The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic ...health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.
Abstract
Monte Carlo and Morris screening techniques are used to examine the relative sensitivity of deep convective simulations to changes in initial conditions (IC) versus changes to microphysical ...parameters (MP). IC are perturbed using a set of empirical orthogonal function–principal component pairs obtained from a database of tropical soundings, while MP are perturbed consistent with their range of realistic values. Monte Carlo experiments provide a broad overview of parameter–output response, while Morris screening techniques identify the most significant influences on specific model output variables. Changes to MP produce a similar order-of-magnitude response in convective hydrologic cycle, dynamics, and latent heating as changes to IC. Changes in IC appear to have a larger effect on radiative fluxes than perturbations to MP. The distribution of low-level latent heating reveals that changes in MP have a larger influence on cold pool properties than changes to the environment. The dominant effects are produced by a subset of cloud MP and thermodynamic structure functions, indicating perturbation of a subset of the control factors may be used to produce most of the variability in a short-term convective-scale ensemble forecast. The most influential MP are the autoconversion threshold, the rain particle size distribution intercept, and the ice particle fall speed parameters. The most influential EOFs are those that correspond to variability in lower- to midtropospheric temperature and water vapor, as well as zonal low-level shear. The results have implications for both the understanding of what influences convective development and the design of ensemble-based prediction and data assimilation systems.
Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide ...association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.
Since the first International Cooperative for Aerosol Prediction (ICAP) multi‐model ensemble (MME) study, the number of ICAP global operational aerosol models has increased from five to nine. An ...update of the current ICAP status is provided, along with an evaluation of the performance of ICAP‐MME over 2012–2017, with a focus on June 2016–May 2017. Evaluated with ground‐based Aerosol Robotic Network (AERONET) aerosol optical depth (AOD) and data assimilation quality MODerate‐resolution Imaging Spectroradiometer (MODIS) retrieval products, the ICAP‐MME AOD consensus remains the overall top‐scoring and most consistent performer among all models in terms of root‐mean‐square error (RMSE), bias and correlation for total, fine‐ and coarse‐mode AODs as well as dust AOD; this is similar to the first ICAP‐MME study. Further, over the years, the performance of ICAP‐MME is relatively stable and reliable compared to more variability in the individual models. The extent to which the AOD forecast error of ICAP‐MME can be predicted is also examined. Leading predictors are found to be the consensus mean and spread. Regression models of absolute forecast errors were built for AOD forecasts of different lengths for potential applications. ICAP‐MME performance in terms of modal AOD RMSEs of the 21 regionally representative sites over 2012–2017 suggests a general tendency for model improvements in fine‐mode AOD, especially over Asia. No significant improvement in coarse‐mode AOD is found overall for this time period.
International Cooperative for Aerosol Predictions (ICAP) model 550 nm total AOD RMSE of the 72 h forecast versus corresponding mean AODs for AERONET sites listed in Table 2. Large black dots are ICAP multi‐model ensemble consensus means. Individual models are in small coloured dots. Validation of fine‐ and coarse‐modal AODs and dust AOD is also available in Figure 2.
Inflammatory bowel disease (IBD), clinically defined as Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in ...genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0-18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn's Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7-10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn's Disease.
Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes
. Here we use exome sequence data on 628,388 individuals to ...identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes
, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.
We present a comparison of 1064 nm aerosol optical depth (AOD) and aerosol
extinction profiles from the Cloud-Aerosol Transport System (CATS) level 2
aerosol product with collocated Aerosol Robotic ...Network (AERONET) AOD, Moderate Imaging Spectroradiometer (MODIS) Aqua
and Terra Dark Target AOD and
Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) AOD and extinction
data for the period of March 2015–October 2017. Upon quality-assurance checks of
CATS data, reasonable agreement is found between aerosol data from CATS and
other sensors. Using quality-assured CATS aerosol data, for the first time,
variations in AODs and aerosol extinction profiles are evaluated at 00:00, 06:00,
12:00 and 18:00 UTC (and/or 00:00, 06:00, 12:00 and 18:00 local time or LT) on both regional and global scales. This study suggests that marginal
variations are found in AOD from a global mean perspective, with the minimum
aerosol extinction values found at 18:00 LT near the surface
layer for global oceans, for both the June–November and December–May
seasons. Over land, below 500 m, the daily minimum and maximum aerosol
extinction values are found at 12:00 and 00:00/06:00 LT,
respectively. Strong diurnal variations are also found over north Africa, the Middle East and
India for the December–May season, and over north Africa, south Africa,
the Middle East and India for the June–November season.
Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the ...United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (
,
,
,
, and
). Protein-truncating variants in
were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of
in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.
Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70–80% ...of clinically diagnosed NS patients, but the genetic basis for the remaining 20–30% of cases is unknown. We performed next-generation sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1) and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2 , MAP2K1 , or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin–Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that next-generation sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.
An algorithm for retrieving nighttime aerosol optical depth (AOD) from the Visible Infrared Imaging Radiometer Suite (VIIRS) Day-Night Band (DNB) observations of reflected moonlight is presented for ...rural areas during the western U.S. fire seasons. The algorithm uses the UNified and Linearized Vector Radiative Transfer Model (UNL-VRTM) with newly developed capabilities for considering lunar illuminations. Cloud and fire pixels are screened out by utilizing the radiance from the VIIRS Moderate-resolution Bands (M-Band) and the DNB. Rural and city pixels are classified based on a pre-calculated city light database. The surface spectral reflectance for DNB ranging from 342 to 1107 nm is estimated by a random forest approach, which is trained using the surface spectral reflectance from the existing spectral libraries. For the fire seasons of 2017 and 2020, the nighttime AOD retrieval is shown to play an indispensable role in describing the nonlinear diurnal movement of smoke transport and discerning the source of smoke plumes heretofore observable only in the daytime. The retrieved AOD values show good agreement with spatiotemporally collocated Aerosol Robotic NETwork (AERONET) and Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) AOD values, with linear correlation coefficient values of ~0.96/0.95 and ~86%/69% of the AOD pairs falling in an uncertainty envelope of ±(0.085 + 0.10AOD), which is superior to AOD reanalysis from Modern-Era Retrospective analysis for Research and Applications, version 2 (MERRA-2). These results affirm the significant potential of nighttime AOD to improve the analysis and forecast of regional to global biomass-burning aerosol distributions, filling a critical gap in the diurnal description of a key element of Earth's climate system.
•First nighttime AOD retrieval algorithm for rural areas from VIIRS lunar observation.•AOD retrievals agree well with the nighttime AERONET and CALIOP observations.•The retrieved nighttime AOD from VIIRS is much more reliable than that from MERRA-2.•Daytime AOD data from VIIRS is insufficient to depict smoke spatiotemporal variations.•Nighttime AOD mapping from VIIRS shed lights to the diurnal transport of smoke layers.
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