Identifying Genetic Modifiers for Left and Right Sided Orofacial Clefts Open Access

Abstract

Orofacial clefts (OFC) are a common congenital malformation that affect 1 in 700 births globally. Affected individuals are also impacted by other health conditions, increased mortality at all ages, and face additional financial burdens associated with years of treatment. OFCs are classified by sub-type, including cleft lip, cleft lip with palate, and cleft lip with or without palate. Additionally, OFC can present as either bilateral, occurring on both sides of the lip/palate, or unilateral, affecting only a single side. The current paradigm in OFC research and treatment is to group unilateral left and unilateral right clefts together for research studies without accounting for subtypes. However, the non-random distribution of OFC sub-types suggests that these subtypes may be pathogenetically distinct and subtype-specific analyses should be considered. One approach to identify genetic factors contributing to OFC subtypes is to compare cases of OFC sub-types against cases of a different OFC sub-type in a genome-wide association study (GWAS). This approach identifies genetic modifiers that distinguish two subtypes and allows us to develop a better understanding of genetic factors that contribute to differences between OFCs. We analyzed a multi-ethnic dataset comprised of singleton 702 cases, 1293 case-parent trios, and 1626 controls using this modifier approach and identified a candidate 4q28 region with suggestive evidence of association (p=8.4x10^-8) and opposite direction of effect between right-sided cleft lip (OR=0.64, 0.45-0.90) and left-sided cleft lip (OR=1.84, 1.43-2.37).

Table of Contents

Introduction................................................ 1

Methods...................................................... 7

Results...................................................... 10

Discusion...................................................13

References................................................ 18

Tables & Figures....................................... 22

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology Biology, Genetics
Keyword	OFC Orofacial Cleft GWAS
Committee Chair / Thesis Advisor	Mulle, Jennifer, Emory University
Committee Members	Leslie, Elizabeth, Emory University

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