SSGAC Risk Tolerance: GWAS and MTAG Polygenic Scores (Ver 1.0)

Introduction. Karlsson Linnér et al.1 conducted genome-wide association analyses of general risk tolerance (n = 975,353), adventurousness and risky behaviors in the driving, drinking, smoking and sexual domains. In separate hold-out cohorts, they analyzed the predictive power of polygenic scores derived from the genome-wide association study (GWAS) estimates. Due to data access restrictions, it is not possible to release summary statistics for more than 10,000 single nucleotide polymorphisms (SNPs). Therefore, researchers with access to the individual-level genotype data cannot reproduce the polygenic scores that were used in the paper from publicly available summary statistics (https://www.thessgac.org/data). As a partial remedy, we are releasing the polygenic scores that were used in the paper’s prediction analyses in the Add Health and UKB-siblings cohorts to researchers (but due to the restrictions, we cannot release the underlying SNP-level weights themselves)

Muscle satellite cells adopt divergent fates: a mechanism for self-renewal?

Growth, repair, and regeneration of adult skeletal muscle depends on the persistence of satellite cells: muscle stem cells resident beneath the basal lamina that surrounds each myofiber. However, how the satellite cell compartment is maintained is unclear. Here, we use cultured myofibers to model muscle regeneration and show that satellite cells adopt divergent fates. Quiescent satellite cells are synchronously activated to coexpress the transcription factors Pax7 and MyoD. Most then proliferate, down-regulate Pax7, and differentiate. In contrast, other proliferating cells maintain Pax7 but lose MyoD and withdraw from immediate differentiation. These cells are typically located in clusters, together with Pax7-ve progeny destined for differentiation. Some of the Pax7+ve/MyoD-ve cells then leave the cell cycle, thus regaining the quiescent satellite cell phenotype. Significantly, noncycling cells contained within a cluster can be stimulated to proliferate again. These observations suggest that satellite cells either differentiate or switch from terminal myogenesis to maintain the satellite cell pool

Why It Is Hard to Find Genes Associated With Social Science Traits: Theoretical and Empirical Considerations

OBJECTIVES: We explain why traits of interest to behavioral scientists may have a genetic architecture featuring hundreds or thousands of loci with tiny individual effects rather than a few with large effects and why such an architecture makes it difficult to find robust associations between traits and genes. METHODS: We conducted a genome-wide association study at 2 sites, Harvard University and Union College, measuring more than 100 physical and behavioral traits with a sample size typical of candidate gene studies. We evaluated predictions that alleles with large effect sizes would be rare and most traits of interest to social science are likely characterized by a lack of strong directional selection. We also carried out a theoretical analysis of the genetic architecture of traits based on R.A. Fisher's geometric model of natural selection and empirical analyses of the effects of selection bias and phenotype measurement stability on the results of genetic association studies. RESULTS: Although we replicated several known genetic associations with physical traits, we found only 2 associations with behavioral traits that met the nominal genome-wide significance threshold, indicating that physical and behavioral traits are mainly affected by numerous genes with small effects. CONCLUSIONS: The challenge for social science genomics is the likelihood that genes are connected to behavioral variation by lengthy, nonlinear, interactive causal chains, and unraveling these chains requires allying with personal genomics to take advantage of the potential for large sample sizes as well as continuing with traditional epidemiological studies.EconomicsPsycholog

Neoadjuvant chemoradiation compared to neoadjuvant radiation alone and surgery alone for Stage II and III soft tissue sarcoma of the extremities

<p>Abstract</p> <p>Background</p> <p>Neoadjuvant chemoradiation (NCR) prior to resection of extremity soft tissue sarcoma (STS) has been studied, but data are limited. We present outcomes with NCR using a variety of chemotherapy regimens compared to neoadjuvant radiation without chemotherapy (NR) and surgery alone (SA).</p> <p>Methods</p> <p>We conducted a retrospective chart review of 112 cases.</p> <p>Results</p> <p>Treatments included SA (36 patients), NCR (39 patients), and NR (37 patients). NCR did not improve the rate of margin-negative resections over SA or NR. Loco-regional relapse-free survival, distant metastases-free survival, and overall survival (OS) were not different among the treatment groups. Patients with relapsed disease (OR 11.6; p = 0.01), and tumor size greater than 5 cm (OR 9.4; p = 0.01) were more likely to have a loco-regional recurrence on logistic regression analysis. Significantly increased OS was found among NCR-treated patients with tumors greater than 5 cm compared to SA (3 year OS 69 vs. 40%; p = 0.03). Wound complication rates were higher after NCR compared to SA (50 vs. 11%; p = 0.003) but not compared to NR (p = 0.36). Wet desquamation was the most common adverse event of NCR.</p> <p>Conclusions</p> <p>NCR and NR are acceptable strategies for patients with STS. NCR is well-tolerated, but not clearly superior to NR.</p

