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; REPETTO LISBOA, MARIA GABRIELA; 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

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

Journal

Circulation: Cardiovascular Genetics

ISSN

1942-325X

1942-3268

Date Issued

2017

Author(s)

Tingwei Guo

REPETTO LISBOA, MARIA GABRIELA

Facultad de Medicina Clínica Alemana Universidad del Desarrollo

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

Type

Resource Types::text::journal::journal article

DOI

10.1161/CIRCGENETICS.116.001690

URL

https://investigadores.udd.cl/handle/123456789/2704

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.