The science behind soft skills: Do’s and Don’ts for early career researchers and beyond. A review paper from the EU-CardioRNA COST Action CA17129

peer reviewedSoft skills are the elementary management, personal, and interpersonal abilities that are vital for an individual to be efficient at workplace or in their personal life. Each work place requires different set of soft skills. Thus, in addition to scientific/technical skills that are easier to access within a short time frame, several key soft skills are essential for the success of a researcher in today’s international work environment. In this paper, the trainees and trainers of the EU-CardioRNA COST Action CA17129 training school on soft skills present basic and advanced soft skills for early career researchers. Here, we particularly emphasize on the importance of transferable and presentation skills, ethics, literature reading and reviewing, research protocol and grant writing, networking, and career opportunities for researchers. All these skills are vital but are often overlooked by some scholars. We also provide tips to ace in aforementioned skills that are crucial in a day-to-day life of early and late career researchers in academia and industry.</ns4:p

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD. 2022, The Author(s).T. Kessler is supported by the Corona-Foundation (Junior Research Group Translational Cardiovascular Genomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02). T.J. was supported by a Medical Research Council DTP studentship (MR/S502443/1). J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health and Care Research (NIHR) Senior Investigator. J.C.H. acknowledges personal funding from the British Heart Foundation (FS/14/55/30806) and is a member of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). R.C. has received funding from the British Heart Foundation and British Heart Foundation Centre of Research Excellence. O.G. has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). P.S.d.V. was supported by American Heart Association grant number 18CDA34110116 and National Heart, Lung, and Blood Institute grant R01HL146860. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology; and Central Norway Regional Health Authority. Whole genome sequencing for the HUNT study was funded by HL109946. The GerMIFs gratefully acknowledge the support of the Bavarian State Ministry of Health and Care, furthermore founded this work within its framework of DigiMed Bayern (grant DMB-1805-0001), the German Federal Ministry of Education and Research (BMBF) within the framework of ERA-NET on Cardiovascular Disease (Druggable-MI-genes, 01KL1802), within the scheme of target validation (BlockCAD, 16GW0198K), within the framework of the e:Med research and funding concept (AbCD-Net, 01ZX1706C), the British Heart Foundation (BHF)/German Centre of Cardiovascular Research (DZHK)-collaboration (VIAgenomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02), the Sonderforschungsbereich SFB TRR 267 (B05), and EXC2167 (PMI). This work was supported by the British Heart Foundation (BHF) under grant RG/14/5/30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School. This work was supported by the European Commission (HEALTH-F2–2013-601456) and the TriPartite Immunometabolism Consortium (TrIC)-NovoNordisk Foundation (NNF15CC0018486), VIAgenomics (SP/19/2/344612), the British Heart Foundation, a Wellcome Trust core award (203141/Z/16/Z to M.F. and H.W.) and the NIHR Oxford Biomedical Research Centre. M.F. and H.W. are members of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. C.P.N. and