Deciphering and characterization of genetic architecture in complex diseases

Abstract

A complex disease, in contrast to single-gene or “simple genetic” diseases, is characterized by an intricate interplay between multiple genetic variants and various environmental factors. Recent advancements in genotyping array, whole exome sequencing (WES) and whole-genome sequencing have enabled researchers to uncover the secrets of complex diseases. This thesis aims to explore the genetic architecture of three complex diseases by integrating various data types and analysis methods. In Chapter 2, we performed the largest multi-ancestry meta-analysis of Hirschsprung’s disease (HSCR) genome-wide association studies (GWAS) to date. Prioritized candidate genes were further characterized using single-cell transcriptomic data of developing human and mouse gut for their roles in enteric nervous system development. We identified five novel HSCR-susceptibility loci, with three loci (JAG1, HAND2 and ZNF25) reaching genome-wide significance and one putative loci (UNC5C) prioritized by functional relevance. We also demonstrated a highly comparable performance for a polygenic risk score (PRS) model derived from multi-ancestry meta-analysis to those ancestry-matched PRS models, supporting its potential clinical application in risk prediction of HSCR across populations. Chapter 3 describes an analysis of common and rare variant contributions to attention-deficit/hyperactivity disorder (ADHD) in a Hong Kong dataset. By leveraging multi-omics data, we identified 41 potential genomic risk loci with a suggestive association (p < 1e-4), pointing to 111 candidate risk genes, which were enriched for genes differentially expressed during late infancy brain development. Further tissue enrichment analysis implicated the involvement of the cerebellum. At the polygenic level, we detected a strong genetic correlation with resting-state functional MRI connectivity of the cerebellum involved in the attention/central executive and subcortical-cerebellum networks. Rare variant analyses revealed the association of ADHD with rare damaging variants in TEP1, MTMR10, DBH, TBCC, and ANO1. In Chapter 4, we employed WES and examined the association of rare or low-frequency deleterious coding variants in Chinese patients with schizophrenia (SCZ). Age-at-onset (AAO) of SCZ was used to classify patients into early-onset (EOS, AAO<=18) and adult-onset (AOS, AAO>18) subgroups. We utilized Sequence Kernel Association Test to investigate the overall associations with AAO at the gene and gene-set levels. In binary-trait association tests, we identified 5 potential candidate risk genes and 10 gene ontology biological processes (GOBP) terms, among which PADI2 reached Family-wise Error Rate-adjusted significance. In quantitative association tests, we found marginally significant correlations of AAO with alterations in 4 candidate risk genes, and 5 GOBP pathways. Chapter 5 presents a Mendelian Randomization (MR) analysis investigating the causal relationship between five major psychiatric disorders and other traits including immune response (which was inspired by the ADHD GWAS and SCZ WES studies of the previous two chapters), longitudinal changes in different brain structures, intelligence, childhood maltreatment, educational attainment, and antisocial behavior. The two-step MR approach was also incorporated to examine potential mediation effects. Overall, this thesis attempts to contribute to a more comprehensive understanding of the genetic basis of HSCR, ADHD, and SCZ, meanwhile providing some novel insights that may inspire the development of novel targets of public health prevention and intervention.