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Gene Regulation in the Human Brain and the Biological Mechanisms Underlying Psychiatric Disorders.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Gene Regulation in the Human Brain and the Biological Mechanisms Underlying Psychiatric Disorders./
Author:	Kim, Minsoo.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2022,
Description:	192 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-12, Section: B.
Contained By:	Dissertations Abstracts International83-12B.
Subject:	Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29215982
ISBN:	9798819398197

Gene Regulation in the Human Brain and the Biological Mechanisms Underlying Psychiatric Disorders.
Kim, Minsoo.

Gene Regulation in the Human Brain and the Biological Mechanisms Underlying Psychiatric Disorders. - Ann Arbor : ProQuest Dissertations & Theses, 2022 - 192 p.

Source: Dissertations Abstracts International, Volume: 83-12, Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2022.

This item must not be sold to any third party vendors.

Large-scale genome-wide association studies (GWAS) have successfully identified hundreds of common variants associated with psychiatric disorders. Meanwhile, large-scale whole exome sequencing (WES) studies that test rare variants in aggregate have identified hundreds of genes for which loss-of-function is associated with increased risk of neurodevelopmental disorders. To understand the exact biological mechanisms in the human brain through which these genetic risk factors impart risk for disease, the first step in post-GWAS analyses is to identify genes that are regulated by disease-associated variants. Thereafter, the functional roles of disease genes from either GWAS or WES studies can be studied in an appropriate experimental system adequately recapitulating the disease-relevant context. In this dissertation, we primarily focus on this two-stage process of identifying genes and understanding their biological functions (herein referred to as the "variant-to-gene-to-function" problem). We approach this problem by integrating existing, large-scale genotype array and postmortem human brain RNA-seq data from PsychENCODE. The first chapter focuses on proof-of-concept isoform-resolution expression analyses, where we fine-map the most significant GWAS locus for autism spectrum disorder and implicate reduced expression of a specific isoform of the XRN2 gene as the underlying driver of GWAS signal. In this chapter, we also jointly model constituent isoforms of a given gene with multivariate variance components linear mixed models, enabling systematic dissection of the genetic architecture of isoform-level expression in the human brain, for the first time. The second chapter shifts its focus to characterizing the functional role of the high-confidence schizophrenia risk gene C4A in the human brain by investigating the effect of complex structural variation of C4 genes on gene expression and co-expression. By annotating changes in C4A co-expression, we find putative molecular correlates of synaptic pruning and convergence of schizophrenia polygenic effects in synaptic processes, indicating that neuronal and synaptic pathways are the driving force conferring schizophrenia risk. Altogether, this dissertation aims to refine and advance our understanding of mental illnesses by characterizing the neurobiological mechanisms through which known genetic risk factors contribute to psychiatric disorders.

ISBN: 9798819398197Subjects--Topical Terms:

530508
Genetics.
Subjects--Index Terms:

Functional genomics

Gene Regulation in the Human Brain and the Biological Mechanisms Underlying Psychiatric Disorders.
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520 $a Large-scale genome-wide association studies (GWAS) have successfully identified hundreds of common variants associated with psychiatric disorders. Meanwhile, large-scale whole exome sequencing (WES) studies that test rare variants in aggregate have identified hundreds of genes for which loss-of-function is associated with increased risk of neurodevelopmental disorders. To understand the exact biological mechanisms in the human brain through which these genetic risk factors impart risk for disease, the first step in post-GWAS analyses is to identify genes that are regulated by disease-associated variants. Thereafter, the functional roles of disease genes from either GWAS or WES studies can be studied in an appropriate experimental system adequately recapitulating the disease-relevant context. In this dissertation, we primarily focus on this two-stage process of identifying genes and understanding their biological functions (herein referred to as the "variant-to-gene-to-function" problem). We approach this problem by integrating existing, large-scale genotype array and postmortem human brain RNA-seq data from PsychENCODE. The first chapter focuses on proof-of-concept isoform-resolution expression analyses, where we fine-map the most significant GWAS locus for autism spectrum disorder and implicate reduced expression of a specific isoform of the XRN2 gene as the underlying driver of GWAS signal. In this chapter, we also jointly model constituent isoforms of a given gene with multivariate variance components linear mixed models, enabling systematic dissection of the genetic architecture of isoform-level expression in the human brain, for the first time. The second chapter shifts its focus to characterizing the functional role of the high-confidence schizophrenia risk gene C4A in the human brain by investigating the effect of complex structural variation of C4 genes on gene expression and co-expression. By annotating changes in C4A co-expression, we find putative molecular correlates of synaptic pruning and convergence of schizophrenia polygenic effects in synaptic processes, indicating that neuronal and synaptic pathways are the driving force conferring schizophrenia risk. Altogether, this dissertation aims to refine and advance our understanding of mental illnesses by characterizing the neurobiological mechanisms through which known genetic risk factors contribute to psychiatric disorders.
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