215 results on '"Eleonora Porcu"'
Search Results
2. Reproductive health in Turner’s syndrome: from puberty to pregnancy
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Eleonora Porcu, Linda Cipriani, and Giuseppe Damiano
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Turner syndrome ,pubertal development ,fertility preservation ,mosaicism ,oocyte cryopreservation ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Turner syndrome (TS) is a genetic pathology that affects about 1/2500 newborn females. Turner’s syndrome is characterized by highly variable genetic anomalies that consist in a partial or complete deletion of the X sexual chromosome; it can be present as a monosomy or as a mosaicism with two o three different cellular lines. 50% of the patients with Turner’s syndrome has a 45 XO karyotype while the remaining cases have karyotypes with mosaicism or X isochromosome or with partial or whole Y chromosome. This pathology is characterized by multiple anomalies that involve physical and cognitive development and in particular endocrine, cardiovascular, reproductive, auditive and visual systems. Integrity of the X chromosome in essential for fertility. In TS is accelerated germ cells apoptosis. About 30% of TS girls have some pubertal development, 10-20% undergo menarche and 2-8% go through spontaneous pregnancy. Women with TS should be informed about the risk of premature menopause and should be referred, if possible, to a specialist evaluation with a doctor expert in assisted reproductive techniques. In adolescents and in adults, Premature Ovarian Insufficiency (POI) can be evaluated clinically and biochemically with the classic combination of amenorrhea and elevated FSH concentrations (hypergonadotropic hypogonadism). However, in postpubertal adolescents and adult women, reproductive hormones may remain within the normal range before POI is clinically evident, despite significant depletion of the ovarian reserve. Today, reproductive medicine offers the opportunity of fertility preservation in women with premature ovarian insufficiency (POI). Two techniques have been suggested such as ovarian cortex cryopreservation and oocytes cryopreservation.
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- 2023
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3. Genome-wide Association Studies of Retinal Vessel Tortuosity Identify Numerous Novel Loci Revealing Genes and Pathways Associated With Ocular and Cardiometabolic Diseases
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Mattia Tomasoni, PhD, Michael Johannes Beyeler, MSc, Sofia Ortin Vela, MSc, Ninon Mounier, PhD, Eleonora Porcu, PhD, Tanguy Corre, PhD, Daniel Krefl, PhD, Alexander Luke Button, PhD, Hana Abouzeid, MD, Konstantinidis Lazaros, MD, Murielle Bochud, MD, PhD, Reinier Schlingemann, MD, PhD, Ciara Bergin, PhD, and Sven Bergmann, PhD
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GWAS ,Retina ,Microvasculature ,Tortuosity ,Mendelian randomization ,Ophthalmology ,RE1-994 - Abstract
Purpose: To identify novel susceptibility loci for retinal vascular tortuosity, to better understand the molecular mechanisms modulating this trait, and reveal causal relationships with diseases and their risk factors. Design: Genome-wide Association Studies (GWAS) of vascular tortuosity of retinal arteries and veins followed by replication meta-analysis and Mendelian randomization (MR). Participants: We analyzed 116 639 fundus images of suitable quality from 63 662 participants from 3 cohorts, namely the UK Biobank (n = 62 751), the Swiss Kidney Project on Genes in Hypertension (n = 397), and OphtalmoLaus (n = 512). Methods: Using a fully automated retina image processing pipeline to annotate vessels and a deep learning algorithm to determine the vessel type, we computed the median arterial, venous and combined vessel tortuosity measured by the distance factor (the length of a vessel segment over its chord length), as well as by 6 alternative measures that integrate over vessel curvature. We then performed the largest GWAS of these traits to date and assessed gene set enrichment using the novel high-precision statistical method PascalX. Main Outcome Measure: We evaluated the genetic association of retinal tortuosity, measured by the distance factor. Results: Higher retinal tortuosity was significantly associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis, and hypertension. We identified 175 significantly associated genetic loci in the UK Biobank; 173 of these were novel and 4 replicated in our second, much smaller, metacohort. We estimated heritability at ∼25% using linkage disequilibrium score regression. Vessel type specific GWAS revealed 116 loci for arteries and 63 for veins. Genes with significant association signals included COL4A2, ACTN4, LGALS4, LGALS7, LGALS7B, TNS1, MAP4K1, EIF3K, CAPN12, ECH1, and SYNPO2. These tortuosity genes were overexpressed in arteries and heart muscle and linked to pathways related to the structural properties of the vasculature. We demonstrated that retinal tortuosity loci served pleiotropic functions as cardiometabolic disease variants and risk factors. Concordantly, MR revealed causal effects between tortuosity, body mass index, and low-density lipoprotein. Conclusions: Several alleles associated with retinal vessel tortuosity suggest a common genetic architecture of this trait with ocular diseases (glaucoma, myopia), cardiovascular diseases, and metabolic syndrome. Our results shed new light on the genetics of vascular diseases and their pathomechanisms and highlight how GWASs and heritability can be used to improve phenotype extraction from high-dimensional data, such as images. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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- 2023
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4. Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases
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Marie C. Sadler, Chiara Auwerx, Kaido Lepik, Eleonora Porcu, and Zoltán Kutalik
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Science - Abstract
The mechanism by which DNA methylation might affect complex traits is not well understood. Here, the authors use Mendelian randomization to reveal a substantial role of transcript levels in mediating DNA methylation effects on complex traits and diseases.
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- 2022
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5. Limited evidence for blood eQTLs in human sexual dimorphism
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Eleonora Porcu, Annique Claringbould, Antoine Weihs, Kaido Lepik, BIOS Consortium, Tom G. Richardson, Uwe Völker, Federico A. Santoni, Alexander Teumer, Lude Franke, Alexandre Reymond, and Zoltán Kutalik
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Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background The genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS-associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits. Methods To explore this scenario, we combined sex-specific whole blood RNA-seq eQTL data from 3447 European individuals included in BIOS Consortium and GWAS data from UK Biobank. Next, to test the presence of sex-biased causal effect of gene expression on complex traits, we performed sex-specific transcriptome-wide Mendelian randomization (TWMR) analyses on the two most sexually dimorphic traits, waist-to-hip ratio (WHR) and testosterone levels. Finally, we performed power analysis to calculate the GWAS sample size needed to observe sex-specific trait associations driven by sex-biased eQTLs. Results Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-biased cis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-biased eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-biased trait-associations. In addition, we observed that sex-specific causal effects of gene expression on complex traits are not driven by sex-specific eQTLs. Power analyses using real eQTL- and causal-effect sizes showed that millions of samples would be necessary to observe sex-biased trait associations that are fully driven by sex-biased cis-eQTLs. Compensatory effects may further hamper their detection. Conclusions Our results suggest that sex-specific eQTLs in whole blood do not translate to detectable sex-specific trait associations of complex diseases, and vice versa that the observed sex-specific trait associations cannot be explained by sex-specific eQTLs.
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- 2022
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6. Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts
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Giuliana Giannuzzi, Nicolas Chatron, Katrin Mannik, Chiara Auwerx, Sylvain Pradervand, Gilles Willemin, Kendra Hoekzema, Xander Nuttle, Jacqueline Chrast, Marie C. Sadler, Eleonora Porcu, p11.2 Consortium, Yann Herault, Bertrand Isidor, Brigitte Gilbert-Dussardier, Evan E. Eichler, Zoltan Kutalik, and Alexandre Reymond
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Medicine ,Genetics ,QH426-470 - Abstract
Abstract Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3–8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.
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- 2022
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7. Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations
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Chiara Auwerx, Marie C Sadler, Tristan Woh, Alexandre Reymond, Zoltán Kutalik, and Eleonora Porcu
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genetics ,metabolomics ,gene expression ,Mendelian Randomization ,Mediation ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Despite the success of genome-wide association studies (GWASs) in identifying genetic variants associated with complex traits, understanding the mechanisms behind these statistical associations remains challenging. Several methods that integrate methylation, gene expression, and protein quantitative trait loci (QTLs) with GWAS data to determine their causal role in the path from genotype to phenotype have been proposed. Here, we developed and applied a multi-omics Mendelian randomization (MR) framework to study how metabolites mediate the effect of gene expression on complex traits. We identified 216 transcript-metabolite-trait causal triplets involving 26 medically relevant phenotypes. Among these associations, 58% were missed by classical transcriptome-wide MR, which only uses gene expression and GWAS data. This allowed the identification of biologically relevant pathways, such as between ANKH and calcium levels mediated by citrate levels and SLC6A12 and serum creatinine through modulation of the levels of the renal osmolyte betaine. We show that the signals missed by transcriptome-wide MR are found, thanks to the increase in power conferred by integrating multiple omics layer. Simulation analyses show that with larger molecular QTL studies and in case of mediated effects, our multi-omics MR framework outperforms classical MR approaches designed to detect causal relationships between single molecular traits and complex phenotypes.
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- 2023
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8. Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome
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Eleonora Porcu, Marie C. Sadler, Kaido Lepik, Chiara Auwerx, Andrew R. Wood, Antoine Weihs, Maroun S. Bou Sleiman, Diogo M. Ribeiro, Stefania Bandinelli, Toshiko Tanaka, Matthias Nauck, Uwe Völker, Olivier Delaneau, Andres Metspalu, Alexander Teumer, Timothy Frayling, Federico A. Santoni, Alexandre Reymond, and Zoltán Kutalik
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Science - Abstract
Identification of gene expression changes between healthy and diseased individuals can reveal mechanistic insights and biomarkers. Here, the authors propose a bi-directional transcriptome-wide Mendelian Randomization approach to assess causal effects between gene expression and complex traits.
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- 2021
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9. Omics-informed CNV calls reduce false-positive rates and improve power for CNV-trait associations
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Maarja Lepamets, Chiara Auwerx, Margit Nõukas, Annique Claringbould, Eleonora Porcu, Mart Kals, Tuuli Jürgenson, Andrew Paul Morris, Urmo Võsa, Murielle Bochud, Silvia Stringhini, Cisca Wijmenga, Lude Franke, Hedi Peterson, Jaak Vilo, Kaido Lepik, Reedik Mägi, and Zoltán Kutalik
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anthropometric traits ,copy-number variation ,gene expression ,methylation ,multi-omics ,PennCNV ,Genetics ,QH426-470 - Abstract
Summary: Copy-number variations (CNV) are believed to play an important role in a wide range of complex traits, but discovering such associations remains challenging. While whole-genome sequencing (WGS) is the gold-standard approach for CNV detection, there are several orders of magnitude more samples with available genotyping microarray data. Such array data can be exploited for CNV detection using dedicated software (e.g., PennCNV); however, these calls suffer from elevated false-positive and -negative rates. In this study, we developed a CNV quality score that weights PennCNV calls (pCNVs) based on their likelihood of being true positive. First, we established a measure of pCNV reliability by leveraging evidence from multiple omics data (WGS, transcriptomics, and methylomics) obtained from the same samples. Next, we built a predictor of omics-confirmed pCNVs, termed omics-informed quality score (OQS), using only PennCNV software output parameters. Promisingly, OQS assigned to pCNVs detected in close family members was up to 35% higher than the OQS of pCNVs not carried by other relatives (p
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- 2022
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10. Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
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Eleonora Porcu, Federica Gilardi, Liza Darrous, Loic Yengo, Nasim Bararpour, Marie Gasser, Pedro Marques-Vidal, Philippe Froguel, Gerard Waeber, Aurelien Thomas, and Zoltán Kutalik
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Medicine ,Science - Abstract
Abstract The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.
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- 2021
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11. Author Correction: Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts
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Giuliana Giannuzzi, Nicolas Chatron, Katrin Mannik, Chiara Auwerx, Sylvain Pradervand, Gilles Willemin, Kendra Hoekzema, Xander Nuttle, Jacqueline Chrast, Marie C. Sadler, Eleonora Porcu, p11.2 Consortium, Yann Herault, Bertrand Isidor, Brigitte Gilbert-Dussardier, Evan E. Eichler, Zoltan Kutalik, and Alexandre Reymond
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Medicine ,Genetics ,QH426-470 - Published
- 2023
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12. Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies
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Cristian Carmeli, Zoltán Kutalik, Pashupati P. Mishra, Eleonora Porcu, Cyrille Delpierre, Olivier Delaneau, Michelle Kelly-Irving, Murielle Bochud, Nasser A. Dhayat, Belen Ponte, Menno Pruijm, Georg Ehret, Mika Kähönen, Terho Lehtimäki, Olli T. Raitakari, Paolo Vineis, Mika Kivimäki, Marc Chadeau-Hyam, Emmanouil Dermitzakis, Nicolas Vuilleumier, and Silvia Stringhini
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Medicine ,Science - Abstract
Abstract Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.