T.R.W. received funding from the British Heart Foundation (SP/16/4/32697). C.J.W. is funded by NIH grant R35-HL135824. B.N.W. is supported by the National Science Foundation Graduate Research Program (DGE, 1256260). This research was supported by BHF (SP/13/2/30111) and conducted using the UK Biobank Resource (application 9922). O.M. was funded by the Swedish Heart and Lung Foundation, the Swedish Research Council, the European Research Council ERC-AdG-2019-885003 and Lund University Infrastructure grant ‘Malmö population-based cohorts’ (STYR 2019/2046). T.R.W. is funded by the British Heart Foundation. I.K., S. Koyama, and K. Ito are funded by the Japan Agency for Medical Research and Development, AMED, under grants JP16ek0109070h0003, JP18kk0205008h0003, JP18kk0205001s0703, JP20km0405209 and JP20ek0109487. The Biobank Japan is supported by AMED under grant JP20km0605001. J.L.M.B. acknowledges research support from NIH R01HL125863, American Heart Association (A14SFRN20840000), the Swedish Research Council (2018-02529) and Heart Lung Foundation (20170265) and the Foundation Leducq (PlaqueOmics: New Roles of Smooth Muscle and Other Matrix Producing Cells in Atherosclerotic Plaque Stability and Rupture, 18CVD02. A.V.K. has been funded by grant 1K08HG010155 from the National Human Genome Research Institute. K.G.A. has received support from the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP3384001), a KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from the Harvard Catalyst (KL2 TR002542) and the NIH (1K08HL153937). A.S.B. has been supported by funding from the National Health and Medical Research Council (NHMRC) of Australia (APP2002375). D.S.A. has received support from a training grant from the NIH (T32HL007604). N.P.B., M.C.C., J.F. and D.-K.J. have been funded by the National Institute of Diabetes and Digestive and Kidney Diseases (2UM1DK105554). EPIC-CVD was funded by the European Research Council (268834) and the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The coordinating center was supported by core funding from the UK Medical Research Council (G0800270; MR/L003120/1), British Heart Foundation (SP/09/002, RG/13/13/30194, RG/18/13/33946) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute.Scopu

Λειτουργική μελέτη της βιολογίας της καρδιαγγειακής νόσου

Cardiovascular disease (CVD) is the prevalent cause of death worldwide and according to the World Health Organization, it is estimated that 17.9 million people die annually from CVDs, which accounts for the 32% of global mortality. CVDs are the most common noncommunicable disease and describe numerous conditions relating to the heart and blood vessel function and morphogenesis. Coronary artery disease (CAD) is the main CVD implication and is developed when inadequate supply of oxygen and nutrients reach the heart through the coronary artery network. The burden of CVDs along with other noncommunicable diseases (such as cancer, diabetes and chronic pulmonary disease) is expected to further increase due to the aging population and lifestyle patterns. Therefore, it is tremendous need to frame CVDs prognosis, prevention, progression and therapy within the spectrum of modifiable and non-modifiable risk factors. It is well known, that the manifestation of CAD is related with risk factors that can be addressed as behavioral/environmental and genetic effectors. Traditional environmental risk factors include hypertension, dyslipidemia, hyperglycemia, obesity and lifestyle behaviors (smoking, lack of physical activity, poor diet, anxiety and stress-related