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- Aragam, KG, et al.
(author)
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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 2022
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
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Journal article (peer-reviewed)abstract
- The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
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- Aragam, KG, et al.
(author)
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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 2022
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
-
Journal article (peer-reviewed)abstract
- The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
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- Chu, Audrey Y, et al.
(author)
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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
- 2017
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 125-130
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Journal article (peer-reviewed)abstract
- Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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- Holguín-Veras, J., et al.
(author)
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The New York city off-hour delivery program: A business and community-friendly sustainability program
- 2018
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In: Interfaces. - : Institute for Operations Research and the Management Sciences (INFORMS). - 0092-2102 .- 1526-551X. ; 48:1, s. 70-86
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Journal article (peer-reviewed)abstract
- The New York City Off-Hour Delivery (NYC OHD) program is the work of a private-public-academic partnership - A collaborative effort of leading private-sector groups and companies, public-sector agencies led by the New York City Department of Transportation, and research partners led by Rensselaer Polytechnic Institute. The efforts of this partnership have induced more than 400 commercial establishments in NYC to accept OHD without supervision. The economic benefits are considerable: The carriers have reduced operational costs and parking fines by 45 percent; the receivers enjoy more reliable deliveries, enabling them to reduce inventory levels; the truck drivers have less stress, shorter work hours, and easier deliveries and parking; the delivery trucks produce 55-67 percent less emissions than they would during regular-hour deliveries, for a net reduction of 2.5 million tons of CO2 per year; and citizens' quality of life increases as a result of reduced conflicts between delivery trucks, cars, bicycles, and pedestrians, and through the use of low-noise delivery practices and technologies that minimize the impacts of noise. The total economic benefits exceed $20 million per year. The success of the OHD program is due largely to the policy design at its core, made possible with the behavioral microsimulation. This unique optimization-simulation system incorporates the research conducted into an operations research/management science tool that assesses the effectiveness of alternative policy designs. This enabled the successful implementation of the project within the most complex urban environment in the United States.
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- Li, Man, et al.
(author)
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SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function
- 2017
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In: Journal of the American Society of Nephrology: JASN. - 1533-3450. ; 28:3, s. 981-994
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Journal article (peer-reviewed)abstract
- Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
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- Osborne, H. L.M., et al.
(author)
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TOI-544 b: a potential water-world inside the radius valley in a two-planet system
- 2024
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In: Monthly Notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 527:4, s. 11138-11157
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Journal article (peer-reviewed)abstract
- We report on the precise radial velocity follow-up of TOI-544 (HD 290498),ã bright K star ( V = 10.8), which hostsã small transiting planet recently disco v ered by the Trãnsiting Exoplanet Survey Satellite (TESS) . We collected 122 high-resolution High Accuracy Radial velocity Planet Searcher (HARPS)ãnd HARPS-N spectra to spectroscopically confirm the transiting planetãnd measure its mass. The nearly 3-yr baseline of our follow-upãllowed us to unveil the presence ofãnãdditional, non-transiting, longer-period companion planet. We derivedã radiusãnd mass for the inner planet, TOI-544 b, of 2.018 ±0.076 R⊙and 2.89 ±0.48 M⊙, respectively, which givesã bulk density of 1 . 93 + 0 . 30 -0 . 25 g cm -3 . TOI-544 c hasã minimum mass of 21.5 ±2.0 M⊙and orbital period of 50.1 ±0.2 d. The low density of planet-b implies that it has eitherãn Earth-like rocky core withã hydrogenãtmosphere, orã composition which harboursã significant fraction of water. The composition interpretation is degenerate depending on the specific choice of planet interior models used. Additionally, TOI-544 b hasãn orbital period of 1.55 dãnd equilibrium temperature of 999 ±14 K, placing it within the predicted location of the radius valley, where few planetsãre expected. TOI-544 b isã top target for futureãtmospheric observations, for example with JWST , which would enable better constraints of the planet composition.
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- Szatmari, Peter, et al.
(author)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Journal article (peer-reviewed)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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