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- 2021
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13. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
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Eleonora Porcu, Sina Rüeger, Kaido Lepik, eQTLGen Consortium, BIOS Consortium, Federico A. Santoni, Alexandre Reymond, and Zoltán Kutalik
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Science - Abstract
Many genetic variants identified in genome-wide association studies are associated with gene expression. Here, Porcu et al. propose a transcriptome-wide summary statistics-based Mendelian randomization approach (TWMR) that, applied to 43 human traits, uncovers hundreds of previously unreported gene–trait associations.
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- 2019
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14. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation
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Alexander Teumer, Layal Chaker, Stefan Groeneweg, Yong Li, Celia Di Munno, Caterina Barbieri, Ulla T. Schultheiss, Michela Traglia, Tarunveer S. Ahluwalia, Masato Akiyama, Emil Vincent R. Appel, Dan E. Arking, Alice Arnold, Arne Astrup, Marian Beekman, John P. Beilby, Sofie Bekaert, Eric Boerwinkle, Suzanne J. Brown, Marc De Buyzere, Purdey J. Campbell, Graziano Ceresini, Charlotte Cerqueira, Francesco Cucca, Ian J. Deary, Joris Deelen, Kai-Uwe Eckardt, Arif B. Ekici, Johan G. Eriksson, Luigi Ferrrucci, Tom Fiers, Edoardo Fiorillo, Ian Ford, Caroline S. Fox, Christian Fuchsberger, Tessel E. Galesloot, Christian Gieger, Martin Gögele, Alessandro De Grandi, Niels Grarup, Karin Halina Greiser, Kadri Haljas, Torben Hansen, Sarah E. Harris, Diana van Heemst, Martin den Heijer, Andrew A. Hicks, Wouter den Hollander, Georg Homuth, Jennie Hui, M. Arfan Ikram, Till Ittermann, Richard A. Jensen, Jiaojiao Jing, J. Wouter Jukema, Eero Kajantie, Yoichiro Kamatani, Elisa Kasbohm, Jean-Marc Kaufman, Lambertus A. Kiemeney, Margreet Kloppenburg, Florian Kronenberg, Michiaki Kubo, Jari Lahti, Bruno Lapauw, Shuo Li, David C. M. Liewald, Lifelines Cohort Study, Ee Mun Lim, Allan Linneberg, Michela Marina, Deborah Mascalzoni, Koichi Matsuda, Daniel Medenwald, Christa Meisinger, Ingrid Meulenbelt, Tim De Meyer, Henriette E. Meyer zu Schwabedissen, Rafael Mikolajczyk, Matthijs Moed, Romana T. Netea-Maier, Ilja M. Nolte, Yukinori Okada, Mauro Pala, Cristian Pattaro, Oluf Pedersen, Astrid Petersmann, Eleonora Porcu, Iris Postmus, Peter P. Pramstaller, Bruce M. Psaty, Yolande F. M. Ramos, Rajesh Rawal, Paul Redmond, J. Brent Richards, Ernst R. Rietzschel, Fernando Rivadeneira, Greet Roef, Jerome I. Rotter, Cinzia F. Sala, David Schlessinger, Elizabeth Selvin, P. Eline Slagboom, Nicole Soranzo, Thorkild I. A. Sørensen, Timothy D. Spector, John M. Starr, David J. Stott, Youri Taes, Daniel Taliun, Toshiko Tanaka, Betina Thuesen, Daniel Tiller, Daniela Toniolo, Andre G. Uitterlinden, W. Edward Visser, John P. Walsh, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Qiong Yang, Hou-Feng Zheng, Anne Cappola, Robin P. Peeters, Silvia Naitza, Henry Völzke, Serena Sanna, Anna Köttgen, Theo J. Visser, and Marco Medici
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Science - Abstract
Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.
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- 2018
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15. CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits
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Aurélien Macé, Marcus A. Tuke, Patrick Deelen, Kati Kristiansson, Hannele Mattsson, Margit Nõukas, Yadav Sapkota, Ursula Schick, Eleonora Porcu, Sina Rüeger, Aaron F. McDaid, David Porteous, Thomas W. Winkler, Erika Salvi, Nick Shrine, Xueping Liu, Wei Q. Ang, Weihua Zhang, Mary F. Feitosa, Cristina Venturini, Peter J. van der Most, Anders Rosengren, Andrew R. Wood, Robin N. Beaumont, Samuel E. Jones, Katherine S. Ruth, Hanieh Yaghootkar, Jessica Tyrrell, Aki S. Havulinna, Harmen Boers, Reedik Mägi, Jennifer Kriebel, Martina Müller-Nurasyid, Markus Perola, Markku Nieminen, Marja-Liisa Lokki, Mika Kähönen, Jorma S. Viikari, Frank Geller, Jari Lahti, Aarno Palotie, Päivikki Koponen, Annamari Lundqvist, Harri Rissanen, Erwin P. Bottinger, Saima Afaq, Mary K. Wojczynski, Petra Lenzini, Ilja M. Nolte, Thomas Sparsø, Nicole Schupf, Kaare Christensen, Thomas T. Perls, Anne B. Newman, Thomas Werge, Harold Snieder, Timothy D. Spector, John C. Chambers, Seppo Koskinen, Mads Melbye, Olli T. Raitakari, Terho Lehtimäki, Martin D. Tobin, Louise V. Wain, Juha Sinisalo, Annette Peters, Thomas Meitinger, Nicholas G. Martin, Naomi R. Wray, Grant W. Montgomery, Sarah E. Medland, Morris A. Swertz, Erkki Vartiainen, Katja Borodulin, Satu Männistö, Anna Murray, Murielle Bochud, Sébastien Jacquemont, Fernando Rivadeneira, Thomas F. Hansen, Albertine J. Oldehinkel, Massimo Mangino, Michael A. Province, Panos Deloukas, Jaspal S. Kooner, Rachel M. Freathy, Craig Pennell, Bjarke Feenstra, David P. Strachan, Guillaume Lettre, Joel Hirschhorn, Daniele Cusi, Iris M. Heid, Caroline Hayward, Katrin Männik, Jacques S. Beckmann, Ruth J. F. Loos, Dale R. Nyholt, Andres Metspalu, Johan G. Eriksson, Michael N. Weedon, Veikko Salomaa, Lude Franke, Alexandre Reymond, Timothy M. Frayling, and Zoltán Kutalik
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Science - Abstract
Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.
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- 2017
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16. Bayesian association scan reveals loci associated with human lifespan and linked biomarkers
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Aaron F. McDaid, Peter K. Joshi, Eleonora Porcu, Andrea Komljenovic, Hao Li, Vincenzo Sorrentino, Maria Litovchenko, Roel P. J. Bevers, Sina Rüeger, Alexandre Reymond, Murielle Bochud, Bart Deplancke, Robert W. Williams, Marc Robinson-Rechavi, Fred Paccaud, Valentin Rousson, Johan Auwerx, James F. Wilson, and Zoltán Kutalik
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Science - Abstract
Along with various environmental factors, a complex genetic architecture influences human lifespan. Here, McDaid and colleagues reveal novel loci associated with human lifespan and linked biomarkers by Bayesian association scan.
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- 2017
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17. Bridging the gap: metabolic and endocrine care of patients during transition
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Anita Hokken-Koelega, Aart-Jan van der Lely, Berthold Hauffa, Gabriele Häusler, Gudmundur Johannsson, Mohamad Maghnie, Jesús Argente, Jean DeSchepper, Helena Gleeson, John W Gregory, Charlotte Höybye, Fahrettin Keleştimur, Anton Luger, Hermann L Müller, Sebastian Neggers, Vera Popovic-Brkic, Eleonora Porcu, Lars Sävendahl, Stephen Shalet, Bessie Spiliotis, and Maithé Tauber
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transition ,developmentally appropriate healthcare ,GH therapy ,metabolic syndrome ,quality of life ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Objective: Seamless transition of endocrine patients from the paediatric to adult setting is still suboptimal, especially in patients with complex disorders, i.e., small for gestational age, Turner or Prader–Willi syndromes; Childhood Cancer Survivors, and those with childhood-onset growth hormone deficiency. Methods: An expert panel meeting comprised of European paediatric and adult endocrinologists was convened to explore the current gaps in managing the healthcare of patients with endocrine diseases during transition from paediatric to adult care settings. Results: While a consensus was reached that a team approach is best, discussions revealed that a ‘one size fits all’ model for transition is largely unsuccessful in these patients. They need more tailored care during adolescence to prevent complications like failure to achieve target adult height, reduced bone mineral density, morbid obesity, metabolic perturbations (obesity and body composition), inappropriate/inadequate puberty, compromised fertility, diminished quality of life and failure to adapt to the demands of adult life. Sometimes it is difficult for young people to detach emotionally from their paediatric endocrinologist and/or the abrupt change from an environment of parental responsibility to one of autonomy. Discussions about impending transition and healthcare autonomy should begin in early adolescence and continue throughout young adulthood to ensure seamless continuum of care and optimal treatment outcomes. Conclusions: Even amongst a group of healthcare professionals with a great interest in improving transition services for patients with endocrine diseases, there is still much work to be done to improve the quality of healthcare for transition patients.
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- 2016
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18. Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
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Marco Medici, Eleonora Porcu, Giorgio Pistis, Alexander Teumer, Suzanne J Brown, Richard A Jensen, Rajesh Rawal, Greet L Roef, Theo S Plantinga, Sita H Vermeulen, Jari Lahti, Matthew J Simmonds, Lise Lotte N Husemoen, Rachel M Freathy, Beverley M Shields, Diana Pietzner, Rebecca Nagy, Linda Broer, Layal Chaker, Tim I M Korevaar, Maria Grazia Plia, Cinzia Sala, Uwe Völker, J Brent Richards, Fred C Sweep, Christian Gieger, Tanguy Corre, Eero Kajantie, Betina Thuesen, Youri E Taes, W Edward Visser, Andrew T Hattersley, Jürgen Kratzsch, Alexander Hamilton, Wei Li, Georg Homuth, Monia Lobina, Stefano Mariotti, Nicole Soranzo, Massimiliano Cocca, Matthias Nauck, Christin Spielhagen, Alec Ross, Alice Arnold, Martijn van de Bunt, Sandya Liyanarachchi, Margit Heier, Hans Jörgen Grabe, Corrado Masciullo, Tessel E Galesloot, Ee M Lim, Eva Reischl, Peter J Leedman, Sandra Lai, Alessandro Delitala, Alexandra P Bremner, David I W Philips, John P Beilby, Antonella Mulas, Matteo Vocale, Goncalo Abecasis, Tom Forsen, Alan James, Elisabeth Widen, Jennie Hui, Holger Prokisch, Ernst E Rietzschel, Aarno Palotie, Peter Feddema, Stephen J Fletcher, Katharina Schramm, Jerome I Rotter, Alexander Kluttig, Dörte Radke, Michela Traglia, Gabriela L Surdulescu, Huiling He, Jayne A Franklyn, Daniel Tiller, Bijay Vaidya, Tim de Meyer, Torben Jørgensen, Johan G Eriksson, Peter C O'Leary, Eric Wichmann, Ad R Hermus, Bruce M Psaty, Till Ittermann, Albert Hofman, Emanuele Bosi, David Schlessinger, Henri Wallaschofski, Nicola Pirastu, Yurii S Aulchenko, Albert de la Chapelle, Romana T Netea-Maier, Stephen C L Gough, Henriette Meyer Zu Schwabedissen, Timothy M Frayling, Jean-Marc Kaufman, Allan Linneberg, Katri Räikkönen, Johannes W A Smit, Lambertus A Kiemeney, Fernando Rivadeneira, André G Uitterlinden, John P Walsh, Christa Meisinger, Martin den Heijer, Theo J Visser, Timothy D Spector, Scott G Wilson, Henry Völzke, Anne Cappola, Daniela Toniolo, Serena Sanna, Silvia Naitza, and Robin P Peeters
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Genetics ,QH426-470 - Abstract
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P
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- 2014
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19. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.