conditions). In addition to that, it is long recognized that CAD is a heritage disease and plethora of human population studies have aimed to unravel the genetic architecture that underlines the basis of the heart disease. The increase of sample size and genome wide association studies (GWAS) have revealed several susceptibility loci for this multifactorial complex disease. Up to date, there have been identified more than 60 genetic loci correlated with traits of CADs. Such variants associated with the appearance of cardiovascular disease are located to the candidate genes: craniofacial development protein 1 (CFDP1) and coiled-coil domain containing 92 (CCDC92). The aim of this dissertation was to investigate the functional role of CFDP1 and CCDC92 in the cardiac development. For this purpose, we utilized zebrafish (Danio rerio), a valuable model organism in Cardiovascular Research due to the high genomic homology, similarity in heart physiology and the ease of experimental manipulation. CFDP1 belongs to the evolutionary conserved Bucentaur (BCNT) family and up to date, the mechanism of action in cardiovascular development remains unclear. During this dissertation, we generated a cfdp1-null zebrafish line using CRISPR-Cas9 system and identified that the mutated allele carries a pre-mature stop codon at the third exon that produces a predicted truncated protein product. cfdp1 loss leads to a lethal phenotype since knockout individuals do not reach adulthood. Phenotypic characterization showed that cfdp1 knockout embryos develop arrhythmic hearts and defective cardiac performance including statistically significant differences in End Diastolic Volume, Cardiac Output, Ejection Fraction and Stroke Volume. Further analysis in cellular level exhibited that myocardial trabeculation is also impaired in cfdp1 knockout embryonic hearts, suggesting its regulatory role in this essential cardiac developmental process. Finally, conduction of both knockdown and knockout experiments showed that abrogation of cfdp1 results in downregulation of Wnt signaling in embryonic hearts during valve development but without affecting Notch activation in this process. CCDC92 belongs to the superfamily of coiled-coil proteins and although a numerous of variants have been identified in human cardiac conditions, its function is still largely unknown. We showed that zebrafish ccdc92 is expressed during the embryonic development, suggesting its important role in proper organogenesis and function. Following, we performed knockdown experiments by silencing the expression of ccdc92 at one-cell stage zebrafish embryos. Phenotypic characterization of knockdown embryos revealed that deficiency of ccdc92 exhibits embryonic cardiac oedema and heart malformation. Further analysis showed that ccdc92 abrogation results in impaired cardiac looping during embryonic heart morphogenesis, an essential process for the proper structure and function of the heart. More studies are needed to be conducted in order to unravel the mechanism and possible signaling pathways that explain its role in proper cardiac morphogenesis. Protein Kinase D2 belongs to a family of evolutionarily conserved enzymes regulating several biological processes. In a forward genetic screen for zebrafish cardiovascular mutants, it was identified a mutation in the prkd2 gene (T757A substitution) which resulted in a complete outflow tract stenosis. In this study, we showed ectopic expression of Notch-activated cells throughout the heart of mutant embryos as well as higher sensitivity to Cyclosporin A (a Calcineurin