Myogenic cell proliferation and generation of a reversible tumorigenic phenotype are triggered by preirradiation of the recipient site

Environmental influences have profound yet reversible effects on the behavior of resident cells. Earlier data have indicated that the amount of muscle formed from implanted myogenic cells is greatly augmented by prior irradiation (18 Gy) of the host mouse muscle. Here we confirm this phenomenon, showing that it varies between host mouse strains. However, it is unclear whether it is due to secretion of proliferative factors or reduction of antiproliferative agents. To investigate this further, we have exploited the observation that the immortal myogenic C2 C12 cell line forms tumors far more rapidly in irradiated than in nonirradiated host muscle. We show that the effect of preirradiation on tumor formation is persistent and dose dependent. However, C2 C12 cells are not irreversibly compelled to form undifferentiated tumor cells by the irradiated muscle environment and are still capable of forming large amounts of muscle when reimplanted into a nonirradiated muscle. In a clonal analysis of this effect, we discovered that C2 C12 cells have a bimodal propensity to form tumors; some clones form no tumors even after extensive periods in irradiated graft sites, whereas others rapidly form extensive tumors. This illustrates the subtle interplay between the phenotype of implanted cells and the factors in the muscle environment

Most Reported Genetic Associations with General Intelligence Are Probably False Positives

General intelligence (g) and virtually all other behavioral traits are heritable. Associations between g and specific single-nucleotide polymorphisms (SNPs) in several candidate genes involved in brain function have been reported. We sought to replicate published associations between g and 12 specific genetic variants (in the genes DTNBP1, CTSD, DRD2, ANKK1, CHRM2, SSADH, COMT, BDNF, CHRNA4, DISC1, APOE, and SNAP25) using data sets from three independent, well-characterized longitudinal studies with samples of 5,571, 1,759, and 2,441 individuals. Of 32 independent tests across all three data sets, only 1 was nominally significant. By contrast, power analyses showed that we should have expected 10 to 15 significant associations, given reasonable assumptions for genotype effect sizes. For positive controls, we confirmed accepted genetic associations for Alzheimer’s disease and body mass index, and we used SNP-based calculations of genetic relatedness to replicate previous estimates that about half of the variance in g is accounted for by common genetic variation among individuals. We conclude that the molecular genetics of psychology and social science requires approaches that go beyond the examination of candidate genes.Economic

Pre-exposure prophylaxis initiation and adherence among Black men who have sex with men (MSM) in three US cities: results from the HPTN 073 study

Abstract : Introduction: Randomized clinical trials have demonstrated the efficacy of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV acquisition among men who have sex with men (MSM). However, limited research has examined initiation and adherence to PrEP among Black MSM (BMSM) in the United States (US) who are disproportionately represented among newly HIV infected and late to care individuals. This research reports on the HIV Prevention Trials Network 073 (HPTN 073) study aimed to examine PrEP initiation, utilization and adherence among Black MSM utilizing the theoretically principled, cul- turally informed and client-centered care coordination (C4) model. Methods: The HPTN 073 study enrolled and followed 226 HIV-uninfected Black MSM in three US cities (Los Angeles, CA; Washington DC; and Chapel Hill, NC) from February 2013 through September 2015. Study participants were offered once daily oral emtricitabine/tenofovir (FTC/TDF) PrEP combined with C4 and followed up for 52 weeks. Participants received HIV testing, risk reduction education and clinical monitoring. Results: Of the 226 men enrolled, 178 participants initiated PrEP (79%), and of these 64% demonstrated PrEP utilization at week 26 (mid-point of the study) based on pharmacokinetic testing. Condomless anal sex with an HIV-infected or unknown status casual male partner was statistically significantly associated with a greater likelihood of PrEP initiation (adjusted odds ratio (OR) 4.4, 95% confidence interval (CI) 1.7, 11.7). Greater age (≥25 vs. <25, OR 2.95, 95% CI 1.37 –6.37), perception of having enough money (OR 3.6, 95% CI 1.7 to 7.7) and knowledge of male partner taking PrEP before sex (OR 2.22, 95% CI 1.03 to 4.79) were statistically significantly associated with increased likelihood of PrEP adherence at week 26. Annualized HIV incidence was 2.9 (95% CI 1.2 to 7.9) among those who initiated PrEP, compared to 7.7 (95% CI 2.5 to 24.1) among those who did not initiate PrEP (p = 0.18). Conclusions: Results suggest a high level of PrEP initiation among at-risk Black MSM, a group historically characterized as hard to reach. The data support the importance of addressing contextual factors that affect PrEP initiation and adherence, and of additional research on the ultimate benefit of PrEP in HIV prevention among Black MSM

