Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the &ITGPR98&IT Locus on 5q14.3

• Type of Material: Article
• Authors: Tingwei Guo, Albert Einstein College of Medicine; Gabriela M. Repetto, Universidad del Desarrollo; Donna M. McDonald McGinn, University of Pennsylvania; Anna Blonska, Wroclaw Medical University; Anne S. Bassett, University of Toronto; Eva W.C. Chow, University of Toronto; Elisabeth E. Mlynarski, University of Pennsylvania; Tiffany Busa, Aix Marseille University; Leila Kushan-Wells, University of California Los Angeles; Carrie E. Bearden, University of California Los Angeles; Flora Tassone, University of California Davis; Tony J. Simon, University of California Davis; H. Richard Johnston, Emory University; David J Cutler, Emory University
• Language: English
• Date: 2017-10-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCGENETICS.116.001690
• Title of Journal or Parent Work: Circulation: Cardiovascular Genetics
• ISSN: 1942-325X
• Volume: 10
• Issue: 5
• Start Page: e001690
• End Page: e001690
• Grant/Funding Information: Dr Repetto was supported by the Fondo National de Desarrollo Cientifico y Tecnologico-Chile (grants 1100131 and 1130392). Dr Bassett was supported by the Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research funding (Missionary Orientation Program-97800 and Missionary Orientation Program-89066), and the University of Toronto McLaughlin Centre. Dr Bearden was supported by National Institutes of Health grant R01 MH085903.; Dr Simon was supported by National Institutes of Health grant R01 HD042974. Dr Mitchell was supported by National Institutes of Health grant R21 HD060309-01. Dr Eliez was supported by the Swiss National Science Foundation (Swiss National Science Foundation 324730_121996; Swiss National Science Foundation 324730_144260).; his work was supported by National Institutes of Health grants R01 HL084410 (Dr Emanuel, Dr Morrow, D.M. McDonald McGinn, Dr Guo, A.S. Bassett), P01 HD070454 (Dr Goldmuntz, Dr Mitchell, Dr Agopian, Emanuel, D.M. McDonald McGinn, Dr Mlynarski, Dr Guo, Dr Wang, Dr Nomaru, Dr Campbell), U01 MH101720 (Dr Emanuel, Dr Morrow, D.M. McDonald McGinn, Dr Repetto, Dr Bassett, Dr Bassett, Dr Swillen, Dr Gothelf, Dr Eliez, Dr Tassone, Dr Philip, Dr Bearden, Dr Simon, E.D.A. van Duin, Dr van Amelsvoort, Dr Kates, Dr Guo, Dr Wang), R21HL118637 (Drs Wang, Morrow, Guo, Goldmuntz), T32GM007491-41 (JHC).; This work was supported by the American Heart Association, grant 14PRE199800006 (Dr Chung).
• Keywords: SYNDROME REGION; Life Sciences & Biomedicine; DROSOPHILA GENOME; GENE-EXPRESSION; chromosomes; DIGEORGE-SYNDROME; DiGeorge syndrome; Science & Technology; Cardiac & Cardiovascular Systems; OUTFLOW TRACT; PROTEIN-COUPLED RECEPTOR; Cardiovascular System & Cardiology; CARDIO-FACIAL SYNDROME; HEART FIELD; CELL-DIFFERENTIATION; Genetics & Heredity; tetralogy of Fallot; ivelo-cardio-facial syndrome; genotype; CHROMATIN ARCHITECTURE
• Research Categories: Biology, Genetics

Abstract

Background - The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort. Methods and Results - To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P=2.98×10-8) in an intron of the adhesion GPR98 (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98, including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. Conclusions - In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.