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.


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*


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