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- Aragam, KG, et al.
(författare)
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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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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Aragam, KG, et al.
(författare)
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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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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
-
Tidskriftsartikel (refereegranskat)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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| 5. |
- Chu, Audrey Y, et al.
(författare)
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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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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 125-130
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Tidskriftsartikel (refereegranskat)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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| 7. |
- Szatmari, Peter, et al.
(författare)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Tidskriftsartikel (refereegranskat)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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- Davis, B, et al.
(författare)
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Voices of chemical biology
- 2021
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Ingår i: Nature chemical biology. - : Springer Science and Business Media LLC. - 1552-4469 .- 1552-4450. ; 17:1, s. 1-4
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Osborne, H. L.M., et al.
(författare)
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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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Ingår i: Monthly Notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 527:4, s. 11138-11157
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Tidskriftsartikel (refereegranskat)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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