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)

Dynamics of Myoblast Transplantation Reveal a Discrete Minority of Precursors with Stem Cell–like Properties as the Myogenic Source

Myoblasts, the precursors of skeletal muscle fibers, can be induced to withdraw from the cell cycle and differentiate in vitro. Recent studies have also identified undifferentiated subpopulations that can self-renew and generate myogenic cells (Baroffio, A., M. Hamann, L. Bernheim, M.-L. Bochaton-Pillat, G. Gabbiani, and C.R. Bader. 1996. Differentiation. 60:47–57; Yoshida, N., S. Yoshida, K. Koishi, K. Masuda, and Y. Nabeshima. 1998. J. Cell Sci. 111:769–779). Cultured myoblasts can also differentiate and contribute to repair and new muscle formation in vivo, a capacity exploited in attempts to develop myoblast transplantation (MT) for genetic modification of adult muscle. Our studies of the dynamics of MT demonstrate that cultures of myoblasts contain distinct subpopulations defined by their behavior in vitro and divergent responses to grafting. By comparing a genomic and a semiconserved marker, we have followed the fate of myoblasts transplanted into muscles of dystrophic mice, finding that the majority of the grafted cells quickly die and only a minority are responsible for new muscle formation. This minority is behaviorally distinct, slowly dividing in tissue culture, but rapidly proliferative after grafting, suggesting a subpopulation with stem cell–like characteristics

Focus on the Future: A Plan for the HOPE Village Initiative Area

http://deepblue.lib.umich.edu/bitstream/2027.42/110953/1/focusonthefuture2010.pd

Incidence of cardiovascular risk factors by education level 2000-2005 : the Australian diabetes, obesity and lifestyle (AusDiab) cohort study

Lower socioeconomic status (SES) is associated with a higher prevalence of major risk factors for cardiovascular disease (CVD). However, few longitudinal studies have examined the association between SES and CVD risk factors over time. We aimed to determine whether SES, using education as a proxy, is associated with the onset of CVD risk factors over 5 years in an Australian adult cohort study. Participants in the Australian Diabetes, Obesity and Lifestyle study (AusDiab) study aged 25 years and over who attended both baseline and 5-year follow-up examinations (n=5 967) were categorised according to educational attainment. Cardiovascular risk factor data at both time points were ascertained through questionnaire and physical measurement. Women with lower education had a greater risk of progressing from normal weight to overweight or obesity than those with higher education (age-adjusted OR 1.57, 95% CI 1.06-2.31). Both men and women with lower education were more likely to develop diabetes (age-adjusted OR from higher education 1.75, 95% CI 1.14-2.71 and 3.01, 95% CI 1.26-7.20, respectively). A lower level of education was associated with a greater number of risk factors accumulated over time in women (OR of progressing from having two or less risk factors at baseline to three or more at follow up, 2.04, 95% 1.32-3.14). In this Australian population-based study, lower educational attainment was associated with an increased risk of developing both individual and total CVD risk factors over a 5-year period. These findings suggest that SES inequalities in CVD will persist into the future.<br /

Psychometric properties of the Late-Life Function and Disability Instrument: a systematic review

Background: The choice of measure for use as a primary outcome in geriatric research is contingent upon the construct of interest and evidence for its psychometric properties. The Late-Life Function and Disability Instrument (LLFDI) has been widely used to assess functional limitations and disability in studies with older adults. The primary aim of this systematic review was to evaluate the current available evidence for the psychometric properties of the LLFDI. Methods: Published studies of any design reporting results based on administration of the original version of the LLFDI in community-dwelling older adults were identified after searches of 9 electronic databases. Data related to construct validity (convergent/divergent and known-groups validity), test-retest reliability and sensitivity to change were extracted. Effect sizes were calculated for within-group changes and summarized graphically. Results: Seventy-one studies including 17,301 older adults met inclusion criteria. Data supporting the convergent/divergent and known-groups validity for both the Function and Disability components were extracted from 30 and 18 studies, respectively. High test-retest reliability was found for the Function component, while results for the Disability component were more variable. Sensitivity to change of the LLFDI was confirmed based on findings from 25 studies. The basic lower extremity subscale and overall summary score of the Function component and limitation dimension of the Disability component were associated with the strongest relative effect sizes. Conclusions: There is extensive evidence to support the construct validity and sensitivity to change of the LLFDI among various clinical populations of community-dwelling older adults. Further work is needed on predictive validity and values for clinically important change. Findings from this review can be used to guide the selection of the most appropriate LLFDI subscale for use an outcome measure in geriatric research and practice

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

IL23R (Interleukin 23 Receptor) variants protective against inflammatory bowel diseases (IBD) display loss of functiondue to impaired protein stability and intracellular trafficking

Genome-wide association studies as well as murine models have shown that the interleukin 23 receptor (IL23R) pathway plays a pivotal role in chronic inflammatory diseases such as Crohn disease (CD), ulcerative colitis, psoriasis, and type 1 diabetes. Genome-wide association studies and targeted re-sequencing studies have revealed the presence of multiple potentially causal variants of the IL23R. Specifically the G149R, V362I, and R381Q IL23R chain variants are linked to protection against the development of Crohn disease and ulcerative colitis in humans. Moreover, the exact mechanism of action of these receptor variants has not been elucidated. We show that all three of these IL23R variants cause a reduction in IL23 receptor activation-mediated phosphorylation of the signaltransducing activator of transcription 3 (STAT3) and phosphorylation of signal transducing activator of transcription 4 (STAT4). The reduction in signaling is due to lower levels of cell surface receptor expression. For G149R, the receptor retention in the endoplasmic reticulum is due to an impairment of receptor maturation, whereas the R381Q and V362I variants have reduced protein stability. Finally, we demonstrate that the endogenous expression of IL23R protein from V362I and R381Q variants in human lymphoblastoid cell lines exhibited lower expression levels relative to susceptibility alleles. Our results suggest a convergent cause of IL23R variant protection against chronic inflammatory disease

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