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Eleonora Porcu, Marco Medici, Giorgio Pistis, Claudia B Volpato, Scott G Wilson, Anne R Cappola, Steffan D Bos, Joris Deelen, Martin den Heijer, Rachel M Freathy, Jari Lahti, Chunyu Liu, Lorna M Lopez, Ilja M Nolte, Jeffrey R O'Connell, Toshiko Tanaka, Stella Trompet, Alice Arnold, Stefania Bandinelli, Marian Beekman, Stefan Böhringer, Suzanne J Brown, Brendan M Buckley, Clara Camaschella, Anton J M de Craen, Gail Davies, Marieke C H de Visser, Ian Ford, Tom Forsen, Timothy M Frayling, Laura Fugazzola, Martin Gögele, Andrew T Hattersley, Ad R Hermus, Albert Hofman, Jeanine J Houwing-Duistermaat, Richard A Jensen, Eero Kajantie, Margreet Kloppenburg, Ee M Lim, Corrado Masciullo, Stefano Mariotti, Cosetta Minelli, Braxton D Mitchell, Ramaiah Nagaraja, Romana T Netea-Maier, Aarno Palotie, Luca Persani, Maria G Piras, Bruce M Psaty, Katri Räikkönen, J Brent Richards, Fernando Rivadeneira, Cinzia Sala, Mona M Sabra, Naveed Sattar, Beverley M Shields, Nicole Soranzo, John M Starr, David J Stott, Fred C G J Sweep, Gianluca Usala, Melanie M van der Klauw, Diana van Heemst, Alies van Mullem, Sita H Vermeulen, W Edward Visser, John P Walsh, Rudi G J Westendorp, Elisabeth Widen, Guangju Zhai, Francesco Cucca, Ian J Deary, Johan G Eriksson, Luigi Ferrucci, Caroline S Fox, J Wouter Jukema, Lambertus A Kiemeney, Peter P Pramstaller, David Schlessinger, Alan R Shuldiner, Eline P Slagboom, André G Uitterlinden, Bijay Vaidya, Theo J Visser, Bruce H R Wolffenbuttel, Ingrid Meulenbelt, Jerome I Rotter, Tim D Spector, Andrew A Hicks, Daniela Toniolo, Serena Sanna, Robin P Peeters, and Silvia Naitza
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Genetics ,QH426-470 - Abstract
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
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- 2013
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20. A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.
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Silvia Naitza, Eleonora Porcu, Maristella Steri, Dennis D Taub, Antonella Mulas, Xiang Xiao, James Strait, Mariano Dei, Sandra Lai, Fabio Busonero, Andrea Maschio, Gianluca Usala, Magdalena Zoledziewska, Carlo Sidore, Ilenia Zara, Maristella Pitzalis, Alessia Loi, Francesca Virdis, Roberta Piras, Francesca Deidda, Michael B Whalen, Laura Crisponi, Antonio Concas, Carlo Podda, Sergio Uzzau, Paul Scheet, Dan L Longo, Edward Lakatta, Gonçalo R Abecasis, Antonio Cao, David Schlessinger, Manuela Uda, Serena Sanna, and Francesco Cucca
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Genetics ,QH426-470 - Abstract
Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.
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- 2012
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21. An Initial Investigation of Mental Well-being Monitoring through Personal Healthcare Devices.
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Silvia Maria Massa, Eleonora Porcu, and Daniele Riboni
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- 2024
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22. Dosage and delivery method of progesterone luteal support in overweight/obese women undergoing cryopreserved cycles
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Eleonora Porcu, Linda Cipriani, and Giuseppe Damiano
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Reproductive Medicine ,Obstetrics and Gynecology - Published
- 2023
23. Author response: Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations
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Chiara Auwerx, Marie C Sadler, Tristan Woh, Alexandre Reymond, Zoltán Kutalik, and Eleonora Porcu
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- 2022
24. Correction for participation bias in the UK Biobank reveals non-negligible impact on genetic associations and downstream analyses
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Tabea Schoeler, Doug Speed, Eleonora Porcu, Nicola Pirastu, Jean-Baptiste Pingault, and Zoltán Kutalik
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While large-scale volunteer-based studies such as the UK Biobank (UKBB) have become the cornerstone of genetic epidemiology, the study participants are rarely representative of their target population.Here, we aim to evaluate the impact of non-random participation in the UKBB, and to pin down areas of research that are particularly susceptible to biases when using non-representative samples for genome-wide discovery. By comparing 14 harmonized characteristics of the UKBB participants to that of a representative sample, we derived a model for participation probability. We then conducted inverse probability weighted genome-wide association analyses (wGWA) on 19 UKBB traits. Comparing the output obtained from wGWA (Neffective=94,643 – 102,215) to standard GWA analyses (N=263,464 – 283,749), we assessed the impact of participation bias on three estimated quantities, namely 1) genotype-phenotype associations, 2) heritability and genetic correlation estimates and 3) exposure-outcome causal effect estimates obtained from Mendelian Randomization. Participation bias can lead to both overestimation (e.g., cancer, education) and underestimation (e.g., coffee intake, depression/anxiety) of SNP effects. Novel SNPs were identified in wGWA for 12 of the included traits, highlighting SNPs missed as a result of participation bias. While the impact of participation bias on heritability estimates was small (average change in h2: 1.5%, maximum: 5%), substantial distortions were present for genetic correlations (average absolute change in rg: 0.07, maximum: 0.31) and Mendelian Randomization estimates (average absolute change in standardized estimates: 0.04, maximum: 0.15), most markedly for socio-behavioural traits including education, smoking and BMI. Overall, the bias mainly affected the magnitude of effects, rather than direction. In contrast, genome-wide findings for more molecular/physical traits (e.g., LDL, SBP) exhibited less bias as a result of selective participation.Our results highlight that participation bias can distort genomic findings obtained in non-representative samples, and we propose a viable solution to reduce such bias. Moving forward, more efforts ensuring either sample representativeness or correcting for participation bias are paramount, especially when investigating the genetic underpinnings of behaviour, lifestyles and social outcomes.
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- 2022
25. A polygenic risk score to predict sudden cardiac arrest in patients with coronary artery disease
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Eleonora Porcu, Christian W. Thorball, Alessandra Pia Porretta, Etienne Pruvot, Kim Wiskott, Federica Gilardi, Aurelien Thomas, Claire Redin, Zoltán Kutalik, Tony Fracasso, Olivier Müller, and Jacques Fellay
- Abstract
Cardiovascular disease (CVD) is a leading health problem and the main cause of death globally. Even when underlying causative factors are known, it is unclear why a cardiovascular condition causes premature death in a victim while others can live longer with the same condition. Here we propose a combined polygenic risk score (metaPRS) based on coronary artery disease (CAD), myocardial infarction (MI), low-density lipoprotein (LDL) cholesterol, body mass index (BMI) and type 2 diabetes (T2D) to predict the risk of sudden cardiac arrest (SCA) in patients affected by severe cardiovascular conditions.We collected 2,114 patients with reported history of acute coronary syndrome from the Centre Hospitalier Universitaire Vaudois (CHUV) Genomic Biobank (BGC) and extracted data from the UK Biobank (UKB) on 13,696 participants with similar medical history. Among them, 303 and 932 had a further reported diagnosis of SCA or ventricular tachycardia/fibrillation according to the International Classification of Diseases (ICD-10) codes in BGC and UKB, respectively. We demonstrate that the metaPRS is significantly associated with SCA in both cohorts (ORBGC = 1.28, PBGC = 8.39 × 10−05 and ORUKB = 1.14, PUKB = 7.07 × 10−05). Furthermore, using the diagnosis based on the International Classification of Diseases (ICD-10) codes available in the UKB, the metaPRS exhibits a strong association with the presence of aortocoronary bypass graft (ORUKB = 1.31, PUKB = 6.93 × 10−33) and coronary angioplasty implant (ORUKB=1.14, PUKB=1.46×10−12).These results show that a combined genetic risk score for CVD and associated risk factors has the potential to predict the occurrence of SCA in patients with myocardial infarction, hence to identify patients who could benefit from further preventive measures.
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- 2022
26. Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts
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Giuliana, Giannuzzi, Nicolas, Chatron, Katrin, Mannik, Chiara, Auwerx, Sylvain, Pradervand, Gilles, Willemin, Kendra, Hoekzema, Xander, Nuttle, Jacqueline, Chrast, Sadler, Marie C., Eleonora, Porcu, Katrin, Männik, Damien, Sanlaville, Caroline, Schluth-Bolard, Cédric Le Caignec, Mathilde, Nizon, Sandra, Martin, Sébastien, Jacquemont, Armand, Bottani, Marion, Gérard, Sacha, Weber, Aurélia, Jacquette, Catherine, Vincent-Delorme, Aurora, Currò, Francesca, Mari, Alessandra, Renieri, Brusco, Alfredo, Ferrero, Giovanni Battista, Yann, Herault, Bertrand, Isidor, Brigitte, Gilbert-Dussardier, Eichler, Evan E., Zoltan, Kutalik, Alexandre, Reymond, 16p11.2 Consortium, Männik, K., Sanlaville, D., Schluth-Bolard, C., Le Caignec, C., Nizon, M., Martin, S., Jacquemont, S., Bottani, A., Gérard, M., Weber, S., Jacquette, A., Vincent-Delorme, C., Currò, A., Mari, F., Renieri, A., Brusco, A., and Ferrero, G.B.
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BOLA2 ,neurodevelopmental disease ,Recurrent copy-number variations, CNV, 16p11.2, BOLA2, neurodevelopmental disease, neutropenia, lymphopenia ,CNV ,Genetics ,neutropenia ,lymphopenia ,16p11.2 ,Recurrent copy-number variations ,Molecular Biology ,Genetics (clinical) - Abstract
Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3–8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.
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- 2022
27. Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations
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Chiara Auwerx, Marie C. Sadler, Alexandre Reymond, Zoltán Kutalik, and Eleonora Porcu
- Abstract
Despite the success of genome-wide association studies (GWASs) in identifying genetic variants associated with complex traits, understanding the mechanisms behind these statistical associations remains challenging. Several methods that integrate methylation, gene expression, and protein quantitative trait loci (QTLs) with GWAS data to determine their causal role in the path from genotype to phenotype have been proposed. Here, we developed and applied a multi-omics Mendelian randomization (MR) framework to study how metabolites mediate the effect of gene expression on complex traits. We identified 206 transcript-metabolite-trait causal triplets for 28 medically relevant phenotypes. Sixty-seven of these associations were missed by classical transcriptome-wide MR, which only uses gene expression and GWAS data. Among these, we identify biologically relevant pathways, such as between ANKH and calcium levels mediated by citrate and SLC6A12 and serum creatinine through modulation of the levels of the renal osmolyte betaine. We show that the signals missed by transcriptome-wide MR are found thanks to the gain in power allowed by integrating multiple omics-layer. Simulation analyses show that with larger molecular QTL studies and in case of mediated effects, our multi-omics MR framework outperforms classical MR approaches designed to detect causal relationships between single molecular traits and complex phenotypes.
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- 2022
28. Two subsequent seminal productions: A good strategy to treat very severe oligoasthenoteratozoospermic infertile couples
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Linda Cipriani, Elena Nardi, Patrizia Ciotti, Giuseppe Damiano, Eleonora Porcu, Silvia Zuffa, N. Calza, Leonardo Notarangelo, Ciotti P.M., Calza N., Zuffa S., Notarangelo L., Nardi E., Damiano G., Cipriani L., and Porcu E.
