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

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dc.contributor.authorGuo, Tingwei
dc.contributor.authorRepetto, Gabriela
dc.contributor.authorMcDonald, Donna
dc.contributor.authorChung, Jonathan
dc.contributor.authorNomaru, Hiroko
dc.contributor.authorCampbell, Christopher
dc.contributor.authorBlonska, Anna
dc.contributor.authorBassett, Anne
dc.contributor.authorChow, Eva
dc.contributor.authorMlynarski, Elisabeth
dc.contributor.authorSwillen, Ann
dc.contributor.authorVermeesch, Joris
dc.contributor.authorDevriendt, Koen
dc.contributor.authorGothelf, Doron
dc.contributor.authorCarmel, Miri
dc.contributor.authorMichaelovsky, Elena
dc.contributor.authorSchneider, Maude
dc.contributor.authorEliez, Stephan
dc.contributor.authorAntonarakis, Stylianos
dc.contributor.authorColeman, Karlene
dc.contributor.authorTomita, Aoy
dc.contributor.authorMitchell, Michael
dc.contributor.authorDigilio, Cristina
dc.contributor.authorDallapiccola, Bruno
dc.contributor.authorMarino, Bruno
dc.contributor.authorPhilip, Nicole
dc.contributor.authorBusa, Tiffany
dc.contributor.authorKushan, Leila
dc.contributor.authorBearden, Carrie
dc.contributor.authorPiotrowicz, Małgorzata
dc.contributor.authorHawuła, Wanda
dc.contributor.authorRoberts, Amy
dc.contributor.authorTassone, Flora
dc.contributor.authorSimon, Tony
dc.contributor.authorvan Duin, Esther
dc.contributor.authorvan Amelsvoort, Thérèse
dc.contributor.authorKates, Wendy
dc.contributor.authorZackai, Elaine
dc.contributor.authorJohnston, Richard
dc.contributor.authorCutler, David
dc.contributor.authorAgopian, A
dc.contributor.authorGoldmuntz, Elizabeth
dc.contributor.authorMitchell, Laura
dc.contributor.authorWang, Tao
dc.contributor.authorEmanuel, Beverly
dc.contributor.authorMorrow, Bernice
dc.contributor.authorthe International 22q11.2 Consortium/Brain and Behavior Consortium
dc.date.accessioned2018-01-10T14:22:15Z
dc.date.available2018-01-10T14:22:15Z
dc.date.issued2017
dc.description.abstractBACKGROUND: 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.
dc.format.extent10
dc.identifier.citationGuo T, Repetto GM, McDonald McGinn DM, Chung JH, Nomaru H, Campbell CL, Blonska A, Bassett AS, Chow EWC, Mlynarski EE, Swillen A, Vermeesch J, Devriendt K, Gothelf D, Carmel M, Michaelovsky E, Schneider M, Eliez S, Antonarakis SE, Coleman K, Tomita-Mitchell A, Mitchell ME, Digilio MC, Dallapiccola B, Marino B, Philip N, Busa T, Kushan-Wells L, Bearden CE, Piotrowicz M, Hawuła W, Roberts AE, Tassone F, Simon TJ, van Duin EDA, van Amelsvoort TA, Kates WR, Zackai E, Johnston HR, Cutler DJ, Agopian AJ, Goldmuntz E, Mitchell LE, Wang T, Emanuel BS, Morrow BE; International 22q11.2 Consortium/Brain and Behavior Consortium*. 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.
dc.identifier.urihttp://hdl.handle.net/11447/1879
dc.identifier.urihttp://dx.doi.org/10.1161/CIRCGENETICS.116.001690
dc.language.isoen_US
dc.publisherLippincott Williams & Wilkins
dc.subjectDiGeorge syndrome
dc.subjectchromosomes
dc.subjectgenotype
dc.subjectivelo-cardio-facial syndrome
dc.subjecttetralogy of Fallot
dc.titleGenome-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
dc.typeArtículo

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