LARGE EXOME SEQUENCING STUDY ANALYZING X-LINKED VARIATION IN AUTISM SPECTRUM DISORDER Open Access
Weaver, Nick (Spring 2024)
Published
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a spectrum of challenges, including difficulties with social communication, repetitive behaviors, limited interests, and sensory sensitivities. Research shows a higher prevalence of ASD in males compared to females, with estimates ranging from 2:1 to 5:1. One area of particular interest in ASD research is the role of the X chromosome. We hope to identify variants strongly associated with the ASD and explore whether these variants have a differential impact on ASD risk in males and females. A total of approximately 74,000 individuals were analyzed, including around 20,000 individuals with ASD. Likelihood ratio tests corresponding to 3 different models of genetic effect: additive, recessive, recessive lethal were analyzed and p-values were FDR corrected. QQ plots were ran to find genetic variants meeting QC criteria and FDR thresholds. Penetrance of variants were calculated via liability scores produced by Quantitative X-Linked Transmitted and De Novo Analysis (QXL-TADA), and odds ratios (ORs) calculated via penetrances. In this analysis 11 genes were associated with one of our three models, and therefore associated with ASD. Among these 11 genes include variants of additive effect (ARHGEF9, p < 1e-8), recessive effect (DGAT2L6, p < 0.001) and lethal effect (DDX3X, p < 1e-8). The overall penetrances of the variants associated with ASD are often higher in males than in females. However, odds ratios (ORs) tell a different story with the rare homozygous females (A2A2) often having a higher OR, and thus higher risk of ASD than the rare hemizygous males (A2(-)). Additive effect variants accounted for six genes associated with ASD, recessive effect variants accounted for four genes, and lethal effect variants accounted for one gene associated with ASD. The majority of genes were associated with neural pathways, and remaining genes were involved in transcriptional or metabolic regulation. Interestingly, males are not always at a higher risk for ASD when carrying rare variants. This study sheds light on the prevalence differences of ASD attributed to the X chromosome, variants associated with ASD, and attempts to reconcile some of the diagnostic disparities we see between males and females.
Table of Contents
Not required per RSPH guidelines
About this Master's Thesis
| School | |
|---|---|
| Department | |
| Subfield / Discipline | |
| Degree | |
| Submission | |
| Language |
|
| Research Field | |
| Keyword | |
| Committee Chair / Thesis Advisor | |
| Committee Members |
Primary PDF
| Thumbnail | Title | Date Uploaded | Actions |
|---|---|---|---|
|
|
LARGE EXOME SEQUENCING STUDY ANALYZING X-LINKED VARIATION IN AUTISM SPECTRUM DISORDER () | 2024-04-24 22:11:18 -0400 |
|
Supplemental Files
| Thumbnail | Title | Date Uploaded | Actions |
|---|