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
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
URL Institutional Repository
Abstract
<jats:sec>
<jats:title>Background—</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods and Results—</jats:title>
<jats:p>
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,
<jats:italic>P</jats:italic>
=2.98×10
<jats:sup>−</jats:sup>
<jats:sup>8</jats:sup>
) in an intron of the adhesion
<jats:italic>GPR98</jats:italic>
(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
<jats:italic>GPR98</jats:italic>
, including
<jats:italic>MEF2C</jats:italic>
(Myocyte-specific enhancer factor 2C).
<jats:italic>MEF2C</jats:italic>
is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions—</jats:title>
<jats:p>In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.</jats:p>
</jats:sec>
<jats:title>Background—</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods and Results—</jats:title>
<jats:p>
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,
<jats:italic>P</jats:italic>
=2.98×10
<jats:sup>−</jats:sup>
<jats:sup>8</jats:sup>
) in an intron of the adhesion
<jats:italic>GPR98</jats:italic>
(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
<jats:italic>GPR98</jats:italic>
, including
<jats:italic>MEF2C</jats:italic>
(Myocyte-specific enhancer factor 2C).
<jats:italic>MEF2C</jats:italic>
is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions—</jats:title>
<jats:p>In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.</jats:p>
</jats:sec>
Subjects
chromosomes
;
digeorge syndrome
;
genotype
;
ivelo-cardio-facial syndrome
;
tetralogy of fallot