Evidence of Early-Stage Selection on EPAS1 and GPR126 Genes in Andean High Altitude Populations.

The aim of this study is to identify genetic variants that harbour signatures of recent positive selection and may facilitate physiological adaptations to hypobaric hypoxia. To achieve this, we conducted whole genome sequencing and lung function tests in 19 Argentinean highlanders (>3500 m) comparing them to 16 Native American lowlanders. We developed a new statistical procedure using a combination of population branch statistics (PBS) and number of segregating sites by length (nSL) to detect beneficial alleles that arose since the settlement of the Andes and are currently present in 15-50% of the population. We identified two missense variants as significant targets of selection. One of these variants, located within the GPR126 gene, has been previously associated with the forced expiratory volume/forced vital capacity ratio. The other novel missense variant mapped to the EPAS1 gene encoding the hypoxia inducible factor 2α. EPAS1 is known to be the major selection candidate gene in Tibetans. The derived allele of GPR126 is associated with lung function in our sample of highlanders (p < 0.05). These variants may contribute to the physiological adaptations to hypobaric hypoxia, possibly by altering lung function. The new statistical approach might be a useful tool to detect selected variants in population studies

Positive selection of AS3MT to arsenic water in Andean populations.

Arsenic is a carcinogen associated with skin lesions and cardiovascular diseases. The Colla population from the Puna region in Northwest Argentinean is exposed to levels of arsenic in drinking water exceeding the recommended maximum by a factor of 20. Yet, they thrive in this challenging environment since thousands of years and therefore we hypothesize strong selection signatures in genes involved in arsenic metabolism. We analyzed genome-wide genotype data for 730,000 loci in 25 Collas, considering 24 individuals of the neighbouring Calchaquíes and 24 Wichí from the Gran Chaco region in the Argentine province of Salta as control groups. We identified a strong signal of positive selection in the main arsenic methyltransferase AS3MT gene, which has been previously associated with lower concentrations of the most toxic product of arsenic metabolism monomethylarsonic acid. This study confirms recent studies reporting selection signals in the AS3MT gene albeit using different samples, tests and control populations

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia

GWAS of epigenetic aging rates in blood reveals a critical role for TERT.

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10-11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening

Genomic analyses inform on migration events during the peopling of Eurasia

High-coverage whole-genome sequence studies have so far focused\ud on a limited number1 of geographically restricted populations2–5,\ud or been targeted at specific diseases, such as cancer6. Nevertheless,\ud the availability of high-resolution genomic data has led to the\ud development of new methodologies for inferring population\ud history7–9 and refuelled the debate on the mutation rate in humans10.\ud Here we present the Estonian Biocentre Human Genome Diversity\ud Panel (EGDP), a dataset of 483 high-coverage human genomes\ud from 148 populations worldwide, including 379 new genomes from\ud 125 populations, which we group into diversity and selection\ud sets. We analyse this dataset to refine estimates of continent-wide\ud patterns of heterozygosity, long- and short-distance gene flow, archaic\ud admixture, and changes in effective population size through time as\ud well as for signals of positive or balancing selection. We find a genetic\ud signature in present-day Papuans that suggests that at least 2% of\ud their genome originates from an early and largely extinct expansion\ud of anatomically modern humans (AMHs) out of Africa. Together\ud with evidence from the western Asian fossil record11, and admixture\ud between AMHs and Neanderthals predating the main Eurasian\ud expansion12, our results contribute to the mounting evidence for\ud the presence of AMHs out of Africa earlier than 75,000 years ago

DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.publishedVersionPeer reviewe

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.