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Adult ,Male ,Infertility ,medicine.medical_specialty ,Pregnancy Rate ,Urology ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,media_common.quotation_subject ,Semen ,Intracytoplasmic sperm injection ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Retrospective Studie ,Pregnancy ,medicine ,Semen Analysi ,Humans ,Sperm Injections, Intracytoplasmic ,short abstinence ,Retrospective Studies ,Sexual Abstinence ,media_common ,030219 obstetrics & reproductive medicine ,Sperm Count ,business.industry ,very severe OAT ,Oligospermia ,Abstinence ,medicine.disease ,Sperm ,Semen Analysis ,Pregnancy rate ,Sexual abstinence ,Reproductive Medicine ,Female ,infertility ,business ,Human - Abstract
Background: Sexual abstinence is considered one of the several factors that influence sperm quality. Recent studies show that a shortening of the abstinence period could be beneficial mostly in oligoasthenoteratozoospermic (OAT) patients. Objective: Retrospective study to verify the efficacy of a second semen sample after a short abstinence to treat severe OAT infertile patients. Materials and methods: 127 couples treated between May 2014 and May 2018 were divided into two groups. Study Group 1 (75 cycles): severe OAT characteristics: count
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- 2021
29. Genome-wide association study of circulating interleukin 6 levels identifies novel loci
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Martina Müller-Nurasyid, Jerome I. Rotter, David M. Evans, John P. Kemp, Emelia J. Benjamin, Graciela E. Delgado, Vilmundur Gudnason, Ann Hammarstedt, Panos Deloukas, Aroon D. Hingorani, Riccardo E. Marioni, David Stacey, Jenny van Dongen, Eric Boerwinkle, Joachim Heinrich, Yongmei Liu, S. Goya Wannamethee, Delilah Zabaneh, Braxton D. Mitchell, Marie Standl, Jackie F. Price, Maria G. Stathopoulou, Yoav Ben-Shlomo, Joris Deelen, Eero Kajantie, Mohammadreza Abdollahi, Christie M. Ballantyne, Johan G. Eriksson, Ilkka Seppälä, Elnaz Naderi, Barbara J. Jefferis, Richard W Morris, Nicholas J. Timpson, George Dedoussis, Sirpa Jalkanen, Mika Kivimäki, Perminder S. Sachdev, Diana van Heemst, Melanie Waldenberger, Gaurav Singhal, Elisabeth Thiering, Olli T. Raitakari, Anders Hamsten, Zoltán Kutalik, L. Bain, Eco J. C. de Geus, Tarunveer S. Ahluwalia, Yuri Milaneschi, Hubert Scharnagl, Juan P. Casas, Georg Homuth, Claes Ohlsson, Abbas Dehghan, Nicola J. Armstrong, Behrooz Z. Alizadeh, Terho Lehtimäki, Steve E. Humphries, Naveed Sattar, Bram P. Prins, Peter Rossing, Sophie Visvikis-Siest, Joana A. Revez, Ilja M. Nolte, Stella Trompet, Harold Snieder, Marian Beekman, Diana Marek, Beate St Pourcain, Thorkild I. A. Sørensen, Silvia Naitza, Karen A. Mather, Uwe Völker, Eline Slagboom, Tina Shah, Magdalene C. Jawahar, Jens Baumert, Alexander Teumer, Dorret I. Boomsma, Marcus E. Kleber, Peter Vollenweider, Wolfgang Koenig, Brenda W.J.H. Penninx, Kenneth Rice, Ian J. Deary, Pedro Marques-Vidal, Donna K. Arnett, Eleonora Porcu, Jouke-Jan Hottenga, Maria Sabater-Lleal, Bruce M. Psaty, Matthias Nauck, Dan Mellström, Joel Eriksson, Bernhard T. Baune, Debbie A Lawlor, Catherine Toben, Peter H. Whincup, Toshiko Tanaka, Stavroula Kanoni, Katri Räikkönen, Gonneke Willemsen, Bengt Sennblad, Julian N. Trollor, Yalda Jamshidi, Sarah E. Harris, Jari Lahti, Joshua C. Bis, Peter Durda, Yen Pei C. Chang, Jorgen Engmann, Tom R. Gaunt, Stella Aslibekyan, Anbupalam Thalamuthu, Mary F. Feitosa, Angela Silveira, Tine Jess, Stela McLachlan, J. Wouter Jukema, Chen Lu, Simon P. Mooijaart, Tim D. Spector, Harald Grallert, Winfried März, Alexandros M. Petrelis, Manuel A. R. Ferreira, Meena Kumari, Stochastics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, CHARGE Inflammation Working Group, Epidemiology, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Steno Diabetes Center, University of Copenhagen = Københavns Universitet (KU), University of Groningen [Groningen], Murdoch University, University of Alabama at Birmingham [ Birmingham] (UAB), QIMR Berghofer Medical Research Institute, University College of London [London] (UCL), Helmholtz-Zentrum München (HZM), Leiden University Medical Center (LUMC), University of Bristol [Bristol], University of Washington [Seattle], University of Maryland School of Medicine, University of Maryland System, Vrije Universiteit Amsterdam [Amsterdam] (VU), VU University Medical Center [Amsterdam], University of Heidelberg, Medical Faculty, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Sahlgrenska Academy at University of Gothenburg [Göteborg], National Institute for Health and Welfare [Helsinki], University of Helsinki, William Harvey Research Institute, Barts and the London Medical School, University of Queensland [Brisbane], School of Public Health [Boston], Boston University [Boston] (BU), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, University of Edinburgh, Amsterdam UMC, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), Karolinska Institutet [Stockholm], University of Tampere [Finland], Adelaide Medical School [Australia], University of Adelaide, Universität Greifswald - University of Greifswald, University of New South Wales [Sydney] (UNSW), Prince of Wales Hospital, Ludwig-Maximilians-Universität München (LMU), Baylor College of Medicine (BCM), Baylor University, Boston University School of Medicine (BUSM), VA Boston Healthcare System, Harokopio University of Athens, Max planck Institute for Biology of Ageing [Cologne], Larner College of Medicine [University of Vermont, Burlington], University of Vermont [Burlington], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, University of Turku, St George's, University of London, Statens Serum Institut [Copenhagen], Medical Faculty [Mannheim], Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Johannes Gutenberg - Universität Mainz (JGU), Vrije Universiteit Medical Centre (VUMC), British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Medical University Graz, Uppsala Universitet [Uppsala], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Kentucky, Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Maryland [Baltimore], Queen Mary University of London (QMUL), University of Iceland [Reykjavik], Ludwig Maximilian University [Munich] (LMU), Melbourne School of Population and Global Health [Melbourne], University of Melbourne, Deutsches Herzzentrum München (DHM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Ulm (UUlm), University of Essex, Greifswald University Hospital, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), King‘s College London, University of Cambridge [UK] (CAM), Harbor UCLA Medical Center [Torrance, Ca.], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Human Genome Sequencing Center [Houston] (HGSC), Baylor University-Baylor University, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, HUS Children and Adolescents, Lastentautien yksikkö, Children's Hospital, Clinicum, Department of Bacteriology and Immunology, Department of Public Health, Department of Psychology and Logopedics, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Doctoral Programme in Human Behaviour, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
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AcademicSubjects/SCI01140 ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,030204 cardiovascular system & hematology ,DISEASE ,Pathogenesis ,Cohort Studies ,0302 clinical medicine ,cytokine ,SYSTEMIC-LUPUS-ERYTHEMATOSUS ,Association Studies Article ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,Genetics ,0303 health sciences ,ARCHITECTURE ,CHRONIC INFLAMMATION ,1184 Genetics, developmental biology, physiology ,General Medicine ,RECEPTOR IL-6R GENE ,C-REACTIVE PROTEIN ,hla-drb1 gene ,3. Good health ,Medical genetics ,Medical Genetics ,chromosomes ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,European Continental Ancestry Group ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,anti-inflammatory agents ,White People ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,Interleukin 6 ,Molecular Biology ,Medicinsk genetik ,030304 developmental biology ,PRODUCE IL-6 ,Interleukin-6 ,Chromosome ,Receptors, Interleukin-6 ,RHEUMATOID-ARTHRITIS ,Interleukin 1 Receptor Antagonist Protein ,Gene Expression Regulation ,Genetic Loci ,CELLS ,biology.protein ,1182 Biochemistry, cell and molecular biology ,Human genome ,3111 Biomedicine ,Genome-Wide Association Study ,HLA-DRB1 Chains ,Interleukin-1 - Abstract
Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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- 2021
30. PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity
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Jamie Inshaw, Fabio Busonero, Eleonora Porcu, Maristella Pitzalis, Eleonora Cocco, Margherita Chessa, Helen M. Colhoun, Annalisa Loizedda, Marco Masala, Gonçalo R. Abecasis, Maria Giovanna Marrosu, Lidia Leoni, Carlo Sidore, Mario Lovicu, Annapaola Frongia, David Schlessinger, Sandra Lai, Nicolò Curreli, Andrea Maschio, Lenuta Balaci, Liana Ap Ferreli, Fausto Pier'Angelo Poddie, Francesca Virdis, Suna Onengut-Gumuscu, John A. Todd, Michele Marongiu, Valeria Orrù, Maria Rossella Ricciardi, Magdalena Zoledziewska, Antonello Pani, Mariano Dei, Stephen S. Rich, Francesca Deidda, Jessica Frau, Mauro Pala, Nazario Olla, Paola Ferrigno, Edoardo Fiorillo, Gabriella Sole, Alessandro P Delitala, Valentina Serra, Francesco Loi, Stuart J. McGurnaghan, Maristella Steri, Maria Grazia Pilia, Antonella Mulas, Matteo Floris, Francesco Cucca, Luisa Mereu, and Catherine C. Robertson
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0301 basic medicine ,Mutation ,Hemophagocytic lymphohistiocytosis ,biology ,Inflammation ,medicine.disease_cause ,medicine.disease ,Article ,3. Good health ,Autoimmunity ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Neurology ,Perforin ,Immunology ,biology.protein ,medicine ,Neurology (clinical) ,Allele ,medicine.symptom ,Cytokine storm ,030217 neurology & neurosurgery - Abstract
Background: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines—cytokine storm. Objective: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D). Methods: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians. Results: We report that PRF1:p.A91V, is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia p = 2.06 × 10−4, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 × 10−5, OR = 0.82. Conclusion: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.
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- 2020
31. Uterine Preservation Treatments in Sarcomas: Oncological Problems and Reproductive Results: A Systematic Review
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Linda Cipriani, Pierandrea De Iaco, Maria Dirodi, Alessandra Palma, Anna Myriam Perrone, Margherita Nannini, Eugenia De Crescenzo, Eleonora Porcu, Giuseppe Damiano, Giulia Dondi, Alessio G. Morganti, Maria Abbondanza Pantaleo, Martina Ferioli, Gloria Ravegnini, Antonio De Leo, Dondi G., Porcu E., De Palma A., Damiano G., De Crescenzo E., Cipriani L., Dirodi M., Ravegnini G., De Leo A., Nannini M., Ferioli M., Morganti A.G., Pantaleo M.A., De Iaco P., and Perrone A.M.
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Leiomyosarcoma ,fertility-sparing ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Assisted reproductive treatment ,assisted reproductive treatments ,Medicine ,Stage (cooking) ,sarcomas ,Cervix ,RC254-282 ,Gynecology ,Pregnancy ,Endometrial stromal sarcoma ,Hysterectomy ,Uterine sarcoma ,business.industry ,Standard treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Sarcoma ,medicine.disease ,uterine cancers ,medicine.anatomical_structure ,Oncology ,Gynecological cancer ,gynecological cancers ,Systematic Review ,business - Abstract
Simple Summary Uterine sarcomas can affect patients of reproductive age. In this setting, the chance of a fertility-sparing treatment would allow women to become pregnant. In the literature, only a few experiences of fertility-sparing treatment of uterine sarcomas have been reported; however, the oncological safety and reproductive outcomes remain unclear. The aim of this systematic review is to report and summarize all the published evidence about the fertility-sparing approach in these rare and heterogenous tumors, and to help physicians in making clinical decisions. Abstract Uterine sarcomas are rare cancers, sometimes diagnosed in women of childbearing age. Hysterectomy is the standard treatment in early stages. The option of lesion removal to save fertility is described in the literature, but it is still considered experimental. The objective of this systematic review is to report on the available evidence on the reproductive and oncological outcomes of fertility-sparing treatment in women with uterine sarcomas. PubMed, Scopus and Cochrane Central Register of Controlled Trials were searched between 1 January 2011 and 21 June 2021 for publications in English about women with uterine sarcoma treated with a fertility-sparing intervention. Thirty-seven studies were included for a total of 210 patients: 63 low-grade endometrial stromal sarcomas, 35 embryonal rhabdomyosarcomas of the cervix, 19 adenosarcomas, 7 leiomyosarcomas and 2 uterine tumors resembling an ovarian sex cord. Conservative treatment ensured pregnancy in 32% of cases. In terms of oncological outcomes, relapse was related to histology and the worst prognosis was reported for leiomyosarcoma, followed by low-grade endometrial stromal sarcoma, which relapsed in 71% and 54% of cases, respectively. The highest death rate was associated with leiomyosarcoma (57.1%). This study demonstrated that fertility-sparing treatments may be employed in selected cases of early stage uterine sarcoma.
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- 2021
32. The individual and global impact of copy-number variants on complex human traits
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Chiara Auwerx, Maarja Lepamets, Marie C. Sadler, Marion Patxot, Miloš Stojanov, David Baud, Reedik Mägi, Eleonora Porcu, Alexandre Reymond, Zoltán Kutalik, Tõnu Esko, Andres Metspalu, Lili Milani, and Mari Nelis
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Multifactorial Inheritance ,Phenotype ,DNA Copy Number Variations ,Liver-Specific Organic Anion Transporter 1 ,Genetics ,Humans ,Female ,Polymorphism, Single Nucleotide ,Genetics (clinical) ,Genome-Wide Association Study - Abstract
The impact of copy-number variations (CNVs) on complex human traits remains understudied. We called CNVs in 331,522 UK Biobank participants and performed genome-wide association studies (GWASs) between the copy number of CNV-proxy probes and 57 continuous traits, revealing 131 signals spanning 47 phenotypes. Our analysis recapitulated well-known associations (e.g., 1q21 and height), revealed the pleiotropy of recurrent CNVs (e.g., 26 and 16 traits for 16p11.2-BP4-BP5 and 22q11.21, respectively), and suggested gene functionalities (e.g., MARF1 in female reproduction). Forty-eight CNV signals (38%) overlapped with single-nucleotide polymorphism (SNP)-GWASs signals for the same trait. For instance, deletion of PDZK1, which encodes a urate transporter scaffold protein, decreased serum urate levels, while deletion of RHD, which encodes the Rhesus blood group D antigen, associated with hematological traits. Other signals overlapped Mendelian disorder regions, suggesting variable expressivity and broad impact of these loci, as illustrated by signals mapping to Rotor syndrome (SLCO1B1/3), renal cysts and diabetes syndrome (HNF1B), or Charcot-Marie-Tooth (PMP22) loci. Total CNV burden negatively impacted 35 traits, leading to increased adiposity, liver/kidney damage, and decreased intelligence and physical capacity. Thirty traits remained burden associated after correcting for CNV-GWAS signals, pointing to a polygenic CNV architecture. The burden negatively correlated with socio-economic indicators, parental lifespan, and age (survivorship proxy), suggesting a contribution to decreased longevity. Together, our results showcase how studying CNVs can expand biological insights, emphasizing the critical role of this mutational class in shaping human traits and arguing in favor of a continuum between Mendelian and complex diseases.
