Identification of Modifying Genes Associated with Fragile X Disorders Using TWAS Open Access

Abstract

Fragile X disorders are a group of genetic conditions that include a neurodegenerative disorder of FXTAS, a fertility disorder of FXPOI, and an epileptic disorder of FXS seizures. To identify the potential genetic modifiers of Fragile X disorders, we proposed to leverage the framework of Transcriptome-Wide Association Studies (TWAS) that integrates transcriptomics data with genetic data to increase the power of identifying genes related to a disorder through gene regulation. Even though only 530 individuals were collected, our study successfully identified 68 genes significantly associated with Fragile X disorders by utilizing reference data of the brain cortex, cerebellum, cerebellar hemisphere, and ovary tissues from the Genotype-Tissue Expression Consortium V8. Many TWAS identifications, such as RGL2, PPP1R12C, and SYNGAP1, were supported by previous studies as they have been found to be associated with relevant clinical features of Fragile X disorders. Moreover, we further validated two genes (CFB and AIF1) for FXPOI in independent TWAS studies of age at menopause from the UK Biobank. These identified significant genes are worthy of further functional validations under the Drosophila or mice model to elucidate their underlying molecular mechanisms. 

Table of Contents

1 Introduction (Page 1)

2 Methods (Page 3)

2.1 Datasets (Page 3)

2.2 Statistical Analysis (Page 4)

3 Results (Page 6)

3.1 FXTAS (Page 6)

3.2 FXPOI (Page 6)

3.3 FXS-Seizure (Page 7)

Figure 1 (Page 8)

Figure 2 (Page 8)

Figure 3 (Page 9)

Figure 4 (Page 9)

Figure 5 (Page 10)

Table 1 (Page 11)

Table 2 (Page 12)

Table 3 (Page 13)

4 Discussion (Page 14)

5 References (Page 15)

6 Supplementary Data (Page 17)

Figure S1 (Page 17)

Figure S2 (Page 17)

Figure S3 (Page 18)

Figure S4 (Page 18)

Figure S5 (Page 19)

About this Master's Thesis

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Biology, Biostatistics
Keyword	FXTAS TWAS FXPOI FXS-Seizure Fragile X disorders
Committee Chair / Thesis Advisor	Epstein, Michael, Emory University
Committee Members	Yang, Jingjing, Emory University Hu, Jian, Emory University

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