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Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects.

Ramachandran D, Zeng Z, Locke AE, Mulle JG, Bean LJ, Rosser TC, Dooley KJ, Cua CL, Capone GT, Reeves RH, Maslen CL, Cutler DJ, Feingold E, Sherman SL, Zwick ME - G3 (Bethesda) (2015)

Bottom Line: We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies.Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome-associated atrioventricular septal defects.Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, 30033.

No MeSH data available.


Related in: MedlinePlus

Genomic region at 1p36.3 with suggestive evidence of association with Down syndrome−associated atrioventricular septal defect. (A) and (B) show the locus zoom plot and University of California, Santa Cruz (UCSC) image at the corresponding genomic region (human genome build 19, hg19). (A) Locus zoom plot of the region of association at single-nucleotide polymorphism (SNP) with strongest signal (rs1698973). Linkage disequilibrium (LD) between this SNP (purple diamond) and nearby markers is color-coded based on the strength of the LD. The left Y-axis shows the -log10 of the association P-value and the right Y-axis indicates the recombination rate across each region. The position on the chromosome (hg19) and the nearby genes are shown below the X-axis. (B) UCSC browser image shows evidence of regulatory activity. Included are a custom track showing the location of most significant SNPs and the annotation tracks from ENCODE showing regulatory activity.
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fig2: Genomic region at 1p36.3 with suggestive evidence of association with Down syndrome−associated atrioventricular septal defect. (A) and (B) show the locus zoom plot and University of California, Santa Cruz (UCSC) image at the corresponding genomic region (human genome build 19, hg19). (A) Locus zoom plot of the region of association at single-nucleotide polymorphism (SNP) with strongest signal (rs1698973). Linkage disequilibrium (LD) between this SNP (purple diamond) and nearby markers is color-coded based on the strength of the LD. The left Y-axis shows the -log10 of the association P-value and the right Y-axis indicates the recombination rate across each region. The position on the chromosome (hg19) and the nearby genes are shown below the X-axis. (B) UCSC browser image shows evidence of regulatory activity. Included are a custom track showing the location of most significant SNPs and the annotation tracks from ENCODE showing regulatory activity.

Mentions: We identified four regions with suggestive evidence of association at 1p36.3, 5p15.31, 8q22.3, and 17q22 (Table 1). A closer examination of the regions tagged by these SNPs revealed they were in close proximity to genes with roles important for heart development and/or function. Furthermore, multiple annotation tracks from ENCODE indicated strong regulatory activity, providing further evidence of putative function. Within the 1p36.3 candidate region, the strongest signal (rs1698973) was located adjacent to NPHP4, a ciliome gene (Figure 2) (Habbig et al. 2011). Interestingly, recent studies on heart phenotypes in a trisomic background implicate a significant role for ciliome genes in the etiology of DS-associated AVSD (Ripoll et al. 2012; Ramachandran et al. 2014; Li et al. 2015). The second region of interest was at 5p15.31. The strongest signal at this region (rs1428986, P < 1.09*10−5) falls within FLJ33360, a long noncoding RNA gene (lncRNA). lncRNAs are associated with gene regulation, and recent studies point to an emerging role in the pathophysiology of complex human diseases (Wapinski and Chang 2011; Ma et al. 2012). Adjacent to FLJ33360 is the MED10 gene (Figure 3). Mutations in MED10 have been associated with cardiac defects (Lin et al. 2007). In addition, multiple ENCODE annotation tracks suggest a weak enhancer activity at both 1p36.3 and 5p15.31 regions (Figure 2 and Figure 3). The third candidate region, 8q22.3 (rs3107646 and rs1522707, both SNPs with P < 2.4*10−5), is located next to FZD6, encoding Wnt receptor protein. Wnt signaling plays a key role in cardiovascular physiology (reviewed by Cohen et al. 2008). Moreover, annotations from ENCODE indicate a strong enhancer activity at this region (Figure S3). The fourth region of interest, at 17q22 (rs7225274, P < 1.2*10−5), is located at an intergenic region. Evidence from multiple annotation tracks suggests a strong regulatory activity. This region includes several binding sites for transcription factors, including GATA proteins and NR2F2 (Figure S4). Mutations in both of these genes have been associated with CHD, including AVSD (Garg et al. 2003; Al Turki et al. 2014). Nevertheless, the association and ENCODE findings at our top four regions are not genome-wide statistically significant and require replication in an independent cohort.


Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects.

Ramachandran D, Zeng Z, Locke AE, Mulle JG, Bean LJ, Rosser TC, Dooley KJ, Cua CL, Capone GT, Reeves RH, Maslen CL, Cutler DJ, Feingold E, Sherman SL, Zwick ME - G3 (Bethesda) (2015)

Genomic region at 1p36.3 with suggestive evidence of association with Down syndrome−associated atrioventricular septal defect. (A) and (B) show the locus zoom plot and University of California, Santa Cruz (UCSC) image at the corresponding genomic region (human genome build 19, hg19). (A) Locus zoom plot of the region of association at single-nucleotide polymorphism (SNP) with strongest signal (rs1698973). Linkage disequilibrium (LD) between this SNP (purple diamond) and nearby markers is color-coded based on the strength of the LD. The left Y-axis shows the -log10 of the association P-value and the right Y-axis indicates the recombination rate across each region. The position on the chromosome (hg19) and the nearby genes are shown below the X-axis. (B) UCSC browser image shows evidence of regulatory activity. Included are a custom track showing the location of most significant SNPs and the annotation tracks from ENCODE showing regulatory activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592978&req=5

fig2: Genomic region at 1p36.3 with suggestive evidence of association with Down syndrome−associated atrioventricular septal defect. (A) and (B) show the locus zoom plot and University of California, Santa Cruz (UCSC) image at the corresponding genomic region (human genome build 19, hg19). (A) Locus zoom plot of the region of association at single-nucleotide polymorphism (SNP) with strongest signal (rs1698973). Linkage disequilibrium (LD) between this SNP (purple diamond) and nearby markers is color-coded based on the strength of the LD. The left Y-axis shows the -log10 of the association P-value and the right Y-axis indicates the recombination rate across each region. The position on the chromosome (hg19) and the nearby genes are shown below the X-axis. (B) UCSC browser image shows evidence of regulatory activity. Included are a custom track showing the location of most significant SNPs and the annotation tracks from ENCODE showing regulatory activity.
Mentions: We identified four regions with suggestive evidence of association at 1p36.3, 5p15.31, 8q22.3, and 17q22 (Table 1). A closer examination of the regions tagged by these SNPs revealed they were in close proximity to genes with roles important for heart development and/or function. Furthermore, multiple annotation tracks from ENCODE indicated strong regulatory activity, providing further evidence of putative function. Within the 1p36.3 candidate region, the strongest signal (rs1698973) was located adjacent to NPHP4, a ciliome gene (Figure 2) (Habbig et al. 2011). Interestingly, recent studies on heart phenotypes in a trisomic background implicate a significant role for ciliome genes in the etiology of DS-associated AVSD (Ripoll et al. 2012; Ramachandran et al. 2014; Li et al. 2015). The second region of interest was at 5p15.31. The strongest signal at this region (rs1428986, P < 1.09*10−5) falls within FLJ33360, a long noncoding RNA gene (lncRNA). lncRNAs are associated with gene regulation, and recent studies point to an emerging role in the pathophysiology of complex human diseases (Wapinski and Chang 2011; Ma et al. 2012). Adjacent to FLJ33360 is the MED10 gene (Figure 3). Mutations in MED10 have been associated with cardiac defects (Lin et al. 2007). In addition, multiple ENCODE annotation tracks suggest a weak enhancer activity at both 1p36.3 and 5p15.31 regions (Figure 2 and Figure 3). The third candidate region, 8q22.3 (rs3107646 and rs1522707, both SNPs with P < 2.4*10−5), is located next to FZD6, encoding Wnt receptor protein. Wnt signaling plays a key role in cardiovascular physiology (reviewed by Cohen et al. 2008). Moreover, annotations from ENCODE indicate a strong enhancer activity at this region (Figure S3). The fourth region of interest, at 17q22 (rs7225274, P < 1.2*10−5), is located at an intergenic region. Evidence from multiple annotation tracks suggests a strong regulatory activity. This region includes several binding sites for transcription factors, including GATA proteins and NR2F2 (Figure S4). Mutations in both of these genes have been associated with CHD, including AVSD (Garg et al. 2003; Al Turki et al. 2014). Nevertheless, the association and ENCODE findings at our top four regions are not genome-wide statistically significant and require replication in an independent cohort.

Bottom Line: We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies.Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome-associated atrioventricular septal defects.Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, 30033.

No MeSH data available.


Related in: MedlinePlus