The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10-8) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 × 10-6). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1, CENPN and MAD1L1) and apoptosis (TP53). We highlight the shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype-array-intensity data enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility.This research has been conducted using the UK Biobank Resource under Application Number 9905. This work was supported by the UK Medical Research Council (Unit Programme numbers MC_UU_12015/1 and MC_UU_12015/2). Research in the S. Jackson laboratory is funded by Cancer Research UK (CRUK; programme grant C6/A18796), with Institute core funding provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S. Jackson receives salary from the University of Cambridge, supplemented by CRUK

Genomic analyses inform on migration events during the peopling of Eurasia.

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.Support was provided by: Estonian Research Infrastructure Roadmap grant no 3.2.0304.11-0312; Australian Research Council Discovery grants (DP110102635 and DP140101405) (D.M.L., M.W. and E.W.); Danish National Research Foundation; the Lundbeck Foundation and KU2016 (E.W.); ERC Starting Investigator grant (FP7 - 261213) (T.K.); Estonian Research Council grant PUT766 (G.C. and M.K.); EU European Regional Development Fund through the Centre of Excellence in Genomics to Estonian Biocentre (R.V.; M.Me. and A.Me.), and Centre of Excellence for Genomics and Translational Medicine Project No. 2014-2020.4.01.15-0012 to EGC of UT (A.Me.) and EBC (M.Me.); Estonian Institutional Research grant IUT24-1 (L.S., M.J., A.K., B.Y., K.T., C.B.M., Le.S., H.Sa., S.L., D.M.B., E.M., R.V., G.H., M.K., G.C., T.K. and M.Me.) and IUT20-60 (A.Me.); French Ministry of Foreign and European Affairs and French ANR grant number ANR-14-CE31-0013-01 (F.-X.R.); Gates Cambridge Trust Funding (E.J.); ICG SB RAS (No. VI.58.1.1) (D.V.L.); Leverhulme Programme grant no. RP2011-R-045 (A.B.M., P.G. and M.G.T.); Ministry of Education and Science of Russia; Project 6.656.2014/K (S.A.F.); NEFREX grant funded by the European Union (People Marie Curie Actions; International Research Staff Exchange Scheme; call FP7-PEOPLE-2012-IRSES-number 318979) (M.Me., G.H. and M.K.); NIH grants 5DP1ES022577 05, 1R01DK104339-01, and 1R01GM113657-01 (S.Tis.); Russian Foundation for Basic Research (grant N 14-06-00180a) (M.G.); Russian Foundation for Basic Research; grant 16-04-00890 (O.B. and E.B); Russian Science Foundation grant 14-14-00827 (O.B.); The Russian Foundation for Basic Research (14-04-00725-a), The Russian Humanitarian Scientific Foundation (13-11-02014) and the Program of the Basic Research of the RAS Presidium “Biological diversity” (E.K.K.); Wellcome Trust and Royal Society grant WT104125AIA & the Bristol Advanced Computing Research Centre (http://www.bris.ac.uk/acrc/) (D.J.L.); Wellcome Trust grant 098051 (Q.A.; C.T.-S. and Y.X.); Wellcome Trust Senior Research Fellowship grant 100719/Z/12/Z (M.G.T.); Young Explorers Grant from the National Geographic Society (8900-11) (C.A.E.); ERC Consolidator Grant 647787 ‘LocalAdaptatio’ (A.Ma.); Program of the RAS Presidium “Basic research for the development of the Russian Arctic” (B.M.); Russian Foundation for Basic Research grant 16-06-00303 (E.B.); a Rutherford Fellowship (RDF-10-MAU-001) from the Royal Society of New Zealand (M.P.C.)

Comparison of variables between Collas and Wichí.

<p>*values correspond to the Commission Internationald'Eclairage L*a*b* system.</p>a<p>p≤0.001,</p>b<p>p<0.05.</p>c<p>Equally significant after correction for further independent variables:</p><p>Weight: corrected for height, age and gender; BMI: corrected for age and gender;</p><p>Systolic blood pressure/Cardiac output: corrected for time since last meal, its caloric amount, age and gender;</p><p>Log (Change in thorax breadth/depth): corrected for age and gender.</p