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- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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- Van Haute, L., et al.
(författare)
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TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.
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- Wang, T, et al.
(författare)
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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4932-
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Tidskriftsartikel (refereegranskat)abstract
- Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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- Buondonno, A., et al.
(författare)
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A Hub and Spoke Learning Program in Bariatric Surgery in a Small Region of Italy
- 2022
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Ingår i: Frontiers in Surgery. - : Frontiers Media SA. - 2296-875X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMetabolic and bariatric surgery (BS) are considered life-changing and life-saving treatments for obese patients. The Italian Society of Obesity Surgery (SICOB) requires at least 25 operations per year to achieve the standard of care in the field. Despite the increasing need to treat obese patients, some small southern regions of Italy, such as Molise, do not have enough experience in bariatric procedures to be allowed to perform them. Therefore, our aim was to run a Hub and Spoke Program with a referral center in BS to treat obese patients and provide a proper learning curve in BS in Molise. MethodsIn 2020, the "A. Cardarelli Hospital" in Campobasso, Molise, started a formal "Learning Model of Hub and Spoke Collaboration" with the Hub center "Ospedale Del Mare", Naples. A multidisciplinary approach was achieved. Patients were supervised and operated under the supervision and tutoring of the referral center. We retrospectively reviewed our prospectively collected database from February 2020 to August 2021 in order to analyze the safety and effectiveness of our learning program. ResultsIn total, 13 (3 men and 10 women) patients underwent BS with the mean age of 47.08 years and a presurgery BMI of 41.79. Seven (53.84%) patients were the American Society of Anesthesiologist (ASA) II, and 6 (46.16%) patients were ASA III. Twelve (92.31%) procedures were laparoscopic sleeve gastrectomies, 1 (7.69%) patient underwent endoscopic BioEnterics Intragastric Balloon (BIB) placement. One (8.33%) sleeve gastrectomy was associated to gastric band removal. Mean surgical time was 110.14 +/- 23.54 min. The mean length of stay was 4.07 +/- 2.40 days. No Clavien-Dindo >= III and mortality were reported. The follow-up program showed a mean decrease of 11.82 in terms of body mass index (BMI) value. The last 5 procedures were performed by the whole equips from "A. Cardarelli" under external tutoring without any impact on complication rate. ConclusionThe setup of a proper Hub and Spoke Program may allow to perform BS to provide the standard of care. This approach may reduce health costs and related patient migration.
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