Genetic variation in Down syndrome associated congenital heart defects Open Access

Locke, Adam Edward (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/h128nf609?locale=en
Published

Abstract

Trisomy 21, the chromosomal abnormality responsible for Down syndrome (DS), is a complex
condition with many characteristic symptoms as well as an increased risk for numerous
congenital anomalies. The combination of these anomalies is often severe, with as few as 20% of
conceptuses with trisomy 21 surviving to term. Heart defects are among the most common
congenital anomalies associated with Down syndrome (DS), affecting nearly half of all people
with DS. Of those with a congenital heart defect, nearly 20% have an atrioventricular septal
defect (AVSD), representing a nearly 2000-fold increased risk of AVSD compared to the general
population.
Through a multi-site recruitment effort, we have ascertained individuals with DS who have a
complete balanced AVSD (cases) and those who have structurally normal hearts (controls) and
their parents. Using this carefully selected sample, we test several different hypotheses aimed
toward identifying the genetic variation underlying susceptibility to AVSD in people with DS.
First, we test the common disease/common variant hypothesis by testing common single
nucleotide (SNP) variation initially in specific candidate genes, and subsequently throughout the
genome for association with AVSD. We further extend the common disease/common variant
hypothesis genome-wide by identifying and test deletions for association with AVSD.
Finally, we also explore the common disease/rare variant hypothesis in two ways. We first test for
accumulation of rare copy number variants (CNVs) in cases with AVSD compared to controls.
Additionally, we attempt to identify rare SNPs or insertions/deletions of functional consequence
through the resequencing of candidate genes. This comprehensive, multi-faceted approach to
studying genetic variation in people with DS has yielded interesting candidate loci for follow-up
analysis.

Table of Contents

DISTRIBUTION AGREEMENT
APPROVAL SHEET
ABSTRACT COVER PAGE
ABSTRACT
COVER PAGE
ACKNOWLEDGMENTS
TABLE OF CONTENTS
LIST OF TABLES
LIST OF FIGURES

I. Introduction
I.I
Historical perspective
I.II
Epidemiology of Down syndrome
I.III
Phenotypes associated with Down syndrome
I.IV
Molecular mechanisms of heart development
I.V
Atrioventricular septal defects
I.V.i
Pathophysiology
I.V.ii
Previous studies: genetic and molecular candidates
I.VI
Models of disease in DS
I.VII Genetic variation and models of complex disease
I.VII.i
Common disease-common variant hypothesis
I.VII.ii
Common disease-rare variant hypothesis
I.VII.iii
Evidence for common and rare variant hypotheses
I.VIII Overview of research
I.IX
References
I.X
Tables
I.XI
Figures

II. Ethnicity, Sex, and the Incidence of Congenital Heart Defects: A Report from the National Down Syndrome Project

II.I
Abstract
II.II
Introduction
II.III
Subjects and Methods
II.III.i
NDSP Subjects
II.III.ii
Other Subjects
II.III.iii
Clinical Information
II.III.iv
Demographic Information
II.III.v
Statistical Analysis
II.III.vi
Laboratory Studies
II.IV Results
II.IV.i
Cardiac Defects
II.IV.ii
Origin of Nondisjunction
II.IV.iii
Maternal Age
II.IV.iv
Infant Sex
II.IV.v
Maternal Ethnicity

II.IV.vi

Assessment of Ancestral Information Markers among Black Infants

II.V
Discussion

II.VI

Acknowledgements

II.VII

References

II.VIII

Tables

II.IX

Figure

III. Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndromes

III.I

Abstract

III.II

Introduction

III.II.i

Down Syndrome and Congenital Heart Defects (CHD)

III.III

Materials and Methods

III.III.i
Ascertainment

III.III.ii

Eligibility and Case Definitions

III.III.iii

DNA Samples

III.III.iv

Gene and SNP selection

III.III.v

Genotyping

III.III.vi

Statistical analyses
III.III.vi.a
Analysis of disomic SNPs

III.III.vi.b

Analysis of trisomic SNPs

III.III.vi.c

Covariates and Substructure

III.III.vi.d

Consideration of multiple testing

III.IV

Results

III.IV.i

Chromosome 21 Candidate Genes

III.IV.ii

Non-Chromosome 21 Candidate Genes

III.V

Discussion

III.V.i

Functional Implications

III.V.ii

Limitations and future studies

III.VI

Acknowledgements

III.VII

References

III.VIII

Tables

III.IX

Figures

IV. Genome-wide SNP association study of atrioventricular septal defects among individuals with Down syndrome

IV.I
Introduction

IV.II

Methods

IV.II.i

Ascertainment & enrollment

IV.II.ii

Array processing & sample quality control

IV.II.iii

SNP quality control

IV.II.iv
Statistical analyses

IV.II.iv.a
Non-chromosome 21
IV.II.iv.b

Chromosome 21

IV.III

Results
IV.III.i

Non-chromosome 21 analysis
IV.III.ii

Interpretation of TDT results

IV.III.iii

SNP validation

IV.III.iv
Chromosome 21 SNPs
IV.IV

Conclusions

IV.IV.i

AVSD implications
IV.V

References

IV.VI

Tables

IV.VII

Figures

V. Genome-wide CNV detection and association with atrioventricular septal defects among individuals with Down syndrome

V.I

Introduction

V.II

Methods
V.II.i

Array processing & sample quality

V.II.ii

Copy number reference samples and log2 ratio generation

V.II.iii

Generation of copy number calls

V.II.iv
Statistical analyses
V.III

Results

V.III.i

CNV counts

V.III.ii

CNV, association & candidate loci
V.IV

Conclusions

V.IV.i

Future directions
V.V

References

V.VI

Tables

V.VII

Figures

VI. Candidate gene resequencing to identify rare variants contributing to atrioventricular septal defects among individuals with Down syndrome

VI.I

Introduction

VI.II

Methods
VI.II.i

Sample collection & enrollment

VI.II.ii

Sequencing

VI.II.iii

Quality control

VI.II.iv
Variant annotation & significance testing
VI.III

Results

VI.III.i

Variants identified & quality control

VI.III.ii

Association testing
VI.IV

Conclusions

VI.V

References

VI.VI

Tables

VI.VII

Figure

VII. Conclusions

VII.I

Findings

VII.II

Future directions

VII.III

References

Appendix

A1. Combining Microarray-based Genomic Selection (MGS) with the Illumina Genome Analyzer Platform to Sequence Diploid Target Regions

A1.I

Summary

A1.II

Materials and Methods

A1.III

Results

A1.IV

Discussion

A1.V

Acknowledgements

A1.VI
References

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