Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae

It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

Background & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Managed Nitrogen Load Decrease Reduces Chlorophyll and Hypoxia in Warming Temperate Urban Estuary

Many urban estuaries worldwide suffer from excess phytoplankton and hypoxia (low oxygen) due to high nutrient loads. A common water quality management strategy is to require wastewater treatment facility upgrades. This case study examines Narragansett Bay, a warming temperate mid-latitude urban estuary with seasonal periodic hypoxia, during June through September from 2005 to 2019. Within this period, numerous facilities were upgraded to nitrogen removal over several years. The response of the bay is more consistent with “textbook” expectations for reduced chlorophyll and hypoxia than what was seen in many other systems—despite its complex coastline geometry, numerous river inputs, and widely-distributed treatment facilities. River flow drives inter-annual variability with increased load, density stratification, chlorophyll, and hypoxia in wet years. Mean 2013-2019 bay-wide total nitrogen load was 34% less than the 2005-2012 mean, a reduction of about 106 kg yr-1, comparable to the range of flow-driven inter-annual variations. Chlorophyll Index and Hypoxia Index event-based metrics applied to high-frequency time series observations at eight sites quantify exceedances of severe and moderate thresholds. Relatively steady 33% and 16% Chlorophyll Index declines, for severe and moderate thresholds, occurred from about 2007 to 2019. The Hypoxia Index declined markedly by 2009 and 2014 for severe and moderate thresholds, respectively, and remained at or near zero from 2014 to 2019. The load reduction explains chlorophyll and hypoxia declines better than physical processes including river flow, stratification, tidal variations, winds, sea level differences, and temperatures. River flow about 55% higher than the 2005-2019 mean would increase non-treatment facility loads by an amount comparable to the managed load decrease, so future wet summers could partially reverse the improvements. Long-term trends include warming of about 0.5°C decade-1, which reduces oxygen saturation by 0.1 mg l-1 decade-1. This rate is likely a lower bound for temperature-driven oxygen decreases, because warming can also accelerate phytoplankton growth and bacterial consumption. Without warming, the managed load decrease would have curtailed hypoxia more effectively. Climate trends should be at least as important to future eutrophication as the managed load decline because, in addition to warming influences, long-term increases in river flow would increase load and stratification

Narragansett Bay hypoxic event characteristics based on fixed-site monitoring network time series: Intermittency, geographic distribution, spatial synchronicity, and interannual variability

Low dissolved oxygen events were characterized in Narragansett Bay (NB), a moderate-size (370 km2) temperate estuary with a complex passage/embayment geometry, using time series from 2001 to 2006 at nine fixed-site monitoring stations. Metrics for event intensity and severity were the event-mean deficit relative to a threshold (mg O2 l-1) and the deficit-duration (mg O2 l-1 day; product of deficit and duration [day]). Hypoxia (threshold 2.9 mg O2 l -1) typically occurred intermittently from late June through August at most stations, as multiple (two to five per season) events each 2 to 7 days long with deficit-duration 2 to 5 mg O2 l-1 day. Conditions were more severe to the north and west, a pattern attributed to a north-south nutrient/productivity gradient and east-west structure of residual circulation. Spatial patterns for suboxic and severely hypoxic events (thresholds 4.8 and 1.4 mg O2 l-1) were similar. The view that different processes govern event variability in different regions, each influenced by local hydrodynamics, is supported by both weak spatial synchronicity (quantified using overlap of event times at different sites) and multiple linear regressions of biological and physical parameters against event severity. Interannual changes were prominent and season-cumulative hypoxia severity correlated with June-mean river runoff and June-mean stratification. Benthic ecological implications for areas experiencing events include: NB hypoxia classifies as periodic/episodic on a near-annual basis; highest direct mortality risk is to sensitive and moderately sensitive sessile species in the northern West Passage and western Greenwich Bay, with some risk to Upper Bay; direct risk to mobile species may be ameliorated by weak spatial synchronicity; and indirect impacts, including reduced growth rates and shifts in predator-prey balances, are very likely throughout the sampled area due to observed suboxic and hypoxic conditions. © 2009 Coastal and Estuarine Research Federation

Risk assessment and genetic counseling for Lynch syndrome – Practice resource of the National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer

Identifying individuals who have Lynch syndrome involves a complex diagnostic workup that includes taking a detailed family history and a combination of various tests such as immunohistochemistry and/or molecular which may be germline and/or somatic. The National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer have come together to publish this practice resource for the evaluation of Lynch syndrome. The purpose of this practice resource was to provide guidance and a testing algorithm for Lynch syndrome as well as recommendations on when to offer testing. This practice resource does not replace a consultation with a genetics professional. This practice resource includes explanations in support of this and a summary of background data. While this practice resource is not intended to serve as a review of Lynch syndrome, it includes a discussion of background information and cites a number of key publications which should be reviewed for a more in-depth understanding. This practice resource is intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses, and other healthcare providers who evaluate patients for Lynch syndrome.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172941/1/jgc41546.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172941/2/jgc41546_am.pd

Performance of PREM1,2,6, MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases

PURPOSE: Lynch syndrome accounts for 2-5% of endometrial cancer cases. Lynch syndrome prediction models have not been evaluated among endometrial cancer cases. METHODS: Area under the receiver operating curve (AUC), sensitivity and specificity of PREMM(1,2,6), MMRpredict, and MMRpro scores were assessed among 563 population-based and 129 clinic-based endometrial cancer cases. RESULTS: A total of 14 (3%) population-based and 80 (62%) clinic-based subjects had pathogenic mutations. PREMM(1,2,6), MMRpredict, and MMRpro were able to distinguish mutation carriers from noncarriers (AUC of 0.77, 0.76, and 0.77, respectively), among population-based cases. All three models had lower discrimination for the clinic-based cohort, with AUCs of 0.67, 0.64, and 0.54, respectively. Using a 5% cutoff, sensitivity and specificity were as follows: PREMM(1,2,6), 93% and 5% among population-based cases and 99% and 2% among clinic-based cases; MMRpredict, 71% and 64% for the population-based cohort and 91% and 0% for the clinic-based cohort; and MMRpro, 57% and 85% among population-based cases and 95% and 10% among clinic-based cases. CONCLUSION: Currently available prediction models have limited clinical utility in determining which patients with endometrial cancer should undergo genetic testing for Lynch syndrome. Immunohistochemical analysis and microsatellite instability testing may be the best currently available tools to screen for Lynch syndrome in endometrial cancer patients