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

on behalf of the International 22q11.2 Consortium/Brain and Behavior Consortium

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere001690
JournalCirculation: Cardiovascular Genetics
Volume10
Issue number5
DOIs
StatePublished - Oct 1 2017

Fingerprint

DiGeorge Syndrome
Tetralogy of Fallot
Genome-Wide Association Study
MEF2 Transcription Factors
Heart Diseases
Genes
Introns
Chromatin
Single Nucleotide Polymorphism
Live Birth
G-Protein-Coupled Receptors
Mammals
Chromosomes
Genotype
Genome

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

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. / on behalf of the International 22q11.2 Consortium/Brain and Behavior Consortium.

In: Circulation: Cardiovascular Genetics, Vol. 10, No. 5, e001690, 01.10.2017.

Research output: Contribution to journalArticle

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title = "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",
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.",
keywords = "chromosomes, DiGeorge syndrome, genotype, ivelo-cardio-facial syndrome, tetralogy of Fallot",
author = "{on behalf of the International 22q11.2 Consortium/Brain and Behavior Consortium} and Tingwei Guo and Repetto, {Gabriela M.} and {McDonald McGinn}, {Donna M.} and Chung, {Jonathan H.} and Hiroko Nomaru and Campbell, {Christopher L.} and Anna Blonska and Bassett, {Anne S.} and Chow, {Eva W.C.} and Mlynarski, {Elisabeth E.} and Ann Swillen and Joris Vermeesch and Koen Devriendt and Doron Gothelf and Miri Carmel and Elena Michaelovsky and Maude Schneider and Stephan Eliez and Antonarakis, {Stylianos E.} and Karlene Coleman and Aoy Tomita-Mitchell and Mitchell, {Michael E.} and Digilio, {M. Cristina} and Bruno Dallapiccola and Bruno Marino and Nicole Philip and Tiffany Busa and Leila Kushan-Wells and Bearden, {Carrie E.} and Małgorzata Piotrowicz and Wanda Hawuła and Roberts, {Amy E.} and Flora Tassone and Simon, {Tony J.} and {Van Duin}, {Esther D.A.} and {Van Amelsvoort}, {Th{\'e}r{\`e}se A.} and Kates, {Wendy R.} and Elaine Zackai and Johnston, {H. Richard} and Cutler, {David J.} and Agopian, {A. J.} and Elizabeth Goldmuntz and Mitchell, {Laura E.} and Tao Wang and Emanuel, {Beverly S.} and Morrow, {Bernice E.}",
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month = "10",
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doi = "10.1161/CIRCGENETICS.116.001690",
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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 - on behalf of the International 22q11.2 Consortium/Brain and Behavior Consortium

AU - Guo, Tingwei

AU - Repetto, Gabriela M.

AU - McDonald McGinn, Donna M.

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, Małgorzata

AU - Hawuła, Wanda

AU - Roberts, Amy E.

AU - Tassone, Flora

AU - Simon, Tony J.

AU - Van Duin, Esther D.A.

AU - Van Amelsvoort, Thérèse 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.

PY - 2017/10/1

Y1 - 2017/10/1

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 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.

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 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.

KW - chromosomes

KW - DiGeorge syndrome

KW - genotype

KW - ivelo-cardio-facial syndrome

KW - tetralogy of Fallot

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U2 - 10.1161/CIRCGENETICS.116.001690

DO - 10.1161/CIRCGENETICS.116.001690

M3 - Article

VL - 10

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 5

M1 - e001690

ER -