Date of Award

January 2023

Document Type

Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Tormod Rogne

Abstract

Background: Clefting of the lip with or without cleft palate (CLP) is the most common congenital craniofacial abnormality globally, affecting one in 700 live births. Traditional observational studies suggest an increased risk of adult depression among subjects with CLP, but these studies are subject to residual confounding.Objective: We aimed to address residual confounding by evaluating the association between the genetically-predicted risk of CLP on the risk of adult depression in a Mendelian randomization framework. Methods: We used single-nucleotide polymorphisms strongly associated with CLP as genetic instruments. Genetic associations with adult depression were extracted from separate studies. Three ancestry groups were evaluated: European, East Asian, and African. Two-sample Mendelian randomization inverse-variance weighted analyses were conducted, and sensitivity analyses using weighted median, weighted mode, and MR-Egger regression were performed to assess bias from genetic pleiotropy. Results: The study included a total of 3,577 CLP cases and 10,345 controls, and 59,406 and 274,957 subjects with and without adult depression. Among subjects of African ancestry, a doubling of the genetically-predicted prevalence of CLP was associated with an odds ratio for adult depression of 1.28 (95% CI 0.94-1.75). Sensitivity analyses supported this finding. There was no clear association between CLP and adult depression in the European or East Asian ancestry groups. Conclusion: This study may suggest a causal association between cleft lip and the risk of depression among subjects of African ancestry. Our findings warrant further investigation into the role of craniofacial malformations as a cause of depression, and an assessment of potential inequity.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 11/10/2023

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