Assessment of potential interaction by maternal smoking in a genome-wide association (GWAS) study of Down Syndrome-associated Atrioventricular Septal Defects (AVSD) Open Access

Abstract

The present analysis examines the potential effect modification by maternal smoking between Down Syndrome (DS) individuals and congenital Atrioventricular Septal Defect (AVSD), using a modified GWAS dataset from several phases of a large Down Syndrome Project based on Emory University. For this analysis, maternal smoking was defined as having had >100 cigarettes before and during pregnancy of the infant with DS. The analyzed population set consisted in a total of 496 individuals with Down Syndrome, 251 were males and 245 were females. The study sample was composed by 243 subjects with DS and complete AVSD (cases) and 253 subjects with DS and structurally normal hearts (controls). The logistic regression analysis was performed in plink 2/1.9 and included maternal smoking, proband’s sex and the first 5 principal components related to ancestry. The model did not provide evidence of large genome-wide significance by maternal smoking interaction effects but highlighted the importance of considering environmental interactions to characterized genetic variants associated with disorders of complex and multifactorial nature.

Table of Contents

I. Background ..................................................................................................... 1

A. Congenital Heart Defects (CHD) ..................................................................... 1

i. General Epidemiology of CHD ........................................................................... 1

ii. Genetics of congenital heart defects .............................................................. 2

iii. Environmental contributors to congenital heart defects ................................. 3

B. Down Syndrome and Congenital Heart Defect ................................................. 4

a. Population based observational studies ............................................................. 5

b. Genetic Association Studies .............................................................................. 7

II. Manuscript ................................................................................................. 8

A. Abstract ...................................................................................................... 8

B. Introduction ................................................................................................. 8

C. Materials and Methods ................................................................................. 10

i. Subject’s description ....................................................................................... 10

ii. Variable selection and preparation of dataset ................................................. 11

iii. Genotyping and Quality Control .................................................................... 13

iv. Analysis approach and model description ....................................................... 13

v. Logistic regression models without considering genome-wide association .......... 14

D. Results and Discussion ................................................................................ 14

E. Conclusion ............................................................................................. 16

F. References ................................................................................................... 18

III. Summary ................................................................................................... 21

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology
Keyword	Genome Wide Association Analysis (GWAS) GXE Down Syndrome (DS) Congenital Heart Defects (CHD) Maternal Smoking
Committee Chair / Thesis Advisor	Sherman, Stephanie, Emory University

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