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 ColemanAoy Tomita-Mitchell, Michael E. Mitchell, M. Cristina Digilio, Bruno Dallapiccola, Bruno Marino, Nicole Philip, Tiffany Busa, Leila Kushan-Wells, Carrie E. Bearden, Malgorzata Piotrowicz, Wanda Hawula, Amy E. Roberts, Flora Tassone, Tony J. Simon, Esther D. A. van Duin, Therese 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*, Int 22q11 2 Consortium, Brain Behav Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)


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.

Original languageEnglish
Article numbere001690
Number of pages10
JournalCirculation : Cardiovascular Genetics
Issue number5
Publication statusPublished - Oct 2017


  • chromosomes
  • DiGeorge syndrome
  • genotype
  • ivelo-cardio-facial syndrome
  • tetralogy of Fallot

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