Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3

Tingwei Guo; Gabriela M Repetto; Donna M McDonald McGinn; Jonathan H Chung; Hiroko Nomaru; Christopher L Campbell; Anna Blonska; Anne S Bassett; Eva W C Chow; Elisabeth E Mlynarski; Ann Swillen; Joris Vermeesch; Koen Devriendt; Doron Gothelf; Miri Carmel; Elena Michaelovsky; Maude Schneider; Stephan Eliez; Stylianos E Antonarakis; Karlene Coleman; Aoy Tomita-Mitchell; Michael E Mitchell; M Cristina Digilio; Bruno Dallapiccola; Bruno Marino; Nicole Philip; Tiffany Busa; Leila Kushan-Wells; Carrie E Bearden; Małgorzata Piotrowicz; Wanda Hawuła; Amy E Roberts; Flora Tassone; Tony J Simon; Esther D A van Duin; Thérèse A van Amelsvoort; Wendy R Kates; Elaine Zackai; H Richard Johnston; David J Cutler; A J Agopian; Elizabeth Goldmuntz; Laura E Mitchell; Tao Wang; Beverly S Emanuel; Bernice E Morrow; International 22q11.2 Consortium/Brain and Behavior Consortium*

doi:10.1161/CIRCGENETICS.116.001690

Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3

Circ Cardiovasc Genet. 2017 Oct;10(5):e001690. doi: 10.1161/CIRCGENETICS.116.001690.

Authors

Tingwei Guo¹, Gabriela M Repetto¹, Donna M McDonald McGinn¹, Jonathan H Chung¹, Hiroko Nomaru¹, Christopher L Campbell¹, Anna Blonska¹, Anne S Bassett¹, Eva W C Chow¹, Elisabeth E Mlynarski¹, Ann Swillen¹, Joris Vermeesch¹, Koen Devriendt¹, Doron Gothelf¹, Miri Carmel¹, Elena Michaelovsky¹, Maude Schneider¹, Stephan Eliez¹, Stylianos E Antonarakis¹, Karlene Coleman¹, Aoy Tomita-Mitchell¹, Michael E Mitchell¹, M Cristina Digilio¹, Bruno Dallapiccola¹, Bruno Marino¹, Nicole Philip¹, Tiffany Busa¹, Leila Kushan-Wells¹, Carrie E Bearden¹, Małgorzata Piotrowicz¹, Wanda Hawuła¹, Amy E Roberts¹, Flora Tassone¹, Tony J Simon¹, Esther D A van Duin¹, Thérèse A van Amelsvoort¹, Wendy R Kates¹, Elaine Zackai¹, H Richard Johnston¹, David J Cutler¹, A J Agopian¹, Elizabeth Goldmuntz¹, Laura E Mitchell¹, Tao Wang¹, Beverly S Emanuel¹, Bernice E Morrow²; International 22q11.2 Consortium/Brain and Behavior Consortium*