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- 2021
33. Quantifying mediation between omics layers and complex traits
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Eleonora Porcu, Marie C. Sadler, Auwerx Cmp, and Z. Kutalik
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Transcriptome ,Proteome ,Mendelian randomization ,dNaM ,Genome-wide association study ,Computational biology ,Quantitative trait locus ,Biology ,Omics ,Genetic association - Abstract
BackgroundHigh-dimensional omics datasets provide valuable resources to determine the causal role of molecular traits in mediating the path from genotype to phenotype. Making use of quantitative trait loci (QTL) and genome-wide association studies (GWASs) summary statistics, we developed a multivariable Mendelian randomization (MVMR) framework to quantify the connectivity between three omics layers (DNA methylome (DNAm), transcriptome and proteome) and their cascading causal impact on complex traits and diseases.ResultsEvaluating 50 complex traits, we found that on average 37.8% (95% CI: [36.0%-39.5%]) of DNAm-to-trait effects were mediated through transcripts in thecis-region, while only 15.8% (95% CI: [11.9%-19.6%]) are mediated through proteins incis. DNAm sites typically regulate multiple transcripts, and while found to predominantly decrease gene expression, this was only the case for 53.4% across ≈ 47,000 significant DNAm-transcript pairs. The average mediation proportion for transcript-to-trait effects through proteins (encoded for by the assessed transcript or located intrans) was estimated to be 5.27% (95%CI: [4.11%-6.43%]). Notable differences in the transcript and protein QTL architectures were detected with only 22% of protein levels being causally driven by their corresponding transcript levels. Several regulatory mechanisms were hypothesized including an example where cg10385390 (chr1:8’022’505) increases the risk of irritable bowel disease by reducingPARK7transcript and protein expression.ConclusionsThe proposed integrative framework identified putative causal chains through omics layers providing a powerful tool to map GWAS signals. Quantification of causal effects between successive layers indicated that molecular mechanisms can be more complex than what the central dogma of biology would suggest.
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- 2021
34. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
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Mahmoud Elansary, Knut Krohn, Eleonora Porcu, Julia Dmitrieva, Michel Georges, Harm-Jan Westra, Isabel Alves, Matthias Nauck, Jan H. Veldink, Joost Verlouw, Anette Kalnapenkis, Silva Kasela, Alex W. Hewitt, Roy Oelen, Willem H. Ouwehand, Frank Beutner, Ilkka Seppälä, Yukihide Momozawa, Samuli Ripatti, Brenda W.J.H. Penninx, Patrick Deelen, Michael Stumvoll, Jenny van Dongen, Jonathan K. Pritchard, Roman Kreuzhuber, Marie-Julie Favé, Bernett Lee, Hailang Mei, Biao Zeng, Philip Awadalla, Shuang Li, Kate Downes, Gibran Hemani, Urko M. Marigorta, Anke Tönjes, Morris Swertz, Robert Warmerdam, Joseph E. Powell, Mika Kähönen, Urmo Võsa, Brandon L. Pierce, Benjamin P. Fairfax, Anand Kumar Andiappan, Bastiaan T. Heijmans, Martina Müller-Nurasyid, Sven Bergmann, Katharina Schramm, Hanieh Yaghootkar, Sina Rüeger, Monique G. P. van der Wijst, Lude Franke, Ting Qi, Rick Jansen, Greg Gibson, Cisca Wijmenga, Marc Jan Bonder, Yungil Kim, Viktorija Kukushkina, Johannes Kettunen, Joachim Thiery, Peter A C 't Hoen, Zoltán Kutalik, Jian Yang, Dylan H. de Vries, Olaf Rötzschke, Maarten van Iterson, Peter Kovacs, Peter M. Visscher, Wibowo Arindrarto, Oliver Stegle, Natalia Pervjakova, Julian C. Knight, Tõnu Esko, Annique Claringbould, Lili Milani, Patrick F. Sullivan, Habibul Ahsan, Timothy M. Frayling, Lin Tong, Uwe Völker, Reyhan Sönmez Flitman, Eline Slagboom, Dorret I. Boomsma, Holger Prokisch, Michel G. Nivard, Mawusse Agbessi, Joyce B. J. van Meurs, Alexis Battle, Futao Zhang, Emmanouil T. Dermitzakis, Morris A. Swertz, Grant W. Montgomery, Terho Lehtimäki, Coen D.A. Stehouwer, Jaanika Kronberg, Holger Kirsten, Olli T. Raitakari, Sina A. Gharib, Bruce M. Psaty, Seyhan Yazar, Markus Loeffler, Harm Brugge, Jose Alquicira Hernandez, Mark W. Christiansen, Andrew A. Brown, Markus Perola, Markus Scholz, Ashis Saha, Alexander Teumer, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), BIOS Consortium, i2QTL Consortium, 't Hoen, PAC, van Meurs, J., van Dongen, J., van Iterson, M., Swertz, M.A., Jan Bonder, M., Biological Psychology, APH - Personalized Medicine, APH - Methodology, Internal Medicine, Interne Geneeskunde, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), and RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome
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DISORDER ,Multifactorial Inheritance ,Quantitative Trait Loci ,Genome-wide association study ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Gene Expression Regulation/genetics ,DISEASE ,LINKS ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,RELEVANCE ,Blood Proteins/genetics ,Gene expression ,Genetics ,Humans ,GENOME-WIDE ASSOCIATION ,Polymorphism ,Gene ,Multifactorial Inheritance/genetics ,030304 developmental biology ,Regulation of gene expression ,RISK ,0303 health sciences ,ARCHITECTURE ,Blood Proteins ,Transcriptome/genetics ,Polymorphism, Single Nucleotide/genetics ,Phenotype ,SERINE BIOSYNTHESIS ,HUMAN TRANSCRIPTOME ,DEFICIENCY ,Gene Expression Regulation ,Expression quantitative trait loci ,genome-wide association studies ,gene expression ,gene regulation ,Quantitative Trait Loci/genetics ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,Single Nucleotide/genetics ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.
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- 2021
35. Genetic insights into biological mechanisms governing human ovarian ageing
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Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
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Gerontology ,Aging ,Far East ,Endocrinology, Diabetes and Metabolism ,Menopause, Premature ,Genome-wide association study ,VARIANTS ,Primary Ovarian Insufficiency ,Inbred C57BL ,Bioinformatics ,DISEASE ,Healthy Aging ,genetics of ovarian aging ,Fragile X Mental Retardation Protein ,Mice ,Endocrinology ,Medicine ,EARLY MENOPAUSE ,media_common ,RISK ,Multidisciplinary ,Asia, Eastern ,Reproduction ,Longevity ,Middle Aged ,Europe ,MENDELIAN RANDOMIZATION ,Medical genetics ,Female ,ICEP ,Menopause ,Adult ,Alleles ,Animals ,Bone and Bones ,Checkpoint Kinase 1 ,Checkpoint Kinase 2 ,Diabetes Mellitus, Type 2 ,Diet ,Fertility ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Mice, Inbred C57BL ,Ovary ,Uterus ,Type 2 ,medicine.medical_specialty ,media_common.quotation_subject ,MEDLINE ,Biology ,Premature ovarian insufficiency ,Article ,genome-wide meta-analysis ,SDG 3 - Good Health and Well-being ,GERMLINE ,Diabetes Mellitus ,Genetic predisposition ,Ovarian reserve ,Premature ,business.industry ,Human genetics ,CHROMOSOME SYNAPSIS ,DNA-DAMAGE ,Ageing ,EXPRESSION ANALYSIS ,business ,MEIOTIC CELL-CYCLE - Abstract
Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
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- 2021
36. P–486 Psychological determinants of the decision to attend couples infertility counselling
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Linda Cipriani, Eleonora Porcu, Francesca Sonia Labriola, M Dirodi, Giuseppe Damiano, Nicolino Cesare Franco Rossi, Paola Salvatori, and Federica Andrei
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Infertility ,medicine.medical_specialty ,Reproductive Medicine ,Family medicine ,Rehabilitation ,medicine ,Obstetrics and Gynecology ,medicine.disease ,Psychology - Abstract
Study question May specific psychological variables related to the experience of infertility have a predicting effect over the decision of accepting counselling? Summary answer Specific infertility related sources of sufferance including low levels of infertility self-efficacy and poor quality of life significantly predict the request for professional help. What is known already Available data on the access to infertility counselling services suggest that only 10–34% of patients who are offered such opportunity actually pursue it. Qualitative studies pointed out that this might be due to a lack of information about available support and to negative attitudes toward counselling. It seems also that women and men who accept counselling have worse levels of psychological distress. However, there is a lack of quantitative studies on the topic and among those available none used measures that are specific to the experience of infertility itself Study design, size, duration The data presented herein are part of a larger data collection promoted by the Italian Ministry of Health on the psychological impact of assisted reproduction. The present study is a cross-sectional research and involves a sample of 184 patients, composed by 92 women waiting for infertility treatment and their partners, enrolled between October 2019 and October 2020 at the Infertility and IVF Unit of the S. Orsola University Hospital in Bologna, Italy. Participants/materials, setting, methods Participants were voluntarily enrolled in the study at their first medical consult. They were informed about the possibility to attend free couples infertility counselling sessions and asked to fill in the following questionnaires: Infertility Self-Efficacy Scale (ISE); Fertility Quality of Life (FERTIQoL); Dyadic Adjustment Scale (DAS). To attend infertility counselling a shared agreement between partners was requested. Couples who agreed to the study but not to counselling sessions were provided only with questionnaires. Main results and the role of chance The 34.8% (n = 32 couples) of the sample accepted to receive counselling sessions. The two groups (counselling vs no-counselling) were comparable in all socio-demographic variables, aside for education, with higher education levels in the counselling group. Overall, the counselling group reported greater psychological sufferance than the no-counselling group, with lower scores at the ISE, FERTIQoL, and DAS questionnaires. Regarding which factors predicted the decision to attend counselling sessions, logistic regression analysis showed that: for the female partner’s dimensions low scores at the ISE and at the Emotional subscale of the FertiQoL were predictive of accepting counselling (when scores increased the odds of being in the counselling group would decrease by 46% and 8% respectively); for the male’s partner dimensions, predictive factors were low scores on the Social subscale and high scores on the Relational subscale of the FertiQoL (when scores increased the odds of being in the counselling group would decrease by 8% and increase by 10% respectively). In conclusion, impairments in self-efficacy, emotional well-being and social life may drive a greater need for help, but a close relationship with the partner may be also necessary to predispose men to accept couples infertility counselling. Limitations, reasons for caution Data were collected from a well enough homogeneous sample which may have helped in better enhancing the specificity of infertile couples’ needs. However, the small sample size and the fact that data were collected from a sole Italian clinic may impact the representativity of our results. Wider implications of the findings: Findings provide important information for clinical interventions with infertile couples. Patients accepting counselling might be having a worse adjustment to the experience of infertility. Besides, women and men may be affected in different ways. Men’s closeness to the partner might be a favourable factor and should be further studied. Trial registration number The study was approved by the Ethical Committee of the S. Orsola Hospital, University of Bologna (CE: 273/2018/Sper/AOUBO) and funded by the Italian Ministry of Health (J33C17000560001)
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- 2021
37. P–098 Use of Dimethylxanthine Theophylline in surgical retrieved sperms that do not recover motility after thawing
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Giuseppe Damiano, Patrizia Ciotti, S. Zuffa, Linda Cipriani, M Dirodi, Maria Lucrezia Tranquillo, A Franceschelli, Eleonora Porcu, Leonardo Notarangelo, and N. Calza
