Exploring candidate loci, genes, pathways, and evolutionary markers in schizophrenia by re-analyzing candidate gene and genome-wide association studies

Abstract

In the last decade, consistent efforts have been made by psychiatric geneticists to elucidate the genetic mechanisms of schizophrenia, especially after the rise of genome-wide association studies (GWAS). However, the genetic etiology of schizophrenia has not been fully discovered, and enormous genetic datasets have been produced, allowing for additional investigation. In my PhD study, I have systematically identified candidate gene and GWAS in schizophrenia. Furthermore, I have re-analyzed these genetic datasets using meta-analyses, pathway analyses and evolutionary-based analyses. The results of these studies revealed new and supported current candidate loci, genes and pathways associated with increased risk of schizophrenia. I also provided evidence supporting a novel evolutionary mechanism for schizophrenia that extended the current conceptualizations of how schizophrenia emerged.

In Chapter 1, I introduced the progress of genetic studies already achieved in schizophrenia, including family and twin studies, linkage studies, candidate gene association studies, genome-wide association studies, copy number variation studies and wholeexome/genome sequencing studies. A literature review of GWAS in schizophrenia and the aims of the thesis are included in this Chapter.

Chapter 2 of this thesis provides a systematic review of genetic association studies in schizophrenia. In this study, I have reviewed more than 3000 association studies and merged them with the data from the existing schizophrenia knowledgebase (SzGene). Two rounds of meta-analyses, i.e. candidate-gene-only meta-analyses and expanded meta-analyses combined with samples from GWAS, have been conducted. In total, I have identified 21 Bonferroni significant single nucleotide polymorphisms (SNPs) in 14 Linkage disequilibrium (LD)-independent loci associated with schizophrenia susceptibility. Three of these loci, including methylenetetrahydrofolate reductase (MTHFR), D-amino acid oxidase activator (DAOA) and ARVCF, delta catenin family member (ARVCF), had never been implicated by a schizophrenia GWAS.

Chapter 3 aimed to test the notion that schizophrenia is a pathway disorder. In this study, I conducted a pathway-wide association study, testing the association between schizophrenia and 255 biological pathways. Five independent GWAS datasets across three distinct ethnic populations were collected for pathway analyses. Almost half of biological pathways were associated with schizophrenia in each of three populations, and five of them (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across three populations. These findings suggest schizophrenia is a poly-pathway disorder, and provide empirical support for that notion.

In Chapter 4, I attempted to address the evolutionary paradox of schizophrenia: why negative genetic selection has not eliminated the deleterious alleles associated to schizophrenia susceptibility from the modern human genome? Using evolutionary markers in the genome, I showed that modern humans carried more protective SNPs for schizophrenia compared with our collateral ancestors: Neanderthals and Denisovans. Based on these findings, I proposed a novel framework to explain the evolutionary paradox and genetic origin of schizophrenia.

In Chapter 5, the main findings and conclusion of my thesis are summarized. In addition, an expanded discussion of the meta-analyses of genetic association studies, the pathway-wide association study, and the evolutionary analysis are provided along with limitations and future directions.