inhibitor). Finally, we identify TBX5 as a potential regulator of PRKD2. Our results implicate PRKD2 catalytic activity in outflow tract development in zebrafish. Finally, we participated in the Greek Recurrent Myocardial Infarction Cohort (GRMIC), which is a prospective epidemiologic study that aims to the stratification of post myocardial infarction (MI) patients by integrating genetic and epigenetic predictors together with biomarkers in a risk prediction model. Up to this stage of the study, sixty-six Greek patients have been recruited at the period of first MI event and re-examined after a six months period. Although the sample size remains small, we analyzed the plasma levels of known biomarkers in patients compared to the two time periods and showed that total cholesterol, low-density lipoprotein cholesterol, apolipoprotein-B, C-reactive protein and creatine phosphokinase are significantly higher at the time of first MI event, confirming their prognostic value for the occurrence of first acute MI event. Taking into account that the design of this study requires the recruitment of 500 re-examined MI patients, our data thus far, represent a premature indication of essential biomarkers for MI. GRMIC is an ongoing prospective study that aims to leverage the power of genetics and biomarkers to design risk models for the post-MI patients, in following future.Τα καρδιαγγειακά νοσήματα (ΚΝ) είναι η κύρια αιτία θανάτου σε παγκόσμια κλίμακα. Σύμφωνα με τον Παγκόσμιο Οργανισμό Υγείας, εκτιμάται πως 17.9 εκατομμύρια άνθρωποι κάθε χρόνο χάνουν τη ζωή τους από καρδιαγγειακές παθήσεις, ποσοστό που αντιστοιχεί στο 32% της παγκόσμιας θνησιμότητας. Τα ΚΝ αποτελούν την πιο συχνή μορφή μη-μεταδοτικών ασθενειών και περιγράφουν ένα ευρύ φάσμα παθήσεων που αφορούν στη λειτουργία και μορφογένεση της καρδιάς και των αιμοφόρων αγγείων. Η στεφανιαία νόσος (ΣΝ) αποτελεί μια βασική κλινική μορφή των ΚΝ και περιγράφει τη στένωση των στεφανιαίων αρτηριών λόγω συσσώρευσης αθηρωματικού υλικού στον αυλό τους με αποτέλεσμα να μην τροφοδοτείται επαρκώς η καρδιά με τα απαραίτητα συστατικά και οξυγόνο για τη λειτουργία της. Αποτελώντας μείζον ζήτημα δημόσιας υγείας, το ολικό κόστος των καρδιαγγειακών νοσημάτων μαζί με τις υπόλοιπες μη-μεταδοτικές ασθένειες (όπως ο καρκίνος, ο διαβήτης και η χρόνια πνευμονοπάθεια) αναμένεται να αυξηθεί ακόμα περισσότερο εξαιτίας της αύξησης του μέσου όρου ζωής του πληθυσμού καθώς και των κοινωνικών προτύπων. Συνεπώς, είναι τεράστιας σημασίας η προσπάθεια να οριστεί την πρόγνωση, πρόληψη, εξέλιξη και θεραπεία των καρδιαγγειακών νοσημάτων εντός πλαισίου φάσματος τροποποιήσιμων και μη-τροποποιήσιμων παραγόντων κινδύνου. Είναι γνωστό πως η εκδήλωση της ΣΝ σχετίζεται με παράγοντες κινδύνου τόσο περιβαλλοντικούς όσο και γενετικούς. Στην πρώτη κατηγορία ανήκουν η αρτηριακή υπέρταση, η δισλιπιδαιμία, το αυξημένο σάκχαρο αίματος, η παχυσαρκία και ο τρόπος ζωής (όπως κάπνισμα, έλλειψη φυσικής δραστηριότητας, κακή διατροφή, άγχος και επιβαρυμένη ψυχική υγεία). Ωστόσο, ιδιαιτέρως σημαντικό ρόλο έχουν και οι γενετικοί παράγοντες που επιδρούν στην εμφάνιση της νόσου. Πληθώρα πληθυσμιακών μελετών έχουν στοχεύσει στην ανακάλυψη της γενετικής αρχιτεκτονικής που καθορίζει τη βάση των καρδιαγγειακών νοσημάτων. Μελέτες συσχέτισης ολόκληρου του γονιδιώματος (Genome-Wide association study - GWAS) έχουν ταυτοποιήσει πάνω από 60 γενετικούς τόπους που σχετίζονται με τη ΣΝ. Τέτοιες γενετικές παραλλαγές έχουν βρεθεί και σε δύο υποψήφια προς μελέτη γονίδια: craniofacial development protein 1 (CFDP1) και coiled-coil domain containing 92 (CCDC92). Ο σκοπός της παρούσας διατριβής