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Chemistry ,Rehabilitation ,Treatment outcome ,Phosphoric Diester Hydrolases ,Obstetrics and Gynecology ,Motility ,Andrology ,Patient referral ,Touch sensation ,Reproductive Medicine ,Age groups ,medicine ,Theophylline ,Sperm motility ,medicine.drug - Abstract
Study question Can the use of Theophylline recover motility of frozen surgically retrieved sperms in case of absence of motility after thawing? Summary answer Theophylline allows to recover motility of thawed surgically retrieved sperms. The utilization of sperms with or without pharmacological activation gives comparable clinical outcomes. What is known already Testicular sperm motility is usually poor. A method is needed to detect viable sperm for ICSI when motility is totally absent after freezing/thawing. Hypo-osmotic swelling test, mechanical touch technique, laser-assisted immotile sperm selection, birefringence-polarization microscopy and exposure to pharmacological stimulation are techniques used for this purpose. Among pharmacological agents Dimethylxanthine Theophylline is a phosphodiesterase inibitor that improves sperm motility by promoting an increase in intracellular cyclic AMP levels. Few studies report that it is efficient for recovery of sperm motility in cases of thawed testicular and retrograde ejaculation samples improving reproductive outcomes. Study design, size, duration Retrospective analysis of sixty frozen surgical sperm cycles (45 patients) utilized from February 2018 to November 2020. After thawing, samples were divided in two Groups according to motility recovery. Group A: presence of motility, Group B: absence of motility. Group B was treated with Theophilline and motility was re-assessed after incubation. Activated sperms were utilized for ICSI when available. Sperm motility recovery, fertilization, pregnancy rate/transfer, implantation and miscarriage rate were evaluated in both Groups. Participants/materials, setting, methods Surgical specimens were treated and concentrated in SpermRinse™ Medium (Vitrolife) and then cryopreservated in nitrogen vapor in TEST Yolk Buffer (Irvine Scientific). After thawing, only samples with no motility recovery were treated with a brief incubation in Theophylline (GM501 SpermMobil, Gynemed) and washed in Polyvinylpyrrolidone (ICSITM Vitrolife) before injection. ICSI was performed in all cases approximately 4–5 hours after sperm thawing. After fertilization check, transfer was scheduled in day 2. Main results and the role of chance Women’s age Group A (34,39±2,29 M±SD) and group B (35,87±4,34 M±SD) and men’s age Group A (37,31±5,12 M±SD) and group B (40,89±8.15 M±SD) were not significantly different (P= .328 and P=.218) respectively. Group A: 13/60 cycles (21.7%) (9 patients). Pre freezing and post thawing total motility percentage were 34.0±19.0 (M±SD) and 13.5±15.6 (M±SD) respectively (39.8% recovery). Group B: 47/60 cycles (78.3%) (36 patients). Pre freezing total motility percentage was 5.3±8.5 (M±SD) and no motility was recovered post thawing (0%). After treatment with Theophylline total motility was 1.8±1.8 (M±SD) (33.5% recovery). Motile sperms were utilized in all cases except from two in the Group B. Number of injected oocytes was 2.8±1.1 (M±SD) in Group A and 4.3±3.1 (M±SD) in Group B (P=.004) respectively. Fertilisation rate (63.1% and 45.4%, P=.066), Number of embryos transferred (1.8±0.7 M±SD and 1.6±0.7 M±SD, P=.271), Pregnancy rate/Transfer (54.5% and 37.1%, P=.502), Implantation rate (30.0% and 27.8%, P=.919) and Miscarriage rate (33.3% and 30.7%, P=.675) were not statistically significant between Group A and B respectively. In the two cases of group B injected with immotile sperm, fertilization rate was 0% (0/3) and 50% (2/4). Limitations, reasons for caution A larger study is needed to investigate the recovery of sperms motility (and/or their activation) and clinical outcomes, in particular referring to the origin of sampling (epididymal aspirate and testicular tissue) and type of azoospermia (obstructive and non-obstructive). Wider implications of the findings: Theophylline is an effective tool for sperm motility recovery after thawing allowing to inject viable sperm and facilitating laboratory handling. Trial registration number Not applicable
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- 2021
38. P–794 Prevalence of positivity for SARS-CoV–2 RNA in follicular fluid in infertile patients
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Maria Lucrezia Tranquillo, S. Zuffa, Eleonora Porcu, Leonardo Notarangelo, C. Vocale, M Dirodi, Linda Cipriani, Francesca Sonia Labriola, N. Calza, Giuseppe Damiano, and Patrizia Ciotti
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2019-20 coronavirus outbreak ,Reproductive Medicine ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Rehabilitation ,Obstetrics and Gynecology ,Medicine ,RNA ,business ,Virology ,Follicular fluid - Abstract
Study question Is Sars-Cov–2 present in the follicular fluid of infertile patients? Summary answer In the experience of the Infertility and IVF Unit, University Of Bologna, Italy, RNA of SARS-Cov–2 was not detected in the follicular fluid. What is known already Data on the risk of virus presence in reproductive cells and transmissibility in IVF procedures are very limited. In literature only one study reports the detection of SARS-Cov–2 viral RNA in oocytes of PCR positive women. Research of RNA in follicular fluid could be a marker able to indicate whether to continue IVF treatments in the case of swab-positive patients. Study design, size, duration Prospective study performed at Infertility and IVF Unit, Sant’Orsola University Hospital, University of Bologna, Italy, from March 2020 to January 2021. 451 IVF cycles were performed on 902 patients. In addition 59 cycles of oocyte cryopreservation were also performed to fertility preservation in oncological patients. In all positive swab patients was analyzed the follicular fluid for RNA virus detection. Participants/materials, setting, methods 961 patients underwent telephone triage before going to the IVF Center to identify subjects with suspected or confirmed infection. Body temperature was measured on all patients before entering the IVF Center. All patients were subjected to real-time analysis (RT PCR) of pharyngeal swab samples 48 hours before transvaginal ultrasound-guided oocyte retrieval. In case of positive swab, PCR was performed on follicular fluid. Main results and the role of chance In our population of infertile patients the incidence of SARS COV–2 infection positivity was 0.4% (4/961). No IVF treatments were suspended. The oocytes of the 4 women with positive swab were cryopreserved using closed devices stored in a special dedicated cryogenic container. No viral RNA was detected in the follicular fluid. Limitations, reasons for caution there are no limitations to the study. Wider implications of the findings: The absence of SARS-COV–2 RNA in the follicular fluid is a reassuring result in the storage and future use of oocytes. Trial registration number Not applicable
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- 2021
39. Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome
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Antoine Weihs, Olivier Delaneau, Marie C. Sadler, Diogo M. Ribeiro, Toshiko Tanaka, Stefania Bandinelli, Andres Metspalu, Maroun Bou Sleiman, Chiara Auwerx, Andrew R. Wood, Zoltán Kutalik, Uwe Völker, Federico Santoni, Eleonora Porcu, Alexander Teumer, Kaido Lepik, Alexandre Reymond, Timothy M. Frayling, and Matthias Nauck
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Statistical methods ,Science ,Quantitative Trait Loci ,body-mass index ,General Physics and Astronomy ,integration ,Genome-wide association study ,Disease ,Biology ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,adipogenesis ,Transcriptome ,blood ,Polymorphism (computer science) ,Pleiotropy ,Gene expression ,Mendelian randomization ,Humans ,Genetic Predisposition to Disease ,Gene ,Genetic Association Studies ,Genetic association study ,Genetics ,Multidisciplinary ,datasets ,STX1B ,Gene Expression Profiling ,Confounding ,General Chemistry ,high-density-lipoprotein ,Mendelian Randomization Analysis ,Phenotype ,Causality ,loci ,genome-wide association ,mendelian randomization ,epidemiology ,Algorithms ,Genome-Wide Association Study - Abstract
Comparing transcript levels between healthy and diseased individuals allows the identification of differentially expressed genes, which may be causes, consequences or mere correlates of the disease under scrutiny. We propose a method to decompose the observational correlation between gene expression and phenotypes driven by confounders, forward- and reverse causal effects. The bi-directional causal effects between gene expression and complex traits are obtained by Mendelian Randomization integrating summary-level data from GWAS and whole-blood eQTLs. Applying this approach to complex traits reveals that forward effects have negligible contribution. For example, BMI- and triglycerides-gene expression correlation coefficients robustly correlate with trait-to-expression causal effects (rBMI = 0.11, PBMI = 2.0 × 10−51 and rTG = 0.13, PTG = 1.1 × 10−68), but not detectably with expression-to-trait effects. Our results demonstrate that studies comparing the transcriptome of diseased and healthy subjects are more prone to reveal disease-induced gene expression changes rather than disease causing ones., Identification of gene expression changes between healthy and diseased individuals can reveal mechanistic insights and biomarkers. Here, the authors propose a bi-directional transcriptome-wide Mendelian Randomization approach to assess causal effects between gene expression and complex traits.
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- 2021
40. Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
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Liza Darrous, Eleonora Porcu, Nasim Bararpour, Loic Yengo, Philippe Froguel, Pedro Marques-Vidal, Zoltán Kutalik, Marie Gasser, Gérard Waeber, Aurélien Thomas, and Federica Gilardi
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Male ,0301 basic medicine ,Metabolic disorders ,Type 2 diabetes ,Bioinformatics ,0302 clinical medicine ,Medicine ,education.field_of_study ,Multidisciplinary ,Valine ,Middle Aged ,Metabolome ,symbols ,Female ,Adult ,Science ,Population ,Glutamic Acid ,030209 endocrinology & metabolism ,Article ,03 medical and health sciences ,symbols.namesake ,Metabolomics ,Leucine ,Carnitine ,Mendelian randomization ,Genetics ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,education ,Aged ,business.industry ,Lysine ,Type 2 Diabetes Mellitus ,Mendelian Randomization Analysis ,medicine.disease ,Betaine ,Early Diagnosis ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Mendelian inheritance ,business ,Mannose ,Biomarkers - Abstract
The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.
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- 2021
41. Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies
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Olli T. Raitakari, Menno Pruijm, Michelle Kelly-Irving, Belen Ponte, Nicolas Vuilleumier, Eleonora Porcu, Silvia Stringhini, Olivier Delaneau, Marc Chadeau-Hyam, Pashupati P. Mishra, Murielle Bochud, Zoltán Kutalik, Terho Lehtimäki, Cristian Carmeli, Mika Kivimäki, Emmanouil T. Dermitzakis, Georg Ehret, Cyrille Delpierre, Mika Kähönen, Nasser A. Dhayat, Paolo Vineis, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, and Commission of the European Communities
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Male ,0301 basic medicine ,Molecular biology ,Bioinformatics ,Epigenesis, Genetic ,Transcriptome ,0302 clinical medicine ,ddc:576.5 ,Longitudinal Studies ,030212 general & internal medicine ,610 Medicine & health ,Child ,Finland ,Aged, 80 and over ,ddc:616 ,Socioeconomic disadvantage ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,Middle Aged ,C-Reactive Protein ,DNA methylation ,Medicine ,Female ,medicine.symptom ,Switzerland ,Cohort study ,Adult ,Science ,Inflammation ,Biology ,Vulnerable Populations ,Article ,Life Change Events ,03 medical and health sciences ,medicine ,Humans ,Epigenetics ,Gene ,Aged ,ddc:613 ,030304 developmental biology ,Models, Statistical ,Gene Expression Profiling ,DNA Methylation ,3126 Surgery, anesthesiology, intensive care, radiology ,Computational biology and bioinformatics ,Disadvantaged ,030104 developmental biology ,Risk factors ,Socioeconomic Factors ,Immune System ,Biomarkers - Abstract
Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.
