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 Academic Article uri icon

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.

authors

  • Guo, Tingwei
  • Repetto, Gabriela M
  • McDonald McGinn, Donna M
  • Chung, Jonathan H
  • Nomaru, Hiroko
  • Campbell, Christopher L
  • Blonska, Anna
  • Bassett, Anne S
  • Chow, Eva WC
  • Mlynarski, Elisabeth E
  • Swillen, Ann
  • Vermeesch, Joris
  • Devriendt, Koen
  • Gothelf, Doron
  • Carmel, Miri
  • Michaelovsky, Elena
  • Schneider, Maude
  • Eliez, Stephan
  • Antonarakis, Stylianos E
  • Coleman, Karlene
  • Tomita-Mitchell, Aoy
  • Mitchell, Michael E
  • Digilio, M Cristina
  • Dallapiccola, Bruno
  • Marino, Bruno
  • Philip, Nicole
  • Busa, Tiffany
  • Kushan-Wells, Leila
  • Bearden, Carrie E
  • Piotrowicz, Małgorzata
  • Hawuła, Wanda
  • Roberts, Amy E
  • Tassone, Flora
  • Simon, Tony J
  • van Duin, Esther DA
  • van Amelsvoort, Thérèse A
  • Kates, Wendy R
  • Zackai, Elaine
  • Johnston, H Richard
  • Cutler, David J
  • Agopian, AJ
  • Goldmuntz, Elizabeth
  • Mitchell, Laura E
  • Wang, Tao
  • Emanuel, Beverly S
  • Morrow, Bernice E

publication date

  • 2017

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