ήταν να μελετήσουμε τον λειτουργικό ρόλο των CFDP1 και CCDC92 στην ανάπτυξη της καρδιάς. Στα πλαίσια της έρευνας αυτής, χρησιμοποιήσαμε το zebrafish (Danio rerio) που έχει αναδειχθεί ως ένα πολύτιμο μοντέλο-οργανισμός στην έρευνα για τις καρδιαγγειακές παθήσεις, λόγω της υψηλής γενετικής ομολογίας, της ομοιότητας στη φυσιολογία της καρδιάς και την ευκολία του πειραματικού χειρισμού του. Το CFDP1 ανήκει στη συντηρημένη οικογένεια των Κενταύρων (Bucentaur, BCNT) και έως σήμερα ο μηχανισμός δράσης του στην καρδιακή ανάπτυξη παραμένει άγνωστος. Ως εκ τούτου, δημιουργήσαμε μια cfdp1 μεταλλαγμένη zebrafish σειρά μέσω του εργαλείου γονιδιωματικής τροποποίησης, CRISPR-Cas9. Ύστερα από ταυτοποίηση του μεταλλαγμένου αλληλομόρφου διαπιστώσαμε πως διαθέτει ένα πρώιμο κωδικόνιο λήξης στο τρίτο εξόνιο το οποίο παράγει ένα ελαττωματικό πρωτεϊνικό προϊόν. Η έλλειψη του cfdp1 οδηγεί σε έναν θνησιγόνο φαινότυπο, αφού τα πλήρως μεταλλαγμένα άτομα δεν φτάνουν στο ενήλικο στάδιο ζωής. Φαινοτυπικός χαρακτηρισμός έδειξε πως τα μεταλλαγμένα cfdp1 έμβρυα αναπτύσσουν καρδιακές αρρυθμίες και ελλιπή καρδιακή λειτουργία όπως αυτή αποτυπώνεται από τα μειωμένα επίπεδα του τελοδιαστολικού όγκου, καρδιακής παροχής, κλάσμα εξώθησης και όγκου παλμού. Περαιτέρω ανάλυση σε κυτταρικό επίπεδο έδειξε πως η κοιλιακή δοκίδωση είναι επίσης μειωμένη στα μεταλλαγμένα cfdp1 έμβρυα, υποδεικνύοντας τον ρυθμιστικό ρόλου του γονιδίου στη μορφογενετική διαδικασία δοκίδωσης κατά την ανάπτυξη της zebrafish εμβρυικής καρδιάς. Τέλος, μετά τη διεξαγωγή knockdown και knockout πειραμάτων δείξαμε πως αποσιώπηση του cfdp1 οδήγησε σε μειωμένα επίπεδα ενεργοποίησης του Wnt σηματοδοτικού μονοπατιού στις καρδιές εμβρύων κατά τη διάρκεια της δημιουργίας καρδιακών βαλβίδων, χωρίς να επηρεάσει την έκφραση του Notch μονοπατιού στη διαδικασία αυτή. Το CCDC92 ανήκει στην υπεροικογένεια των πρωτεϊνών σπειροειδούς ελίκωσης (coiled-coil proteins) και μολονότι πληθυσμιακές μελέτες έχουν αναδείξει πολυάριθμες παραλλαγές του γονιδίου να σχετίζονται με κλινικές μορφές της ανθρώπινης καρδίας, η λειτουργία του δεν έχει εξακριβωθεί, ούτε μελετηθεί επαρκώς. Στην παρούσα διατριβή, δείξαμε πως το zebrafish ccdc92 εκφράζεται κατά τη διάρκεια την εμβρυικής ανάπτυξης από τα πρώτα στάδια, καταδεικνύοντας το σημαντικό ρόλο του γονιδίου για τη σωστή οργανογένεση και λειτουργία του οργανισμού. Ακολούθως, διεξήγαμε πειράματα αποσιώπησης της έκφρασης του ccdc92 (knockdown) σε έμβρυα zebrafish και μέσω φαινοτυπικού χαρακτηρισμού εντοπίσαμε ανάπτυξη περικαρδιακού οιδήματος και δομική δυσμορφία της καρδιάς. Περαιτέρω ανάλυση έδειξε πως αναστολή της έκφρασης του γονιδίου αυτού οδηγεί σε ελλαττωματική καρδιακή περιστροφή (cardiac looping), μια απαραίτητη διαδικασία για τη φυσιολογική μορφογένεση της καρδιάς κατά την ανάπτυξή της. Η Protein Kinase D2 (prkd2) ανήκει σε οικογένεια εξελικτικά συντηρημένων ενζύμων που ρυθμίζουν πληθώρα βιολογικών διεργασιών. Προσέγγιση ορθόδρομης μεταλλαξιγέννεσης στο μοντέλο zebrafish ανέδειξε μια μεταλλαγή στο γονίδιο prkd2 (T757A) που προκαλεί στένωση αγωγού καρδιακής εκροής. Στην παρούσα μελέτη, καταγράψαμε την έκτοπη έκφραση του Notch μονοπατιού στην καρδιά μεταλλαγμένων εμβρύων, καθώς επίσης και αυξημένη ευαισθησία στην κυκλοσπορίνη Α (αναστολέας καλσινευρίνης). Ακόμα, αναδείξαμε την πιθανή ρύθμιση του Prkd2 από τον μεταγραφικό παράγοντα Tbx5 στα zebrafish έμβρυα. Τέλος, στα πλαίσια της παρούσας διατριβής συμμετείχαμε στη συνεργασία GRMIC (Greek Recurrent Myocardial Infarction Cohort), μία προοπτική επιδημιολογική μελέτη με σκοπό τη διαστρωμάτωση των ασθενών ύστερα από εμφάνιση πρώτου επεισοδίου εμφράγματος