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- 2021
42. A cross-disorder dosage sensitivity map of the human genome
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Swaroop Aradhya, Konrad J. Karczewski, Farid Ullah, Georgios Kellaris, Diane Lucente, Benjamin M. Neale, Selin Everett, Xander Nuttle, Daniel P. Howrigan, Ryan L. Collins, Michael E. Talkowski, Hilary K. Finucane, Alexandre Reymond, Eleonora Porcu, Jack Fu, Zoltán Kutalik, Nicholas Katsanis, Ludmilla Matyakhina, Kiana Mohajeri, Chelsea Lowther, Kaitlin E. Samocha, Hakon Hakonarson, Jennelle C. Hodge, Lisa-Marie Niestroj, Erica E. Davis, James F. Gusella, Shamil R. Sunyaev, Jacob C. Ulirsch, Harrison Brand, Jeanne Meck, Joseph T. Glessner, Philip M. Boone, and Dennis Lal
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Genetics ,Gene duplication ,medicine ,Autism ,Human genome ,Disease ,Copy-number variation ,Biology ,medicine.disease ,Haploinsufficiency ,Gene ,Exome sequencing - Abstract
SUMMARYRare deletions and duplications of genomic segments, collectively known as rare copy number variants (rCNVs), contribute to a broad spectrum of human diseases. To date, most disease-association studies of rCNVs have focused on recognized genomic disorders or on the impact of haploinsufficiency caused by deletions. By comparison, our understanding of duplications in disease remains rudimentary as very few individual genes are known to be triplosensitive (i.e., duplication intolerant). In this study, we meta-analyzed rCNVs from 753,994 individuals across 30 primarily neurological disease phenotypes to create a genome-wide catalog of rCNV association statistics across disorders. We discovered 114 rCNV-disease associations at 52 distinct loci surpassing genome-wide significance (P=3.72×10−6), 42% of which involve duplications. Using Bayesian fine-mapping methods, we further prioritized 38 novel triplosensitive disease genes (e.g., GMEB2 in brain abnormalities), including three known haploinsufficient genes that we now reveal as bidirectionally dosage sensitive (e.g., ANKRD11 in growth abnormalities). By integrating our results with prior literature, we found that disease-associated rCNV segments were enriched for genes constrained against damaging coding variation and identified likely dominant driver genes for about one-third (32%) of rCNV segments based on de novo mutations from exome sequencing studies of developmental disorders. However, while the presence of constrained driver genes was a common feature of many pathogenic large rCNVs across disorders, most of the rCNVs showing genome-wide significant association were incompletely penetrant (mean odds ratio=11.6) and we also identified two examples of noncoding disease-associated rCNVs (e.g., intronic CADM2 deletions in behavioral disorders). Finally, we developed a statistical model to predict dosage sensitivity for all genes, which defined 3,006 haploinsufficient and 295 triplosensitive genes where the effect sizes of rCNVs were comparable to deletions of genes constrained against truncating mutations. These dosage sensitivity scores classified disease genes across molecular mechanisms, prioritized pathogenic de novo rCNVs in children with autism, and revealed features that distinguished haploinsufficient and triplosensitive genes, such as insulation from other genes and local cis-regulatory complexity. Collectively, the cross-disorder rCNV maps and metrics derived in this study provide the most comprehensive assessment of dosage sensitive genomic segments and genes in disease to date and set the foundation for future studies of dosage sensitivity throughout the human genome.
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- 2021
43. Genetic insights into the biological mechanisms governing human ovarian ageing
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Unnur Styrkarsdottir, Daniel I. Chasman, Rehannah Borup, Anne B. Newman, Kristina W. Olsen, Lude Franke, Stefania Bandinelli, Nora Franceschini, Celine M. Vachon, Nicholas J. Timpson, James F. Wilson, Micaella Joaquim, Christa Meisinger, Felix R. Day, Charles Kooperberg, Qin Wang, Pascal Timshel, Dennis O. Mook-Kanamori, Luigi Ferrucci, Jennifer A. Smith, Miriam Dwek, Pascal Guénel, Claus Yding Andersen, Peter A. Fasching, Sven Bergmann, Thomas Meitinger, Nicholas Bowker, Jane L. Tarry-Adkins, Jeremy A. Daniel, Katharina E. Schraut, Mikael Eriksson, Amruta Shrikhande, Jacques E. Rossouw, Amber N. Wilcox, Simon S. Cross, Stasa Stankovic, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Annette Peters, David Schlessinger, Sheila Ulivi, Mònica Ferrer-Roda, Immaculata De Vivo, Michela Traglia, Jessica Tyrrell, Paul R. H. J. Timmers, Rico Rueedi, Ko Willems van Dijk, N. Charlotte Onland-Moret, Doris Stöckl, Anthony J. Swerdlow, Paul M. Ridker, Zoltán Kutalik, Patrick Deelen, Gerardo Heiss, Marie Louise Grøndahl, Alison M. Dunning, Dale R. Nyholt, Nicholas J. Wareham, Reedik Mägi, Stephen J. Chanock, Martina La Bianca, Ozren Polasek, Daniel F. Gudbjartsson, Rebecca D. Jackson, Alison D. Murray, Lynda M. Rose, Hironori Abe, Joanne M. Murabito, Henry Völzke, Daniela Ruggiero, Dorret I. Boomsma, Harald Grallert, Stefania Benonisdottir, Javier Martin Gonzalez, Esther M. John, Natalia Perjakova, Georgia Chenevix-Trench, John R. B. Perry, Jenny Chang-Claude, Archie Campbell, Teresa Nutile, Ellen W. Demerath, Robin N Beaumont, Jouke J. Hottenga, Albert V. Smith, David Karasik, Linda Broer, Raymond Noordam, Wei He, Niclas Håkansson, Catherine E. Aiken, Robert Karlsson, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Sharon L.R. Kardia, Nicholas G. Martin, Jodie N. Painter, Peter K. Joshi, Gonneke Willemsen, Lenore J. Launer, Alicja Wolk, Konstantin Strauch, Stig E. Bojesen, Manjeet K. Bolla, Allison W. Kurian, Renée de Mutsert, Joop S.E. Laven, Antonella Mulas, Igor Rudan, Vallari Shukla, Kathyrn L Lunetta, Susan E. Ozanne, Loic Le Marchand, Jenny A. Visser, Gad Rennert, Jennifer A. Brody, Paul D.P. Pharoah, Tune H. Pers, Sara Lindström, Ignasi Roig, Angela Cox, Unnur Þorsteinsdottir, Graham G. Giles, Toshiko Tanaka, Eva Hoffmann, Melissa A. Troester, Claudia Langenberg, Serena Sanna, Julie E. Buring, Anna Pujol, Mike A. Nalls, Kamila Czene, Tõnu Esko, Jian'an Luan, Lili Milani, Iffat Rahman, Sarah E. Medland, Caterina Barbieri, Emil Peter Trane Hertz, Behrooz Z. Alizadeh, David G. Hunter, Sandra Turon, Antonietta Robino, Marina Ciullo, Barbara McKnight, Chunyan He, Bruce H. R. Wolffenbuttel, David R. Weir, Daniela Toniolo, Ulrike Peters, George Davey-Smith, Saleh Shekari, Caroline Hayward, Elinor J. Sawyer, Patrick Sulem, Simin Liu, Tanguy Corre, Susan M. Ring, Peter Kraft, Alexander Teumer, Marjanka K. Schmidt, André G. Uitterlinden, Arto Mannermaa, Kristan J. Aronson, Heiko Becher, John L. Hopper, Alpa V. Patel, Joyce B. J. van Meurs, kConFab Investigators, Hamdi Mbarek, Frits R. Rosendaal, Minouk J. Schoemaker, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Nancy L. Pedersen, Jessica D. Faul, Patrik K. E. Magnusson, Jingmei Li, Christopher G. Scott, Joe Dennis, Genevieve Lachance, Ajuna Azad, Yongmei Liu, Elnaz Naderi, Andrew R. Wood, Yan Huang, Anna Murray, Annique Claringbould, Stephen Burgess, Jose E. Castelao, Brumat Marco, Eco J. C. de Geus, Veronique Vitart, Ken K. Ong, Kari Stefansson, Blair H. Smith, Francesco Cucca, Grant W. Montgomery, Emmanouil Saloustros, Andrés J. López-Contreras, Jonathan Marten, Håkan Olsson, Dale P. Sandler, Alice M. Arnold, Ana Martínez-Marchal, Tim D. Spector, Chloé Sarnowski, John J. Spinelli, Vilmundur Gudnason, Frank B. Hu, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Eric Boerwinkle, Matthias W. Beckmann, Jazib Hussain, Uwe Völker, Peter Vollenweider, Douglas F. Easton, Irene L. Andrulis, Harry Campbell, Manuela Gago-Dominguez, Cari M. Kitahara, Yvonne T. van der Schouw, Eleonora Porcu, Annika Lindblom, Martha S. Linet, Meir J. Stampfer, Eulalia Catamo, Roger L. Milne, Ivana Kolcic, Annelie Augustinsson, Cinzia Sala, Debbie A Lawlor, Cristina Menni, Timothy M. Frayling, Lauren R. Teras, Marek Zygmunt, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Per Hall, Rossella Sorice, Wei Zhao, Andres Metspalu, Katherine S. Ruth, Andrew F. Olshan, Massimo Mezzavilla, Murielle Bochud, and Christian Gieger
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media_common.quotation_subject ,Genetic predisposition ,Longevity ,Fertility ,Disease ,Biology ,Premature ovarian insufficiency ,Bioinformatics ,Ovarian reserve ,FMR1 ,Human genetics ,media_common - Abstract
Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenicFMR1premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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- 2021
44. High-security closed devices are efficient and safe to protect human oocytes from potential risk of viral contamination during vitrification and storage especially in the COVID-19 pandemic
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Eleonora Porcu, Maria Lucrezia Tranquillo, Lisa Mori, Linda Cipriani, Maria Dirodi, Leonardo Notarangelo, Francesca Sonia Labriola, N. Calza, Giuseppe Damiano, Patrizia Ciotti, Silvia Zuffa, Elena Nardi, Porcu E., Tranquillo M.L., Notarangelo L., Ciotti P.M., Calza N., Zuffa S., Mori L., Nardi E., Dirodi M., Cipriani L., Labriola F.S., and Damiano G.
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0301 basic medicine ,Pregnancy Rate ,medicine.medical_treatment ,Letter to Editor ,Intracytoplasmic sperm injection ,Miscarriage ,0302 clinical medicine ,Human fertilization ,Pregnancy ,Freezing ,Obstetrics and Gynaecology ,Genetics(clinical) ,Prospective Studies ,Assisted Reproduction Technologies ,Genetics (clinical) ,High-security devices ,030219 obstetrics & reproductive medicine ,Oocyte Donation ,Obstetrics and Gynecology ,General Medicine ,Embryo transfer ,Italy ,Female ,Infertility ,Adult ,Reproductive Techniques, Assisted ,Nitrogen ,Fertilization in Vitro ,Oocyte vitrification ,Andrology ,03 medical and health sciences ,Closed system vitrification ,High-security device ,medicine ,Genetics ,Humans ,Embryo Implantation ,Sperm Injections, Intracytoplasmic ,Survival rate ,Pandemics ,Cryopreservation ,Pandemic ,business.industry ,SARS-CoV-2 ,COVID-19 ,medicine.disease ,Embryo Transfer ,Pregnancy rate ,030104 developmental biology ,Reproductive Medicine ,Oocytes ,business ,Developmental Biology - Abstract
PurposeThe main purpose and research question of the study are to compare the efficacy of high-security closed versus open devices for human oocytes’ vitrification.MethodsA prospective randomized study was conducted. A total of 737 patients attending the Infertility and IVF Unit at S.Orsola University Hospital (Italy) between October 2015 and April 2020 were randomly assigned to two groups. A total of 368 patients were assigned to group 1 (High-Security Vitrification™ - HSV) and 369 to group 2 (Cryotop® open system). Oocyte survival, fertilization, cleavage, pregnancy, implantation, and miscarriage rate were compared between the two groups.ResultsNo statistically significant differences were observed on survival rate (70.3% vs. 73.3%), fertilization rate (70.8% vs. 74.9%), cleavage rate (90.6% vs. 90.3%), pregnancy/transfer ratio (32.0% vs. 31.8%), implantation rate (19.7% vs. 19.9%), nor miscarriage rates (22.1% vs. 21.5%) between the two groups. Women’s mean age in group 1 (36.18 ± 3.92) and group 2 (35.88 ± 3.88) was not significantly different (P= .297). A total of 4029 oocytes were vitrified (1980 and 2049 in groups 1 and 2 respectively). A total of 2564 were warmed (1469 and 1095 in groups 1 and 2 respectively). A total of 1386 morphologically eligible oocytes were inseminated by intracytoplasmic sperm injection (792 and 594 respectively,P= .304).ConclusionsThe present study shows that the replacement of the open vitrification system by a closed one has no impact on in vitro and in vivo survival, development, pregnancy and implantation rate. Furthermore, to ensure safety, especially during the current COVID-19 pandemic, the use of the closed device eliminates the potential samples’ contamination during vitrification and storage.
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- 2021
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45. Self-efficacy, coping strategies and quality of life in women and men requiring assisted reproductive technology treatments for anatomical or non-anatomical infertility
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Paola Salvatori, Federica Andrei, Maria Dirodi, Elena Trombini, Giuseppe Damiano, Linda Cipriani, Eleonora Porcu, Nicolino Cesare Franco Rossi, Andrei F., Salvatori P., Cipriani L., Damiano G., Dirodi M., Trombini E., Rossi N., and Porcu E.
