Supplemental Material, Supp_TABLE_v1_2017_6_27 - Association of Habitual Activity and Body Mass Index in Survivors of Congenital Heart Surgery: A Study of Children and Adolescents With Tetralogy of Fallot, Transposition of the Great Arteries, and Fontan Palliation

<p>Supplemental Material, Supp_TABLE_v1_2017_6_27 for Association of Habitual Activity and Body Mass Index in Survivors of Congenital Heart Surgery: A Study of Children and Adolescents With Tetralogy of Fallot, Transposition of the Great Arteries, and Fontan Palliation by Michael L. O’Byrne, Michael G. McBride, Stephen Paridon, and Elizabeth Goldmuntz in World Journal for Pediatric and Congenital Heart Surgery</p

Genome-Wide Association Study of Maternal and Inherited Loci for Conotruncal Heart Defects

<div><p>Conotruncal and related heart defects (CTDs) are a group of serious and relatively common birth defects. Although both maternal and inherited genotypes are thought to play a role in the etiology of CTDs, few specific genetic risk factors have been identified. To determine whether common variants acting through the genotype of the mother (e.g. via an in utero effect) or the case are associated with CTDs, we conducted a genome-wide association study of 750 CTD case-parent triads, with follow-up analyses in 358 independent triads. Log-linear analyses were used to assess the association of CTDs with the genotypes of both the mother and case. No association achieved genomewide significance in either the discovery or combined (discovery+follow-up) samples. However, three loci with p-values suggestive of association (p<10⁻⁵) in the discovery sample had p-values <0.05 in the follow-up sample and p-values in the combined data that were lower than in the discovery sample. These included suggestive association with an inherited intergenic variant at 20p12.3 (rs6140038, combined p = 1.0×10⁻⁵) and an inherited intronic variant in <i>KCNJ4</i> at 22q13.1 (rs2267386, combined p = 9.8×10⁻⁶), as well as with a maternal variant in <i>SLC22A24</i> at 11q12.3 (rs11231379, combined p = 4.2×10⁻⁶). These observations suggest novel candidate loci for CTDs, including loci that appear to be associated with the risk of CTDs via the maternal genotype, but further studies are needed to confirm these associations.</p></div

Characteristics of cases with conotruncal and related heart defects.

A<p>Includes conoventricular, posterior malalignment and conoseptal hypoplasia.</p

Loci showing suggestive associations with conotruncal malformations in the discovery sample.

<p>A) SNPs in <i>SLC22A24</i> B) SNPs near <i>FHIT</i> C) rs2267386 D) rs6140038. Each pane shows the log-linear model association statistic (−log₁₀ p) on the left y axis for the discovery sample variant with the highest regional value that was confirmed in our follow-up sample (purple diamond) and nearby markers (circles). Linkage disequilibrium (r²) between this variant and nearby markers is indicated by red shading and recombination rates across each region in 1000 Genomes CEU data are indicated by blue lines on the right y axis. The position on the chromosome (hg18) and the position of nearby genes is shown on the x-axis.</p

Summary data for top variants with suggestive inherited or maternal association with conotruncal heart defects.

A<p>Chromosome.</p>B<p>Hg18/NCBI build 36.</p>C<p>Minor allele frequency among non-Hispanic white study participant founders (i.e. mother and father).</p>D<p>For SNPs mapping within genes, gene names are listed, and for intergenic SNPs, the nearest gene is listed in parentheses.</p>E<p>Relative risk estimate for carrying one copy of the high-risk allele compared to no copies, and corresponding 95% confidence interval.</p>F<p>Imputed SNP; concordance between the imputed and assay-based genotypes in 21 samples from the discovery sample that were genotyped with the follow-up sample was 98.5%.</p

Demographic, pregnancy, and birth history comparisons of nonsyndromic^a cases across major types of congenital heart defect in the Pediatric Cardiac Genetic Consortium Cohort.

<p>Demographic, pregnancy, and birth history comparisons of nonsyndromic<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191319#t004fn002" target="_blank">^a</a> cases across major types of congenital heart defect in the Pediatric Cardiac Genetic Consortium Cohort.</p

Description of nonsyndromic^a cases in the Pediatric Cardiac Genetic Consortium Cohort.

<p>Description of nonsyndromic<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191319#t003fn002" target="_blank">^a</a> cases in the Pediatric Cardiac Genetic Consortium Cohort.</p

Diagnostic types of congenital heart defect in the Pediatric Cardiac Genetic Consortium Cohort.

<p>Diagnostic types of congenital heart defect in the Pediatric Cardiac Genetic Consortium Cohort.</p

Syndromic diagnoses in the Pediatric Cardiac Genetic Consortium Cohort.

<p>Syndromic diagnoses in the Pediatric Cardiac Genetic Consortium Cohort.</p

<i>Dnah6</i> genetically interacts with <i>Dnai1</i> and <i>Dnah5</i> to cause heterotaxy and PCD.

<p><b>(A,B)</b> Embryos injected with subthreshold dose of <i>dnah6</i> and <i>dnai1</i> MO show increased heart looping defects compared with Ctrl MO injections (n = 177, p-value = 3.8x10^-8), or single injection of either <i>dnai1</i> (p = 9.29x10^-9) or <i>dnah6</i> (p = 2.04x10^-8) MO at the same MO dose (A). Similar results were observed with subthreshold <i>dnah5/dnah6</i> double MO knockdown (n = 82; p = 1.74x10^-5, Bonferroni corrected)<b>. (C,D)</b> Reciliating mouse airway epithelia from wildtype (+/+) and heterozygous (+/-) <i>Dnai1</i> knockout (C) or <i>Dnah5</i> mutant (D) mice show robust ciliation and ciliary motion (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005821#pgen.1005821.s017" target="_blank">S5 Movie</a> and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005821#pgen.1005821.s018" target="_blank">S6 Movie</a>). 30nM <i>Dnah6</i> siRNA had no effect on ciliation or cilia motility in wildtype airway epithelia, but in heterozygous <i>Dnai1 or Dnah5</i> mutant airway, ciliation was reduced and ciliary motion was dyskinetic (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005821#pgen.1005821.s017" target="_blank">S5 Movie</a> and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005821#pgen.1005821.s018" target="_blank">S6 Movie</a>). With 50nM siRNA, little or no cilia was seen in wildtype and heterozygous <i>Dnai1</i> or <i>Dnah5</i> mutant mouse airway.</p