Genomics of Down Syndrome Associated Congenital Heart Defects Open Access

Rambo-Martin, Benjamin Livingston (2016)

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Individuals with Down syndrome are 2,000 times more likely to be born with an atrioventricular septal defect than people in the euploid population. The genetic loci that incite this risk, causing AVSD in 1 in 5 individuals with DS, are poorly understood. Within this dissertation we test the hypothesis that genes interrupted by copy number variants on chromosome 21 provide protection from AVSD by reducing that locus to disomy. We followed stringent quality control methods in producing a high quality set of deletions and duplications across 188 case individuals with DS+AVSD and 211 control individuals with DS and a normal heart. We found that no individual CNV, or any individual gene intersected by a CNV associated with AVSD in DS. From burden analyses, we found that African American controls had more bases covered by rare deletions than did cases. Inversely, Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. We performed gene set enrichment analysis in Caucasians and found a suggestion of cilia genes being more often intersected by deletions in controls and more often by duplications in cases. Pathway analyses of genes intersected only by deletions show an overrepresentation in genes involved in protein heterotrimerization and of genes intersected only by duplications being overrepresented in synaptic vesicle endocytosis. We also show that CNVs on chromosome 21 previously associated with DS+AVSD are likely false positives. We then apply whole genome and whole exome sequencing to a sub-cohort and test for epistatic SNP effects in cilia genes and find suggestive enrichment. Finally, we perform pathway analysis of genes harboring rare variants nominally associated to cases or controls, leading us to a novel candidate pathways perturbed in congenital heart defects. This research adds to the swell of evidence indicating that DS- associated AVSD is similarly heterogeneous as is AVSD in the euploid population.

Table of Contents










I. Introduction

I.I. Early Heart Development Overview

I.II. Congenial Heart Defects (CHD)

I.II.i. Atrioventricular Septal Defects (AVSD) epidemiology

I.II.ii. AVSD heritability

I.II.iii. Genetics of CHDs

I.II.iv. Down Syndrome (DS) as a Model to Identify Genetic Variation Contributing to CHD

I.II.v. CHDs gene discover in Down syndrome Mouse models of CHDs in Down syndrome

I.III. Copy Number Variants Contribute to the Susceptibility of Complex Human Diseases including CHD

I.III.i.CNV origins

I.III.ii. CNVs and disease

I.III.iii. CNVs and CHDs

I.IV. The Ciliome: A Candidate Pathway involved in AVSDs

I.IV.i. Overview of cilia and heart development

I.IV.ii. Cilia defects and AVSD

I.V. References

I.VI. Tables

I.VII. Figures

II. Analysis of Copy Number Variants on Chromosome 21 in Down Syndrome Associated Congenital Heart Defects

II.I. Abstract

II.II. Introduction

II.III. Results

II.III.i. Basic CNV association testing

II.III.ii. Burden of chromosome 21 deletions

II.III.iii. Burden of chromosome 21 duplications

II.III.iv. Burden of CNV-interrupted genes

II.III.v. Burden of duplicated genes Gene Set Enrichment and Gene Ontology analyses

II.III.vii. Replication of previous findings

II.IV. Discussion

II.V. Methods

II.V.i. DNA samples

II.V.ii. Microarray design

II.V.iii. Sample quality control

II.V.iv. CNV calling

II.V.v. Replication of Sailani et al., 2013 findings CNV association and burden analyses

II.V.vii. Gene Set Enrichment and Gene Ontology analyses

II.VI. References

II.VII. Tables

II.VIII. Figures

III. Whole Genome and Whole Exome Sequencing Analysis of Down Syndrome Associated Congenital Heart Defects

III.I. Introduction

III.II. Methods

III.II.i. Subjects

III.II.ii. Data cleaning

III.II.iii. Exome wide association analysis

III.II.iv. SKAT-O analysis

III.II.v. Rare variant pathway analysis

III.III. Results

III.III.i. Exome wide association analysis

III.III.ii. SKAT-O analysis

III.III.ii.1. van Dam ciliome

III.III.ii.2. Leroux ciliome

III.III.iii. Rare variant pathway analysis

III.III.iii.1. Case pathways

III.III.iii.2. Control pathways

III.IV. Discussion

III.V. References

III.VI. Tables

III.VII. Figures

IV. Discussion

IV.I. Conclusion and future directions

IV.II. References

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