Affiliations

¹ From the Department of Genetics (T.G., J.H.C., H.N., C.L.C., T.W., B.E.M.) and Department of Epidemiology and Population Health (T.W.), Albert Einstein College of Medicine, Bronx, NY; Center for Human Genetics, Facultad de Medicina Clinica Alemana Universidad del Desarrollo, Santiago, Chile (G.M.R.); Division of Human Genetics (D.M.M.M., E.E.M., E.Z., B.S.E.), Division of Cardiology (E.G.), and Department of Pediatrics (E.G.), Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Genetics, Wroclaw Medical University, Poland (A.B.); Clinical Genetics Research Program, Center for Addiction and Mental Health and Department of Psychiatry, University of Toronto (A.S.B., E.W.C.C.); Dalglish Family 22q Clinic, Department of Psychiatry and Toronto General Research Institute, University Health Network, Canada (A.S.B.); Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada (A.S.B.); Center for Human Genetics, University of Leuven (KU Leuven), Belgium (A.S., J.V., K.D.); The Child Psychiatry Division, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel (D.G.); Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Israel (D.G., M.C., E.M.); Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel (M.C., E.M.); Developmental Imaging and Psychopathology Lab, University of Geneva School of Medicine, Switzerland (M.S., S.E.); Department of Genetic Medicine, UNIGE and iGE3 Institute of Genetics and Genomics of Geneva, University of Geneva Medical Center, Switzerland (S.E.A.); Marcus Autism Center, Children's Healthcare of Atlanta, GA (K.C.); Division of Pediatric Cardiovascular Surgery, Children's Hospital of Wisconsin, Milwaukee (A.T.-M., M.E.M.); Department of Surgery, Medical College of Wisconsin, Milwaukee (A.T.-M., M.E.M.); Department of Medical Genetics, Bambino Gesù Hospital, Rome, Italy (M.C.D., B.D.); Department of Pediatrics, La Sapienza University of Rome, Italy (B.M.); Department of Medical Genetics, Aix Marseille University, APHM, GMGF, Timone Hospital, France (N.P., T.B.); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles (L.K.-W., C.E.B.); Department of Genetics, Polish Mother's Memorial Hospital, Research Institute, Łódź, Poland (M.P., W.H.); Department of Cardiology and Division of Genetics, Boston Children's Hospital, MA (A.E.R.); M.I.N.D. Institute and Department of Psychiatry and Behavioral Sciences (F.T.) and M.I.N.D. Institute and Department of Biochemistry and Molecular Medicine (T.J.S.), University of California, Davis; Department of Psychiatry and Psychology, University of Maastricht, The Netherlands (E.D.A.V.D., T.A.v.A.); Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY (T.A.v.A., W.R.K.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (H.R.J., D.J.C.); Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA (H.R.J.); and Human Genetics Center and Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, TX (A.J.A., L.E.M.).
² From the Department of Genetics (T.G., J.H.C., H.N., C.L.C., T.W., B.E.M.) and Department of Epidemiology and Population Health (T.W.), Albert Einstein College of Medicine, Bronx, NY; Center for Human Genetics, Facultad de Medicina Clinica Alemana Universidad del Desarrollo, Santiago, Chile (G.M.R.); Division of Human Genetics (D.M.M.M., E.E.M., E.Z., B.S.E.), Division of Cardiology (E.G.), and Department of Pediatrics (E.G.), Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Genetics, Wroclaw Medical University, Poland (A.B.); Clinical Genetics Research Program, Center for Addiction and Mental Health and Department of Psychiatry, University of Toronto (A.S.B., E.W.C.C.); Dalglish Family 22q Clinic, Department of Psychiatry and Toronto General Research Institute, University Health Network, Canada (A.S.B.); Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada (A.S.B.); Center for Human Genetics, University of Leuven (KU Leuven), Belgium (A.S., J.V., K.D.); The Child Psychiatry Division, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel (D.G.); Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Israel (D.G., M.C., E.M.); Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel (M.C., E.M.); Developmental Imaging and Psychopathology Lab, University of Geneva School of Medicine, Switzerland (M.S., S.E.); Department of Genetic Medicine, UNIGE and iGE3 Institute of Genetics and Genomics of Geneva, University of Geneva Medical Center, Switzerland (S.E.A.); Marcus Autism Center, Children's Healthcare of Atlanta, GA (K.C.); Division of Pediatric Cardiovascular Surgery, Children's Hospital of Wisconsin, Milwaukee (A.T.-M., M.E.M.); Department of Surgery, Medical College of Wisconsin, Milwaukee (A.T.-M., M.E.M.); Department of Medical Genetics, Bambino Gesù Hospital, Rome, Italy (M.C.D., B.D.); Department of Pediatrics, La Sapienza University of Rome, Italy (B.M.); Department of Medical Genetics, Aix Marseille University, APHM, GMGF, Timone Hospital, France (N.P., T.B.); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles (L.K.-W., C.E.B.); Department of Genetics, Polish Mother's Memorial Hospital, Research Institute, Łódź, Poland (M.P., W.H.); Department of Cardiology and Division of Genetics, Boston Children's Hospital, MA (A.E.R.); M.I.N.D. Institute and Department of Psychiatry and Behavioral Sciences (F.T.) and M.I.N.D. Institute and Department of Biochemistry and Molecular Medicine (T.J.S.), University of California, Davis; Department of Psychiatry and Psychology, University of Maastricht, The Netherlands (E.D.A.V.D., T.A.v.A.); Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY (T.A.v.A., W.R.K.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (H.R.J., D.J.C.); Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA (H.R.J.); and Human Genetics Center and Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, TX (A.J.A., L.E.M.). [email protected].

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.

Keywords: DiGeorge syndrome; chromosomes; genotype; ivelo-cardio-facial syndrome; tetralogy of Fallot.

MeSH terms

Chromatin / metabolism
Chromosomes, Human, Pair 5
DiGeorge Syndrome / complications
DiGeorge Syndrome / genetics*
Genetic Loci
Genome-Wide Association Study*
Genotype
High-Throughput Nucleotide Sequencing
Humans
Linkage Disequilibrium
MEF2 Transcription Factors / genetics
Oligonucleotide Array Sequence Analysis
Phenotype
Polymorphism, Single Nucleotide
Receptors, G-Protein-Coupled / genetics*
Receptors, G-Protein-Coupled / metabolism
Sequence Analysis, DNA
Tetralogy of Fallot / complications
Tetralogy of Fallot / genetics*

Substances

ADGRV1 protein, human
Chromatin
MEF2 Transcription Factors
MEF2C protein, human
Receptors, G-Protein-Coupled

Abstract

MeSH terms

Substances

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