του μυοκαρδίου, μέσα από τη δημιουργία μοντέλου πρόβλεψης ενσωματώνοντας γενετικούς παράγοντες μαζί με τη δράση βιοδεικτών. Μέχρι την ολοκλήρωση της διατριβής, 66 ασθενείς είχαν επανεξετασθεί μετά το πέρας των έξι μηνών από την εμφάνιση ισχαιμικού επεισοδίου. Ανάλυση επιπέδων γνωστών βιοδεικτών στο πλάσμα ασθενών στις δύο χρονικές περιόδους ανέδειξε πως η ολική χοληστερόλη, η χαμηλής πυκνότητας λιποπρωτεϊνική χοληστερόλη, απολιποπρωτεΐνη Β, C-αντιδρώσα πρωτεΐνη και η φωσφατάση της κρεατίνης παρουσίασαν στατιστικά σημαντικά αυξημένα επίπεδα την περίοδο εμφάνισης επεισοδίου σε σύγκριση με τα επίπεδά τους στο πλάσμα των ασθενών μετά το πέρας των έξι μηνών, επιβεβαιώνοντας τον προγνωστικό τους ρόλο για την πιθανότητα εμφάνισης εμφράγματος του μυοκαρδίου

On Zebrafish Disease Models and Matters of the Heart

Coronary artery disease (CAD) is the leading form of cardiovascular disease (CVD), which is the primary cause of mortality worldwide. It is a complex disease with genetic and environmental risk factor contributions. Reports in human and mammalian models elucidate age-associated changes in cardiac function. The diverse mechanisms involved in cardiac diseases remain at the center of the research interest to identify novel strategies for prevention and therapy. Zebrafish (Danio rerio) have emerged as a valuable vertebrate model to study cardiovascular development over the last few decades. The facile genetic manipulation via forward and reverse genetic approaches combined with noninvasive, high-resolution imaging and phenotype-based screening has provided new insights to molecular pathways that orchestrate cardiac development. Zebrafish can recapitulate human cardiac pathophysiology due to gene and regulatory pathways conservation, similar heart rate and cardiac morphology and function. Thus, generations of zebrafish models utilize the functional analysis of genes involved in CAD, which are derived from large-scale human population analysis. Here, we highlight recent studies conducted on cardiovascular research focusing on the benefits of the combination of genome-wide association studies (GWAS) with functional genomic analysis in zebrafish. We further summarize the knowledge obtained from zebrafish studies that have demonstrated the architecture of the fundamental mechanisms underlying heart development, homeostasis and regeneration at the cellular and molecular levels

The basal transcription complex component TAF3 transduces changes in nuclear phosphoinositides into transcriptional output

Phosphoinositides (PI) are important signaling molecules in the nucleus that influence gene expression. However, if and how nuclear PI directly affects the transcriptional machinery is not known. We report that the lipid kinase PIP4K2B regulates nuclear PI5P and the expression of myogenic genes during myoblast differentiation. A targeted screen for PI interactors identified the PHD finger of TAF3, a TATA box binding protein-associated factor with important roles in transcription regulation, pluripotency, and differentiation. We show that the PI interaction site is distinct from the known H3K4me3 binding region of TAF3 and that PI binding modulates association of TAF3 with H3K4me3 in vitro and with chromatin in vivo. Analysis of TAF3 mutants indicates that TAF3 transduces PIP4K2B-mediated alterations in PI into changes in specific gene transcription. Our study reveals TAF3 as a direct target of nuclear PI and further illustrates the importance of basal transcription components as signal transducers

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD