Biology subjects

Williams, B.

Publications and source records attributed to Williams, B..

63 records · Page 4Linked to original sources

bioRxiv2020

Quantification of the pace of biological aging in humans through a blood test: a DNA methylation algorithm

Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed to serve as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood DNA-methylation measure that is sensitive to variation in the pace of biological aging among individuals born the same year. We first modeled longitudinal change in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in the Dunedin birth cohort. Rates of change in each biomarker were composited to form a measure of aging-related decline, termed Pace of Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace of Aging, called DunedinPoAm for Dunedin (P)ace (o)f (A)ging (m)ethylation. Validation analyses showed DunedinPoAm was associated with functional decline in the Dunedin Study and more advanced biological age in the Understanding Society Study, predicted chronic disease and mortality in the Normative Aging Study, was accelerated by early-life adversity in the E-risk Study, and DunedinPoAm prediction was disrupted by caloric restriction in the CALERIE trial. DunedinPoAm generally outperformed epigenetic clocks. Findings provide proof-of-principle for DunedinPoAm as a single-time-point measure of a persons pace of biological aging.

genomics↗

bioRxiv2020

Only ten percent of the global terrestrial protected area network is connected via intact land

Land free of direct anthropogenic disturbance is considered essential for achieving biodiversity conservation outcomes but is rapidly eroding. In response, many nations are increasing their protected area estates but little consideration is given to the context of the surrounding landscape. This is despite the fact that connectivity between protected areas is critical in a changing climate and mandated in international protected area targets. By utilizing the latest human pressure assessment, which shows that [~]40% of the terrestrial planet is still intact, and a connectivity method, we found just 9.7% of Earths terrestrial protected network can be considered connected. On average, 11% of each nations protected area estate is connected via intact land. As the global community commits to bolder action on abating biodiversity loss, only an increased focus on landscape-scale habitat retention and restoration efforts will ensure those critical areas safeguarded for conservation outcomes will remain (or become) connected. One Sentence SummaryOnly 9.7% of the global protected area network can be considered connected by intact land.

ecology↗

bioRxiv2020

Investigating the Genetic Architecture of Non-Cognitive Skills Using GWAS-by-Subtraction

Educational attainment (EA) is influenced by cognitive abilities and by other characteristics and traits. However little is known about the genetic architecture of these "non-cognitive" contributions to EA. Here, we use Genomic Structural Equation Modelling and results of prior genome-wide association studies (GWASs) of EA (N = 1,131,881) and cognitive test performance (N = 257,841) to estimate SNP associations with variation in EA that is independent of cognitive ability. We identified 157 genome-wide significant loci and a polygenic architecture accounting for 57% of genetic variance in EA. Phenotypic and biological annotation revealed that (1) both cognitive and non-cognitive contributions to EA were genetically correlated with socioeconomic success and longevity; and (2) non-cognitive contributions to EA were related to personality, decision making, risk-behavior, and increased risk for psychiatric disorders; (3) non-cognitive and cognitive contributions to EA were enriched in the same tissues and cell types, but (4) showed different associations with gray-matter neuroimaging phenotypes.

genetics↗

bioRxiv2019

Protein polyglutamylation catalyzed by the bacterial Calmodulin-dependent pseudokinase SidJ

Pseudokinases are considered to be the inactive counterparts of conventional protein kinases and comprise approximately 10% of the human and mouse kinomes. Here we report the crystal structure of the Legionella pneumophila effector protein, SidJ, in complex with the eukaryotic Ca2+-binding regulator, Calmodulin (CaM). The structure reveals that SidJ contains a protein kinase-like fold domain, which retains a majority of the characteristic kinase catalytic motifs. However, SidJ fails to demonstrate kinase activity. Instead, mass spectrometry and in vitro biochemical analysis demonstrate that SidJ modifies another Legionella effector SdeA, an unconventional phosphoribosyl ubiquitin ligase, by adding glutamate molecules to a specific residue of SdeA in a CaM-dependent manner. Furthermore, we show that SidJ-mediated polyglutamylation suppresses the ADP-ribosylation activity. Our work further implies that some pseudokinases may possess ATP-dependent activities other than conventional phosphorylation.

biochemistry↗

bioRxiv2018

Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases

PurposeLimb Girdle Muscular Dystrophies (LGMD) are a genetically heterogeneous category of autosomal inherited muscle diseases. Many genes causing LGMD have been identified, and clinical trials are beginning for treatment of some genetic subtypes. However, even with the gene-level mechanisms known, it is still difficult to get a reliable and generalizable prevalence estimation for each subtype due to the limited amount of epidemiology data and the low incidence of LGMDs. MethodsTaking advantage of recently published whole exome and genome sequencing data from the general population, we used a Bayesian method to develop a reliable disease prevalence estimator. ResultsThis method was applied to nine recessive LGMD subtypes. The estimated disease prevalence calculated by this method were largely comparable to published estimates from epidemiological studies, however highlighted instances of possible under-diagnosis for LGMD2B and 2L. ConclusionThe increasing size of aggregated population variant databases will allow for robust and reproducible prevalence estimates of recessive disease, which is critical for the strategic design and prioritization of clinical trials.

epidemiology↗

bioRxiv2018

Using DNA from mothers and children to study parental investment in children’s educational attainment