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Infertility ,Quality of life ,Adult ,Male ,Coping (psychology) ,Reproductive Techniques, Assisted ,Cross-sectional study ,medicine.medical_treatment ,media_common.quotation_subject ,Fertility ,Coping strategie ,Surveys and Questionnaires ,Adaptation, Psychological ,medicine ,Humans ,Surveys and Questionnaire ,media_common ,Response rate (survey) ,Cross-Sectional Studie ,Assisted reproductive technology ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Self Efficacy ,Health psychology ,Cross-Sectional Studies ,Reproductive Medicine ,Female ,business ,Self-efficacy ,Stress, Psychological ,Clinical psychology ,Human - Abstract
Objective To examine the magnitude and the predictors of emotional reactions to an infertility diagnosis, comparing women and men who were clinically diagnosed with an anatomical cause of infertility or non-anatomical cause of infertility. Study design Cross-sectional study involving a total of 133 adults waiting for infertility treatment at the IVF and Infertility Unit of the S. Orsola University Hospital in Bologna (Italy). Of these, 107 patients (55 with anatomical causes of infertility and 52 with non-anatomical causes of infertility; response rate: 80%) took part to the study. After providing informed written consent, each participant was asked to complete the Infertility Self-efficacy Scale, the Fertility Quality of Life, and the Brief Coping Orientation to Problem Experienced, which they returned at their second access to the Unit. Differences between the groups were analyzed through a series of univariate ANOVA, whereas a multiple regression analysis was used to jointly examine the predictors of fertility quality of life. Results Results showed both gender related and diagnosis related differences. Women had statistically significant lower scores than men on the Infertility Self-Efficacy Scale and on the global, emotional, and mind–body subscales of the Fertility Quality of Life, while they scored significantly higher on the emotion focused and socially supported subscales of the Coping Orientation to Problem Experienced. Independently of gender, patients with non-anatomical causes of infertility scored poorly than patients with anatomical causes of infertility on the relational subscale of the Fertility Quality of Life and on the Avoidant scale of the Brief Coping Orientation to Problem Experienced. Hierarchical multiple regression analyses revealed that higher levels of self-efficacy and a lower use of avoidant coping strategies predicted a more positive quality of life over and above gender and cause of infertility. Conclusion This study partly confirms data on gender differences in experiencing the psychological burden of infertility and adds some new information, particularly with respect to the prediction of quality of life indicators over and above infertility cause.
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- 2021
46. A cross-disorder dosage sensitivity map of the human genome
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Ryan L. Collins, Joseph T. Glessner, Eleonora Porcu, Maarja Lepamets, Rhonda Brandon, Christopher Lauricella, Lide Han, Theodore Morley, Lisa-Marie Niestroj, Jacob Ulirsch, Selin Everett, Daniel P. Howrigan, Philip M. Boone, Jack Fu, Konrad J. Karczewski, Georgios Kellaris, Chelsea Lowther, Diane Lucente, Kiana Mohajeri, Margit Nõukas, Xander Nuttle, Kaitlin E. Samocha, Mi Trinh, Farid Ullah, Urmo Võsa, Matthew E. Hurles, Swaroop Aradhya, Erica E. Davis, Hilary Finucane, James F. Gusella, Aura Janze, Nicholas Katsanis, Ludmila Matyakhina, Benjamin M. Neale, David Sanders, Stephanie Warren, Jennelle C. Hodge, Dennis Lal, Douglas M. Ruderfer, Jeanne Meck, Reedik Mägi, Tõnu Esko, Alexandre Reymond, Zoltán Kutalik, Hakon Hakonarson, Shamil Sunyaev, Harrison Brand, Michael E. Talkowski, Andres Metspalu, Mari Nelis, and Lili Milani
- Subjects
DNA Copy Number Variations ,Genome, Human ,Gene Dosage ,Humans ,Haploinsufficiency ,General Biochemistry, Genetics and Molecular Biology - Abstract
Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplopTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.
- Published
- 2020
47. Successful Pregnancies, Births, and Children Development Following Oocyte Cryostorage in Female Cancer Patients During 25 Years of Fertility Preservation
- Author
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Eleonora Porcu, Linda Cipriani, Maria Dirodi, Pierandrea De Iaco, Anna Myriam Perrone, Pier Luigi Zinzani, Mario Taffurelli, Claudio Zamagni, Patrizia Maria Ciotti, Leonardo Notarangelo, Nilla Calza, Giuseppe Damiano, Porcu, Eleonora, Cipriani, Linda, Dirodi, Maria, De Iaco, Pierandrea, Perrone, Anna Myriam, Zinzani, Pier Luigi, Taffurelli, Mario, Zamagni, Claudio, Ciotti, Patrizia Maria, Notarangelo, Leonardo, Calza, Nilla, and Damiano, Giuseppe
- Subjects
child development ,Cancer Research ,oocyte cryopreservation ,fertility preservation ,oncofertility ,Oncology - Abstract
Simple Summary The study goal is to demonstrate that oocyte cryopreservation is a feasible and efficient option for fertility preservation in cancer patients through the comparison of in vitro fertilization treatments in nononcological patients. The preservation of fertility in cancer patients is a crucial aspect of modern reproductive medicine. Amenorrhea and infertility often occur after cancer therapy, worsening the quality of life. Cryopreservation of oocytes in young cancer patients is a therapeutic option for preserving fertility. A prospective study was conducted on 508 cancer patients who underwent oocyte cryopreservation to preserve fertility between 1996 and 2021 including the COVID-19 pandemic period. Patients underwent ovarian stimulation, followed by egg retrieval, and oocytes were cryopreserved by slow freezing or vitrification. Sixty-four thawing/warming cycles were performed. Survival, fertilization, pregnancy, and birth rate over the thawing/warming cycles were obtained. The data were compared with those from a group of 1042 nononcological patients who cryopreserved supernumerary oocytes. An average of 8.8 +/- 6.9 oocytes were retrieved per cycle, and 6.1 +/- 4.2 oocytes were cryopreserved. With their own stored oocytes, 44 patients returned to attempt pregnancy. From a total of 194 thawed/warmed oocytes, 157 survived (80%). In total, 100 embryos were transferred in 57 transfer/cycles, and 18 pregnancies were achieved. The pregnancy rate per transfer and pregnancy rate per patient were 31% and 41%, respectively. No statistically significant differences were observed between oncological patients and nononcological patients. A total of 15 babies were born from oncological patients. Children born showed normal growth and development. One minor malformation was detected.
- Published
- 2022
48. HIGH SECURITY CLOSED DEVICES ARE EFFICIENT AND SAFE FOR VITRIFICATION TO PROTECT HUMAN OOCYTES FROM THE RISK OF VIRAL CONTAMINATION ESPECIALLY DURING THE COVID-19 PANDEMIC
- Author
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Maria Lucrezia Tranquillo, Maria Dirodi, Leonardo Notarangelo, Linda Cipriani, N. Calza, Elena Nardi, Eleonora Porcu, Silvia Zuffa, Patrizia Ciotti, Lisa Mori, Francesca Sonia Labriola, Giuseppe Damiano, Eleonora Porcu, Maria Lucrezia Tranquillo, Leonardo Notarangelo, Patrizia Maria Ciotti, Nilla Calza, Silvia Zuffa, Lisa Mori, Elena Nardi, Maria Dirodi, Linda Cipriani, Giuseppe Damiano, and Francesca Sonia Labriola
- Subjects
Infertility ,high security devices, opend devices, human oocytes vitrification ,business.industry ,media_common.quotation_subject ,Obstetrics and Gynecology ,Oocyte ,medicine.disease ,Cryopreservation ,Embryo transfer ,Article ,Miscarriage ,Andrology ,medicine.anatomical_structure ,Human fertilization ,Reproductive Medicine ,Obstetrics and Gynaecology ,medicine ,Vitrification ,business ,Ovulation ,media_common - Abstract
Objective: To compare the efficacy of high security versus open devices for human oocytes vitrification Design: Prospective study Between October 2015 and April 2020, 737 patients (775 oocytes cryopreservation cycles) were randomly assigned to two Groups: Group 1: 368 patients (389 vitrification cycles) by High Security Vitrification™ (HSV) Group 2: 369 patients (386 vitrification cycles) by Cryotop® open system Vitrification was performed in case of Ovarian Hyper Stimulation Syndrome, failure semen production and supernumerary oocytes Materials and Methods: All patients attending IVF and Infertility Center, University Hospital S Orsola (Italy), were stimulated with recombinant-follicle stimulating hormone and gonadotropin releasing hormone analogues Oocyte retrieval by transvaginal needle aspiration was performed 36 hours after ovulation triggering with recombinant Human chorionic gonadotropin injection Metafase II oocytes were vitrified by Kuwayama’s protocol (2005) and microinjected after warming Results: Results are shown in Table 1 [Formula presented] Conclusions: The efficacy of vitrification was assessed in vitro using survival, fertilization and cleavage rates and in vivo after embryo transfer by pregnancy, implantation and miscarriage rates Results shows no statistically significant differences using HSV or Cryotop® for oocytes vitrification Therefore, in order to ensure safety, especially during the current COVID-19 pandemic, the use of the closed device eliminates the potential sample contamination during vitrification and storage without compromising its in vitro and in vivo survival and development
- Published
- 2020
49. Identification of metabolomics biomarkers for type 2 diabetes: triangulating evidence from longitudinal and Mendelian randomization analyses
- Author
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Philippe Froguel, Pedro Marques Vidal, Liza Darrous, Loic Yengo, Eleonora Porcu, Gérard Waeber, Zoltán Kutalik, Aurélien Thomas, Marie Gasser, Nasim Bararpour, and Federica Gilardi
- Subjects
education.field_of_study ,business.industry ,Incidence (epidemiology) ,Population ,Type 2 Diabetes Mellitus ,Type 2 diabetes ,medicine.disease ,Bioinformatics ,symbols.namesake ,Metabolomics ,Mendelian randomization ,Mendelian inheritance ,symbols ,Genetic predisposition ,Medicine ,business ,education - Abstract
The number of people affected by Type 2 Diabetes Mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. As the case for many other complex diseases, early diagnosis is key to prevent irreversible end-organ damages. However, given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs 1’360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than five years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM, and also confirmed to be causal by 2-sample Mendelian randomisation (based on independent data). Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. These findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.
- Published
- 2020
50. The enrichment of breakpoints in late-replicating chromatin provides novel insights into chromoanagenesis mechanisms
- Author
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Marie-France Portnoï, Alexandre Reymond, Sandra Chantot-Bastaraud, Giuliana Giannuzzi, Eleonora Porcu, Yvan Herenger, Flavie Ader, Tony Yammine, Patrick Edery, Pierre-Antoine Rollat-Farnier, Flavie Diguet, Laurence Faivre, Alice Masurel-Paulet, Nathalie Marle, Kévin Uguen, Claire Bardel, Julia Lauer Zillhardt, Alistair T. Pagnamenta, Nicolas Chatron, Jenny C. Taylor, Stéphanie Valence, Andrew O.M. Wilkie, Solveig Heide, Emilie Chopin, Fabienne Prieur, Nora Chelloug, Christèle Dubourg, Marlène Rio, Eduardo Calpena, Zohra-Lydia Bellil, Arthur Sorlin, Laurence Lohmann, Sylvie Jaillard, Alexandra Afenjar, Corinne Metay, Jean-Pierre Siffroi, Damien Sanlaville, Marie-Pierre Cordier, Boris Keren, Françoise Girard, Caroline Schluth-Bolard, Joris Andrieux, Samantha J. L. Knight, Reza Maroofian, James Lespinasse, Michèle Mathieu-Dramard, and Patrick Callier
- Subjects
chemistry.chemical_compound ,Chromothripsis ,chemistry ,Evolutionary biology ,Premature chromosome condensation ,Breakpoint ,Chromosomal rearrangement ,Biology ,Gene ,DNA ,Sequence (medicine) ,Chromatin - Abstract
The rise of pangenomic molecular assays allowed uncovering complex rearrangements named chromoanagenesis that were hypothesized to result from catastrophic shattering events. Constitutional cases have typically been reported individually preventing identification of common features and uncovering the mechanisms at play. We characterized 20 new chromoanagenesis and discovered yet undescribed features. While literature differentiates chromothripsis and its shattering event repaired through non-homologous end joining from chromoanasynthesis born to aberrant replicative processes, we identified shattered chromosomes repaired through a combination of mechanisms. In particular, three samples present with “rearrangement hubs” comprising a fragmented kilobase-long sequence threaded throughout the rearrangement.To assess the mechanisms at play, we merged our data with those of 20 published constitutional complex chromosomal rearrangement cases. We evaluated if the distribution of their 1032 combined breakpoints was distinctive using bootstrap simulations and found that breakpoints tend to keep away from haplosensitive genes suggesting selective pressure. We then compared their distribution with that of 13,310 and 468 breakpoints of cancer complex chromosomal rearrangements and constitutional simple rearrangement samples, respectively. Both complex rearrangement groups showed breakpoint enrichment in late replicating regions suggesting similar origins for constitutional and cancer cases. Simple rearrangement breakpoints but not complex ones were depleted from lamina-associated domains (LADs), possibly as a consequence of reduced mobility of DNA ends bound to lamina.The enrichment of breakpoints in late-replicating chromatin for both constitutional and cancer chromoanagenesis provides an orthogonal support to the premature chromosome condensation hypothesis that was put forward to explain chromoanagenesis.
- Published
- 2020
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