The variation in weight within a shared environment is largely attributable to genetic factors. Whilst many genes/loci confer susceptibility to obesity, little is known about the genetic architecture ...of healthy thinness. Here, we characterise the heritability of thinness which we found was comparable to that of severe obesity (h2 = 28.07 vs 32.33% respectively), although with incomplete genetic overlap (r = -0.49, 95% CI -0.17, -0.82, p = 0.003). In a genome-wide association analysis of thinness (n = 1,471) vs severe obesity (n = 1,456), we identified 10 loci previously associated with obesity, and demonstrate enrichment for established BMI-associated loci (pbinomial = 3.05x10-5). Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. In further analyses, we detected a novel obesity and BMI-associated locus at PKHD1 (rs2784243, obese vs. thin p = 5.99x10-6, obese vs. controls p = 2.13x10-6 pBMI = 2.3x10-13), associations at loci recently discovered with much larger sample sizes (e.g. FAM150B and PRDM6-CEP120), and novel variants driving associations at previously established signals (e.g. rs205262 at the SNRPC/C6orf106 locus and rs112446794 at the PRDM6-CEP120 locus). Our ability to replicate loci found with much larger sample sizes demonstrates the value of clinical extremes and suggest that characterisation of the genetics of thinness may provide a more nuanced understanding of the genetic architecture of body weight regulation and may inform the identification of potential anti-obesity targets.
Understanding the genetic structure of Native American populations is important to clarify their diversity, demographic history, and to identify genetic factors relevant for biomedical traits. Here, ...we show a demographic history reconstruction from 12 Native American whole genomes belonging to six distinct ethnic groups representing the three main described genetic clusters of Mexico (Northern, Southern, and Maya). Effective population size estimates of all Native American groups remained below 2,000 individuals for up to 10,000 years ago. The proportion of missense variants predicted as damaging is higher for undescribed (~ 30%) than for previously reported variants (~ 15%). Several variants previously associated with biological traits are highly frequent in the Native American genomes. These findings suggest that the demographic and adaptive processes that occurred in these groups shaped their genetic architecture and could have implications in biological processes of the Native Americans and Mestizos of today.
Escherichia coli strains lacking the phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS), which is the major bacterial component involved in glucose transport and its phosphorylation, ...accumulate high amounts of phosphoenolpyruvate that can be diverted to the synthesis of commercially relevant products. However, these strains grow slowly in glucose as sole carbon source due to its inefficient transport and metabolism. Strain PB12, with 400% increased growth rate, was isolated after a 120 hours adaptive laboratory evolution process for the selection of faster growing derivatives in glucose. Analysis of the genetic changes that occurred in the PB12 strain that lacks PTS will allow a better understanding of the basis of its growth adaptation and, therefore, in the design of improved metabolic engineering strategies for enhancing carbon diversion into the aromatic pathways.
Whole genome analyses using two different sequencing methodologies: the Roche NimbleGen Inc. comparative genome sequencing technique, and high throughput sequencing with Illumina Inc. GAIIx, allowed the identification of the genetic changes that occurred in the PB12 strain. Both methods detected 23 non-synonymous and 22 synonymous point mutations. Several non-synonymous mutations mapped in regulatory genes (arcB, barA, rpoD, rna) and in other putative regulatory loci (yjjU, rssA and ypdA). In addition, a chromosomal deletion of 10,328 bp was detected that removed 12 genes, among them, the rppH, mutH and galR genes. Characterization of some of these mutated and deleted genes with their functions and possible functions, are presented.
The deletion of the contiguous rppH, mutH and galR genes that occurred simultaneously, is apparently the main reason for the faster growth of the evolved PB12 strain. In support of this interpretation is the fact that inactivation of the rppH gene in the parental PB11 strain substantially increased its growth rate, very likely by increasing glycolytic mRNA genes stability. Furthermore, galR inactivation allowed glucose transport by GalP into the cell. The deletion of mutH in an already stressed strain that lacks PTS is apparently responsible for the very high mutation rate observed.
Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery ...plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.
