Genomic studies of common neurodevelopmental conditions

Abstract

Dyslexia and related neurodevelopmental conditions are significantly influenced by genetics. This thesis investigated how genetic variations contribute to these conditions, analysing both common and rare variants and their interactions. Common variants were analysed for sensory and motor traits, including visual acuity (VA) and grip strength (GS). The effectiveness of various bioinformatics tools, including FINDOR, a package that reweights p-values estimated from genome-wide association studies (GWAS), and a Bayesian-based polygenic risk score (PRS) method, was assessed. Overall, no major difference was observed across the performance of different tools. GWAS is a powerful and cost-effective method for identifying common genetic variants linked to complex disorders, enabling the analysis of thousands of variants across the genome in large cohorts. However, GWAS typically accounts for only a small portion of heritability and excludes rare variants, highlighting the need for complementary methods such as whole exome sequencing (WES). WES was performed on individuals diagnosed with dyslexia, their family members, and typically developing controls. The analysis identified five novel candidate genes (CACNA1D, CACNA1G, CLDN3, CNGB1, and CP) and highlighted the activity of voltage-gated calcium channels (VGCCs) and the transport of ions across the membrane as important pathways associated with dyslexia. A replication study of these variants found that three out of five genes were replicated, and the biological pathways, including the activity of VGCCs, converged. Prioritised genes were investigated in the UK Biobank to test for associations with cognitive traits and to evaluate their expressivity. This thesis has identified novel candidate genes for dyslexia and suggests that larger WES studies are likely to identify additional genetic associations.

Date of Award	2 Dec 2025
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Silvia Paracchini (Supervisor), Juan Ye (Supervisor), Ian Poole (Supervisor) & Simon E. Fisher (Supervisor)