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Genetic Control of Expression and Splicing in the Developing Human Brain


Neurodevelopmental and neuropsychiatric diseases, such as autism spectrum disorder (ASD) and schizophrenia (SCZ), are highly heritable, with hundreds of risk loci contributing to disease risk identified through large-scale genomic studies. The ability to interpret these susceptibility variants and their contributions to disease has been difficult due to the fact that many of these variants fall in non-coding regions of the genome, or in regions of high linkage disequilibrium. Given the non-coding nature of the majority of these variants, as well as their enrichment in known enhancers, many of these variants are predicted to regulate gene expression, which is known to be dependent on tissue, cell type and developmental stage.

Here, I have characterized functional genetic variation controlling transcriptional regulation in developing human brain to dissect common variation contributing to neurodevelopmental and early onset neuropsychiatric diseases, characterized by phenotypes originating in utero or early postnatal life. I have comprehensively profiled expression and splicing levels by RNA sequencing and high-density genotyping in 201 mid-gestational human brains and have performed expression and splicing quantitative trait loci analysis, which is currently the largest eQTL study in the developing brain. I identified 7962 expression QTL (eQTL) and 4635 splice QTL (sQTL), including several thousand fetal-specific regulatory regions when compared to published QTL studies of the adult brain. I leveraged these eQTL and sQTL to identify splicing and transcriptional drivers affected by human genetic variation, by significant enrichment in experimentally determined transcription factor, DNA binding proteins, and RNA bringing proteins binding sides. Further integration with experimental transcription factor knockdown data provide evidence that the regulatory regions identified through the eQTL and sQTL analysis are functional and validate that the changes seen in gene expression levels and/or splicing are likely due to the transcription factor’s role in regulating that gene.

By integration with GWAS, I characterized the genes and isoforms contributing to specific neuropsychiatric disorders, including SCZ and ASD, as well as other cognitive or behavioral-related phenotypes. Specifically showing prenatal brain regulatory regions are significantly enriched for SCZ GWAS risk in a complimentary and additive manner to adult brain regulatory regions. I then perform gene co-expression network analysis and identify co-expressed modules of genes representing distinct biological processes in the developing brain. By integrating the QTL identified gene regulatory regions with co-expression modules and GWAS risk loci, I find SCZ and ASD impact distinct developmental gene co-expression modules. Yet, in both disorders, common and rare genetic variation converge. In ASD this convergence also implicates a specific cell type as well, superficial cortical neurons.

Additionally, integration of eQTL and sQTL with GWAS via transcriptome wide association identified dozens of novel candidate risk genes, highlighting shared and stage-specific mechanisms in SCZ. These analyses demonstrate the highly distinctive effects of transcriptional control, as well as divergent age-related contributions to disease. More broadly, these findings demonstrate the genetic mechanisms by which early developmental events have a striking and widespread influence on adult anatomical and behavioral phenotypes.

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