The Promises and Pitfalls of Genoeconomics

This article reviews existing research at the intersection of genetics and economics, presents some new findings that illustrate the state of genoeconomics research, and surveys the prospects of this emerging field. Twin studies suggest that economic outcomes and preferences, once corrected for measurement error, appear to be about as heritable as many medical conditions and personality traits. Consistent with this pattern, we present new evidence on the heritability of permanent income and wealth. Turning to genetic association studies, we survey the main ways that the direct measurement of genetic variation across individuals is likely to contribute to economics, and we outline the challenges that have slowed progress in making these contributions. The most urgent problem facing researchers in this field is that most existing efforts to find associations between genetic variation and economic behavior are based on samples that are too small to ensure adequate statistical power. This has led to many false positives in the literature. We suggest a number of possible strategies to improve and remedy this problem: (a) pooling data sets, (b) using statistical techniques that exploit the greater information content of many genes jointly, and (c) focusing on economically relevant traits that are most proximate to known biological mechanisms.EconomicsSociolog

Skeletal muscle stem cells express anti-apoptotic ErbB receptors during activation from quiescence

To be effective for tissue repair, satellite cells (the stem cells of adult muscle) must survive the initial activation from quiescence. Using an in vitro model of satellite cell activation, we show that erbB1, erbB2 and erbB3, members of the EGF receptor tyrosine kinase family, appear on satellite cells within 6 h of activation. We show that signalling via erbB2 provides an anti-apoptotic survival mechanism for satellite cells during the first 24 h, as they progress to a proliferative state. Inhibition of erbB2 signalling with AG825 reduced satellite cell numbers, concomitant with elevated caspase-8 activation and TUNEL labelling of apoptotic satellite cells. In serum-free conditions, satellite cell apoptosis could be largely prevented by a mixture of erbB1, erbB3 and erbB4 ligand growth factors, but not by neuregulin alone (erbB3/erbB4 ligand). Furthermore, using inhibitors specific to discrete intracellular signalling pathways, we identify MEK as a pro-apoptotic mediator, and the erbB-regulated factor STAT3 as an anti-apoptotic mediator during satellite cell activation. These results implicate erbB2 signalling in the preservation of a full compliment of satellite cells as they activate in the context of a damaged muscle

On the sources of the height–intelligence correlation: New insights from a bivariate ACE model with assortative mating

A robust positive correlation between height and intelligence, as measured by IQ tests, has been established in the literature. This paper makes several contributions toward establishing the causes of this association. First, we extend the standard bivariate ACE model to account for assortative mating. The more general theoretical framework provides several key insights, including formulas to decompose a cross-trait genetic correlation into components attributable to assortative mating and pleiotropy and to decompose a cross-trait within-family correlation. Second, we use a large dataset of male twins drawn from Swedish conscription records and examine how well genetic and environmental factors explain the association between (i) height and intelligence and (ii) height and military aptitude, a professional psychogologist’s assessment of a conscript’s ability to deal with wartime stress. For both traits, we find suggestive evidence of a shared genetic architecture with height, but we demonstrate that point estimates are very sensitive to assumed degrees of assortative mating. Third, we report a significant within-family correlation between height and intelligence \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$(\hat{\rho}=0.10),$$\end{document} suggesting that pleiotropy might be at play