Low Levels of Genetic Divergence across Geographically and Linguistically Diverse Populations from India

Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studies of genetic disease. Here, by genotyping India-born individuals sampled in the United States, we carry out an extensive study of Indian genetic variation. We analyze 1,200 genome-wide polymorphisms in 432 individuals from 15 Indian populations. We find that populations from India, and populations from South Asia more generally, constitute one of the major human subgroups with increased similarity of genetic ancestry. However, only a relatively small amount of genetic differentiation exists among the Indian populations. Although caution is warranted due to the fact that United States–sampled Indian populations do not represent a random sample from India, these results suggest that the frequencies of many genetic variants are distinctive in India compared to other parts of the world and that the effects of population heterogeneity on the production of false positives in association studies may be smaller in Indians (and particularly in Indian-Americans) than might be expected for such a geographically and linguistically diverse subset of the human population

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Identification of genes that modify ataxin-1-induced neurodegeneration

International audienceA growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease. Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease

Sample Sizes and Geographic Origins of Samples

<p>The latitudes and longitudes used for the various groups are given in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020215#pgen-0020215-st002" target="_blank">Table S2</a>.</p

Mean <i>F_st</i> Values for Each Indian Group across Comparisons with 18 Populations from East Asia, 12 Populations from Europe and the Middle East, and the Other 14 Groups from India

<div><p>(A) 715 microsatellites.</p><p>(B) 207 indels.</p><p>Error bars denote standard deviations across comparisons.</p></div

Cumulative Distribution Function for the Absolute Allele Frequency Difference between Various Populations and (Non-Gujarati) Indians

<div><p>(A) All alleles at 715 microsatellites.</p><p>(B) All alleles at 207 indels.</p><p>(C) Common alleles at 715 microsatellites (alleles whose frequencies average more than 0.05 in the two groups).</p><p>(D) Common alleles at 207 indels (alleles whose frequencies have a mean above 0.05 and below 0.95 in the two groups).</p></div

Correlation Coefficient of Allele Frequencies in India with Linear Combinations of the Allele Frequencies in Europe and East Asia, as a Function of the Fraction of the Linear Combination Drawn from Europe

<p>Graphs with “all populations” compare the frequencies in the pooled Indian sample with linear combinations of the pooled European/Middle Eastern sample and the pooled East Asian sample; graphs with “larger populations” exclude the Parsi group from the Indian sample and utilize only the pooled French, Italian, and Russian genotypes in Europe and the pooled Han Chinese and Japanese genotypes in East Asia. The maxima of the four graphs, from top to bottom, occur at (0.685, 0.967), (0.656, 0.957), (0.679, 0.918), and (0.654, 0.898), respectively. The analysis considers all alleles found worldwide at the 715 microsatellites and 207 indels.</p

Comparison of Allele Frequencies in India to Allele Frequencies in East Asia and Europe/Middle East

<div><p>(A) East Asia, 8,618 alleles at 715 microsatellites.</p><p>(B) East Asia, 414 alleles at 207 indels.</p><p>(C) Europe/Middle East, 8,618 alleles at 715 microsatellites.</p><p>(D) Europe/Middle East, 414 alleles at 207 indels.</p></div

Relationship of <i>F_st</i> and Geographic Distance for Pairs of Groups from India

<div><p>(A) 715 microsatellites (correlation coefficient of −0.10 [<i>p</i> = 0.32], or 0.09 [<i>p</i> = 0.41] if comparisons involving the Parsi group are excluded).</p><p>(B) 207 indels (correlation coefficient of −0.02 [<i>p</i> = 0.84], or 0.28 [<i>p</i> = 0.007] when excluding comparisons involving the Parsi group). </p><p>A complete list of pairwise values of <i>F_st</i> is contained in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020215#pgen-0020215-st003" target="_blank">Table S3</a>.</p></div

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

Background: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit