Oligogenic Architecture of Rare Noncoding Variants Distinguishes 4 Congenital Heart Disease Phenotypes.
| Autor: | Yu M; Department of Pediatrics (M.Y., M.A., A.C.-P., C.T., J.R.P.), Stanford University School of Medicine.; Fudan University, Shanghai, Chinia (M.Y.)., Aguirre M; Department of Pediatrics (M.Y., M.A., A.C.-P., C.T., J.R.P.), Stanford University School of Medicine.; Department of Biomedical Data Science, Stanford University, CA (M.A.)., Jia M; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry Munich, Germany (M.J., B.M.-M.)., Gjoni K; Gladstone Institutes; University of California San Francisco (K.G., C.T., D.S., K.S.P.)., Cordova-Palomera A; Department of Pediatrics (M.Y., M.A., A.C.-P., C.T., J.R.P.), Stanford University School of Medicine., Munger C; Department of Genetics (C.M., D.A., X.R.M., J.M.E.), Stanford University School of Medicine., Amgalan D; Department of Genetics (C.M., D.A., X.R.M., J.M.E.), Stanford University School of Medicine., Rosa Ma X; Department of Genetics (C.M., D.A., X.R.M., J.M.E.), Stanford University School of Medicine., Pereira A; Department of Genetics, Harvard University, Cambridge, MA (A.P., C.S., J.S.)., Tcheandjieu C; Department of Pediatrics (M.Y., M.A., A.C.-P., C.T., J.R.P.), Stanford University School of Medicine.; Gladstone Institutes; University of California San Francisco (K.G., C.T., D.S., K.S.P.)., Seidman C; Department of Genetics, Harvard University, Cambridge, MA (A.P., C.S., J.S.)., Seidman J; Department of Genetics, Harvard University, Cambridge, MA (A.P., C.S., J.S.)., Tristani-Firouzi M; Department of Pediatrics, University of Utah, Salt Lake City (M.T.-F.)., Chung W; Department of Pediatrics, Columbia University, NY (W.C.)., Goldmuntz E; Department of Pediatrics, University of Pennsylvania, Philadelphia (E.G.)., Srivastava D; Gladstone Institutes; University of California San Francisco (K.G., C.T., D.S., K.S.P.)., Loos RJF; Icahn School of Medicine at Mount Sinai, NY (R.J.F.L., N.C.)., Chami N; Icahn School of Medicine at Mount Sinai, NY (R.J.F.L., N.C.)., Cordell H; Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom (H.C.)., Dreßen M; Department of Cardiovascular Surgery, Division of Experimental Surgery, Institute Insure (Institute for Translational Cardiac Surgery), German Heart Center Munich & Technical University of Munich, School of Medicine & Health, Germany (M.D., H.L., M.K.)., Mueller-Myhsok B; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry Munich, Germany (M.J., B.M.-M.)., Lahm H; Department of Cardiovascular Surgery, Division of Experimental Surgery, Institute Insure (Institute for Translational Cardiac Surgery), German Heart Center Munich & Technical University of Munich, School of Medicine & Health, Germany (M.D., H.L., M.K.)., Krane M; Department of Cardiovascular Surgery, Division of Experimental Surgery, Institute Insure (Institute for Translational Cardiac Surgery), German Heart Center Munich & Technical University of Munich, School of Medicine & Health, Germany (M.D., H.L., M.K.).; Department of Cardiac Surgery, Yale School of Medicine, New Haven, CT (M.K.)., Pollard KS; Gladstone Institutes; University of California San Francisco (K.G., C.T., D.S., K.S.P.).; Chan Zuckerberg Biohub, San Francisco (K.S.P.)., Engreitz JM; Department of Genetics (C.M., D.A., X.R.M., J.M.E.), Stanford University School of Medicine.; Basic Sciences and Engineering (BASE) Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA (J.M.E.)., Gagliano Taliun SA; Department of Medicine & Department of Neurosciences, Faculty of Medicine, University ersité de Montréal (S.A.G.T.).; Montreal Heart Institute, Montreal, Quebec, Canada (S.A.G.T.)., Gelb BD; The Mindich Child Health & Development Institute at the Hess Center for Science & Medicine at Mount Sinai, NY (B.D.G.)., Priest JR; Department of Pediatrics (M.Y., M.A., A.C.-P., C.T., J.R.P.), Stanford University School of Medicine. |
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| Jazyk: | angličtina |
| Zdroj: | Circulation. Genomic and precision medicine [Circ Genom Precis Med] 2023 Jun; Vol. 16 (3), pp. 258-266. Date of Electronic Publication: 2023 Apr 07. |
| DOI: | 10.1161/CIRCGEN.122.003968 |
| Abstrakt: | Background: Congenital heart disease (CHD) is highly heritable, but the power to identify inherited risk has been limited to analyses of common variants in small cohorts. Methods: We performed reimputation of 4 CHD cohorts (n=55 342) to the TOPMed reference panel (freeze 5), permitting meta-analysis of 14 784 017 variants including 6 035 962 rare variants of high imputation quality as validated by whole genome sequencing. Results: Meta-analysis identified 16 novel loci, including 12 rare variants, which displayed moderate or large effect sizes (median odds ratio, 3.02) for 4 separate CHD categories. Analyses of chromatin structure link 13 of the genome-wide significant loci to key genes in cardiac development; rs373447426 (minor allele frequency, 0.003 [odds ratio, 3.37 for Conotruncal heart disease]; P =1.49×10 -8 ) is predicted to disrupt chromatin structure for 2 nearby genes BDH1 and DLG1 involved in Conotruncal development. A lead variant rs189203952 (minor allele frequency, 0.01 [odds ratio, 2.4 for left ventricular outflow tract obstruction]; P =1.46×10 - 8 ) is predicted to disrupt the binding sites of 4 transcription factors known to participate in cardiac development in the promoter of SPAG9 . A tissue-specific model of chromatin conformation suggests that common variant rs78256848 (minor allele frequency, 0.11 [odds ratio, 1.4 for Conotruncal heart disease]; P =2.6×10 - 8 ) physically interacts with NCAM1 ( P Conclusions: We describe a set of rare noncoding variants conferring significant risk for individual heart malformations which are linked to genes governing cardiac development. These results illustrate that the oligogenic basis of CHD and significant heritability may be linked to rare variants outside protein-coding regions conferring substantial risk for individual categories of cardiac malformation. Competing Interests: Disclosures Dr Priest is a full-time employee and shareholder of Tenaya Therapeutics. The other authors report no conflicts. |
| Databáze: | MEDLINE |
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