TY - JOUR
T1 - 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
AU - Guo, Tingwei
AU - Repetto, Gabriela M.
AU - McGinn, Donna M. McDonald
AU - Chung, Jonathan H.
AU - Nomaru, Hiroko
AU - Campbell, Christopher L.
AU - Blonska, Anna
AU - Bassett, Anne S.
AU - Chow, Eva W. C.
AU - Mlynarski, Elisabeth E.
AU - Swillen, Ann
AU - Vermeesch, Joris
AU - Devriendt, Koen
AU - Gothelf, Doron
AU - Carmel, Miri
AU - Michaelovsky, Elena
AU - Schneider, Maude
AU - Eliez, Stephan
AU - Antonarakis, Stylianos E.
AU - Coleman, Karlene
AU - Tomita-Mitchell, Aoy
AU - Mitchell, Michael E.
AU - Digilio, M. Cristina
AU - Dallapiccola, Bruno
AU - Marino, Bruno
AU - Philip, Nicole
AU - Busa, Tiffany
AU - Kushan-Wells, Leila
AU - Bearden, Carrie E.
AU - Piotrowicz, Malgorzata
AU - Hawula, Wanda
AU - Roberts, Amy E.
AU - Tassone, Flora
AU - Simon, Tony J.
AU - van Duin, Esther D. A.
AU - van Amelsvoort, Therese A.
AU - Kates, Wendy R.
AU - Zackai, Elaine
AU - Johnston, H. Richard
AU - Cutler, David J.
AU - Agopian, A. J.
AU - Goldmuntz, Elizabeth
AU - Mitchell, Laura E.
AU - Wang, Tao
AU - Emanuel, Beverly S.
AU - Morrow, Bernice E.
AU - Int 22q11 2 Consortium
AU - Brain Behav Consortium
PY - 2017/10
Y1 - 2017/10
N2 - 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 (he cohort.& para;& para;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=2.98x10(-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 genomewide 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 5814.3. 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.& para;& para;Conclusions-In conclusion, common variants may contribute to TOP in 22q11.2DS and may function in cardiac outflow tract development.
AB - 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 (he cohort.& para;& para;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=2.98x10(-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 genomewide 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 5814.3. 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.& para;& para;Conclusions-In conclusion, common variants may contribute to TOP in 22q11.2DS and may function in cardiac outflow tract development.
KW - chromosomes
KW - DiGeorge syndrome
KW - genotype
KW - ivelo-cardio-facial syndrome
KW - tetralogy of Fallot
KW - PROTEIN-COUPLED RECEPTOR
KW - CARDIO-FACIAL SYNDROME
KW - DIGEORGE-SYNDROME
KW - CHROMATIN ARCHITECTURE
KW - CELL-DIFFERENTIATION
KW - DROSOPHILA GENOME
KW - GENE-EXPRESSION
KW - SYNDROME REGION
KW - OUTFLOW TRACT
KW - HEART FIELD
U2 - 10.1161/CIRCGENETICS.116.001690
DO - 10.1161/CIRCGENETICS.116.001690
M3 - Article
C2 - 29025761
SN - 1942-325X
VL - 10
JO - Circulation : Cardiovascular Genetics
JF - Circulation : Cardiovascular Genetics
IS - 5
M1 - e001690
ER -