This study tested implications of new genetic discoveries for understanding the association between parental investment and childrens educational attainment. A novel design matched genetic data from 860 British mothers and their children with home-visit measures of parenting: the E-Risk Study. Three findings emerged. First, both mothers and childrens education-associated genetics, summarized in a genome-wide polygenic score, predicted parenting -- a gene-environment correlation. Second, accounting for genetic influences slightly reduced associations between parenting and childrens attainment -- indicating some genetic confounding. Third, mothers genetics influenced childrens attainment over and above genetic mother-to-child transmission, via cognitively-stimulating parenting -- an environmentally-mediated effect. Findings imply that, when interpreting parents effects on children, environmentalists must consider genetic transmission, but geneticists must also consider environmental transmission.

genetics↗

bioRxiv2018

Genetics & the Geography of Health, Behavior, and Attainment

Peoples life chances can be predicted by their neighborhoods. This observation is driving efforts to improve lives by changing neighborhoods. Some neighborhood effects may be causal, supporting neighborhood-level interventions. Other neighborhood effects may reflect selection of families with different characteristics into different neighborhoods, supporting interventions that target families/individuals directly. To test how selection affects different neighborhood-linked problems, we linked neighborhood data with genetic, health, and social-outcome data for >7,000 European-descent UK and US young people in the E-Risk and Add Health Studies. We tested selection/concentration of genetic risks for obesity, schizophrenia, teen-pregnancy, and poor educational outcomes in high-risk neighborhoods, including genetic analysis of neighborhood mobility. Findings argue against genetic selection/concentration as an explanation for neighborhood gradients in obesity and mental-health problems, suggesting neighborhoods may be causal. In contrast, modest genetic selection/concentration was evident for teen-pregnancy and poor educational outcomes, suggesting neighborhood effects for these outcomes should be interpreted with care.

genetics↗

bioRxiv2018

A Polygenic Score for Higher Educational Attainment is Associated with Larger Brains

People who score higher on intelligence tests tend to have larger brains. Twin studies suggest the same genetic factors influence both brain size and intelligence. This has led to the hypothesis that genetics influence intelligence partly by contributing to development of larger brains. We tested this hypothesis with molecular genetic data using discoveries from a genome-wide association study (GWAS) of educational attainment, a correlate of intelligence. We analyzed genetic, brain imaging, and cognitive test data from the UK Biobank, the Dunedin Study, the Brain Genomics Superstruct Project (GSP), and the Duke Neurogenetics Study (DNS) (combined N=8,271). We measured genetics using polygenic scores based on published GWAS. We conducted meta-analysis to test associations among participants genetics, total brain volume (i.e., brain size), and cognitive test performance. Consistent with previous findings, participants with higher polygenic scores achieved higher scores on cognitive tests, as did participants with larger brains. Participants with higher polygenic scores also had larger brains. We found some evidence that brain size partly mediated associations between participants education polygenic scores and their cognitive test performance. Effect-sizes were larger in the population-based UK Biobank and Dunedin samples than in the GSP and DNS samples. Sensitivity analysis suggested this effect-size difference partly reflected restricted range of cognitive performance in the GSP and DNS samples. Recruitment and retention of population-representative samples should be a priority for neuroscience research. Findings suggest promise for studies integrating GWAS discoveries with brain imaging data to understand neurobiology linking genetics with individual differences in cognitive performance.

neuroscience↗

bioRxiv2017

Antiretroviral treatment, prevention of transmission, and modeling the HIV epidemic: why the ART efficacy, coverage, and effectiveness parameters matter

IntroductionHIV remains a major public health threat with over 75 million deaths, 2 million annual infections and over 1 million HIV-associated TB cases a year. Population-based studies suggest a marked decline in incidence, prevalence and deaths, mostly likely due to treatment expansion, in countries in East and Southern Africa. This calls into question the ART efficacy, effectiveness and coverage parameters used by many modelers to project HIV incidence and prevalence.\n\nMethodsFor 2015 and 2016 we reviewed global and national mathematical modeling studies regarding ART impact (with or without other HIV prevention interventions) and/or 90-90-90 on either new HIV infections or investment or both. We reviewed these HIV epidemiologic and costing models for their structure and parameterization around ART; we directly compared two models to illustrate differences in outcome.\n\nResultsThe nine models published in 2015 or 2016 included parameters for ART effectiveness ranging from 20% to 86% for ART effectiveness. Model 1 limits eligibility for ART initiation to 80% coverage of people living with HIV and with a CD4+ cell count below 350 cells/L, 70% retention, and ART reduces transmission by 80%, with a derived ART effectiveness of 20%. Model 2 assumes 90-90-90 by 2020 (i.e., 73% viral suppression of estimated PLHIV), ART reduces transmission by 96% in those on ART and virally suppressed, and by 88% in those on ART but not virally suppressed with a derived effectiveness of 86% and consequent decline towards ending AIDS and HIV elimination. ART parameter selection and assumptions dominate and low ART effectiveness translates into lower impact.\n\nDiscussionUsing more realistic parameters for ART effectiveness suggests that through expanding access and supporting sustainable viral suppression it will be possible to significantly reduce transmission and eliminate HIV in many settings.

epidemiology↗