Klebsiella
sp. strain AqSCr, isolated from Cr(VI)-polluted groundwater, reduces Cr(VI) both aerobically and anaerobically and resists up 34 mM Cr(VI); this resistance is independent of the ChrA ...efflux transporter. In this study, we report the whole genome sequence and the transcriptional profile by RNA-Seq of strain AqSCr under Cr(VI)-adapted conditions and found 255 upregulated and 240 downregulated genes compared to controls without Cr(VI) supplementation. Genes differentially transcribed were mostly associated with oxidative stress response, DNA repair and replication, sulfur starvation response, envelope-osmotic stress response, fatty acid (FA) metabolism, ribosomal subunits, and energy metabolism. Among them, genes not previously associated with chromium resistance, for example,
cybB
, encoding a putative superoxide oxidase (SOO),
gltA2
, encoding an alternative citrate synthase, and
des
, encoding a FA desaturase, were upregulated. The
sodA
gene encoding a manganese superoxide dismutase was upregulated in the presence of Cr(VI), whereas
sodB
encoding an iron superoxide dismutase was downregulated. Cr(VI) resistance mechanisms in strain AqSCr seem to be orchestrated by the alternative sigma factors
fecl
,
rpoE
, and
rpoS
(all of them upregulated). Membrane lipid analysis of the Cr(IV)-adapted strain showed a lower proportion of unsaturated lipids with respect to the control, which we hypothesized could result from unsaturated lipid peroxidation followed by degradation, together with
de novo
synthesis mediated by the upregulated FA desaturase-encoding gene,
des
. This report helps to elucidate both Cr(VI) toxicity targets and global bacterial response to Cr(VI).
The mammalian olfactory system displays species-specific adaptations to different ecological niches. To investigate the evolutionary dynamics of olfactory sensory neuron (OSN) subtypes across ...mammalian evolution, we applied RNA sequencing of whole olfactory mucosa samples from mouse, rat, dog, marmoset, macaque, and human. We find that OSN subtypes, representative of all known mouse chemosensory receptor gene families, are present in all analyzed species. Further, we show that OSN subtypes expressing canonical olfactory receptors are distributed across a large dynamic range and that homologous subtypes can be either highly abundant across all species or species/order specific. Highly abundant mouse and human OSN subtypes detect odorants with similar sensory profiles and sense ecologically relevant odorants, such as mouse semiochemicals or human key food odorants. Together, our results allow for a better understanding of the evolution of mammalian olfaction in mammals and provide insights into the possible functions of highly abundant OSN subtypes.
•A new integrated risk tool combines clinical and polygenic risk scores.•Prediction is significantly enhanced in multiple ethnicities and ancestries.•Ethnicities include Black and White, ancestries ...include African and European.•This is the first positive cross-ethnicity cross-ancestry validation of such a tool.
The American College of Cardiology / American Heart Association pooled cohort equations tool (ASCVD-PCE) is currently recommended to assess 10-year risk for atherosclerotic cardiovascular disease (ASCVD). ASCVD-PCE does not currently include genetic risk factors. Polygenic risk scores (PRSs) have been shown to offer a powerful new approach to measuring genetic risk for common diseases, including ASCVD, and to enhance risk prediction when combined with ASCVD-PCE. Most work to date, including the assessment of tools, has focused on performance in individuals of European ancestries. Here we present evidence for the clinical validation of a new integrated risk tool (IRT), ASCVD-IRT, which combines ASCVD-PCE with PRS to predict 10-year risk of ASCVD across diverse ethnicity and ancestry groups. We demonstrate improved predictive performance of ASCVD-IRT over ASCVD-PCE, not only in individuals of self-reported White ethnicities (net reclassification improvement NRI; with 95% confidence interval = 2.7% 1.1 to 4.2) but also Black / African American / Black Caribbean / Black African (NRI = 2.5% 0.6–4.3) and South Asian (Indian, Bangladeshi or Pakistani) ethnicities (NRI = 8.7% 3.1 to 14.4). NRI confidence intervals were wider and included zero for ethnicities with smaller sample sizes, including Hispanic (NRI = 7.5% −1.4 to 16.5), but PRS effect sizes in these ethnicities were significant and of comparable size to those seen in individuals of White ethnicities. Comparable results were obtained when individuals were analyzed by genetically inferred ancestry. Together, these results validate the performance of ASCVD-IRT in multiple ethnicities and ancestries, and favor their generalization to all ethnicities and ancestries.
Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a ...single genome-wide association study (GWAS) including 8,951 U.S. White and 2,712 U.S. Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association near GCK (rs3757840, βmeta = 0.0062; minor allele frequency MAF = 0.49; Pmeta = 3.66 × 10-8) and confirmed the association near RCN3 (rs113886122, βmeta = 0.0134; MAF = 0.17; Pmeta = 5.71 × 10-18). Colocalization analysis with whole-blood expression quantitative trait loci data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2 = 7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (P > 0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni-corrected P < 0.0012). Our results broaden knowledge of the genetic architecture of fructosamine and prioritize FCGRT for downstream functional studies at the established RCN3 locus.
Abstract only Risk-guided intervention in the US, informed by the pooled cohort equations (PCE) risk calculator, is the accepted practice for prevention of atherosclerotic cardiovascular disease ...(ASCVD). We recently showed that a polygenic risk score (PRS, summarising common genetic risk) can be integrated with PCE into an integrated risk tool (IRT) and we validated its utility across multiple contexts including sex, age, genetic ancestry and self-identified ethnicity (Weale et al 2021). The addition of PRS is always beneficial, but its contribution varies by context. When meta-analysed across multiple cohorts, the PRS is more predictive in men (odds ratio per standard deviation, ORsd=1.57) than women (ORsd=1.46). Across ethnicities, the group with the lowest effect size is African American (ORsd=1.14 in men, ORsd=1.11 in women), a result that predominantly reflects a lack of available training samples. The availability of a CVD IRT has practical clinical implications. Because the IRT substantially spreads the risk scores in a given patient stratum, the inclusion of genetic factors can result in some individuals crossing actionable risk thresholds in both directions. Using UK Biobank, a large UK population cohort aged 45-64 with extensive medical and genetic information, we show that the rates of up/down classification are 7.8%/4.2% in younger men (40-54yo), 1.9%/11.6% in older men (55-69yo), 1.0%/0.2% in younger women, and 6.5%/6.6% in older women. This implies a tendency to under-treat in younger and over-treat in older individuals under current guidelines. Model discrimination (Harrell’s C, a measure of area-under-the-curve for survival data) is also greatest in the younger (C=0.751/0.732 in men/women) vs older (C=0.666/0.697 in men/women) age group. Given the increased up-classification and discrimination in the younger group, the addition of genetics provides an opportunity for earlier intervention in those most at risk.
Abstract only
Introduction:
We have previously shown that combining a polygenic risk score (PRS) for cardiovascular disease (CVD), a numerical summary of an individual’s genetic predisposition to ...CVD, with standard clinical risk calculators such as ASCVD-PCE and QRISK results in improved estimates of CVD risk. Implementation of such a cardiovascular integrated risk tool (CVD IRT) into real world clinical practice is a key focus for further study.
Hypothesis:
We assessed the hypothesis that a CVD IRT can be incorporated into routine primary care.
Methods:
The Healthcare Evaluation of Absolute Risk Testing Study (NCT05294419) is a prospective trial recruiting up to 1,000 healthy participants undergoing health checks across 12 UK NHS general practices. Both QRISK2 and CVD IRT scores were generated and returned to clinicians, who then communicated the results to participants. The primary outcome of this study is operational success as well as feedback from health care providers (HCPs) and participants. The study also measures the impact of the CVD IRT on clinical decision making.
Results:
These are interim analyses. As of April 2022, 624 eligible participants (62% female, mean age 55) have been recruited. A total of 371 CVD IRT reports have been generated, with 100% of blood samples generating scores that were all returned within the designated time frame. Among the primary care HCPs, 89% (8/9) agreed that the incorporation of CVD IRT into routine care could be done in a straightforward manner. Among the participants who have completed a survey to date, 93% (125/135) would likely or very likely recommend the CVD IRT to friends and family. Average QRISK2 (6.3%) and CVD IRT (6.6%) risk scores did not differ significantly, but there were broad changes in risk among individual patients, with 5% (19/371) of patients crossing above the risk threshold to treat according to NICE guidelines (10-year risk ≥ 10%) as well as 3% (11/371) of patients reclassified as very high risk (10-year risk ≥ 20%).
Conclusions:
The rollout of an integrated risk tool combining polygenic risk into a standardized CVD risk calculator within primary care is feasible and well accepted by clinicians and participants. The CVD IRT results suggest clinically actionable changes in a substantial proportion of this population.
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