 23 °C, possibly within a seasonal oceanic thermocline. An upsection decrease in abundance of carbonate by the early Edenian is associated with a dramatic increase in siliciclastic supply. The Turinian–Edenian succession of platform drowning, oceanographic transition to cool-water carbonate production, and, later, its termination by increased siliciclastic supply reflects a first-order tectonic control proximal to uplift within the Taconic Orogen. Similar structural and oceanographic changes along the contemporary distal Laurentian margin provides the basis, with improved biostratigraphic control, for future analysis of the significance of proximal–distal stratigraphies in response to regional foreland tectonism