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UNIVERSITY of CALIFORNIA Los Angeles Informing Genetic Models UNIVERSITY OF CALIFORNIA Los Angeles Informing Genetic Models of Autism via Transcriptional Network Analysis in Brain and Blood A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Human Genetics by Rui Luo 2014 © Copyright by Rui Luo 2014 ABSTRACT OF THE DISSERTATION Informing Genetic Models of Autism via Transcriptional Network Analysis in Brain and Blood by Rui Luo Doctor of Philosophy in Human Genetics University of California, Los Angeles, 2014 Professor Daniel Geschwind, Chair Autism Spectrum Disorders (ASDs) are a group of heritable neruodevlopmental disorders. Both common and rare genetic variants are known to play a role in ASDs. However the functional impact of genetic variants remains largely unexplored. In this study, we conducted transcriptome profiling analysis to uncover the expression alterations that are associated with autism. The transcriptome profiling also aids us exploring the regulatory patterns of genetic variants, and better understanding the genetic models of autism. Since brain tissue is not accessible on a large scale, we profiled mRNAs of lymphoblast cell lines (LCLs) from three independent cohorts to determine whether we could detect a reproducible blood gene expression pattern associated with ASD. RNA from a total of 978 patients, and 651 controls, including 607 unaffected siblings analyzed for differential expression. Although few genes were consistently ii differentially expressed between ASD and controls, we did find five (CMKOR1, DKFZP564O0823, PITPNC1, PRKCB1 and VIM) that were differentially expressed in at least two cohorts LCLs and previously published brain samples. Similarly, using LCL gene expression to classify subjects by disease status performed only slightly above chance. Using weighted gene co-expression network analysis (WGCNA), we were able to identify a module correlated with ASD in both AGRE and NIMH cohorts that overlapped with genes previously found to be mis- expressed in post mortem brain from ASD cases. eQTL analysis identified SNPs that were associated with LCL gene expression, including several in AHI1, a Joubert Syndrome gene dysregulated in ASD brain and lymphoblasts. Four of the 23 SNPs that were significantly correlated with the expression level of AHI1 reside in the same haplotype block previously associated with ASD, suggesting that risk for ASD is mediated via AHI1 transcript levels. Overall, we found a weak, but consistent signal in LCLs further suggesting that peripheral lymphoblast gene expression may be useful for studying ASD. Rare variants including Copy Number Variants (CNVs) and Single Nucleotide Variants (SNVs) are found to play an important role to the etiology of ASD together with common variants. We next interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly mis-expressed genes (which we refer to here as outliers) identified in probands and unaffected siblings do not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways including neuropeptide signaling, synaptogenesis and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used to prioritize rare CNVs of potentially iii unknown significance. Several non-recurrent CNVs with significant gene expression alterations are identified, including deletions on chromosome 3q27, 3p13 and 3p26, and duplications at 2p15, suggesting these as potential novel ASDs loci. In addition, we identify distinct pathways disrupted in 16p11.2 microdeletions, microduplications and 7q11.23 duplications, and show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASDs relevant phenotype. This study provides evidence that pathogenic structural variants have functional impact on transcriptome alterations in ASDs at a genome-wide level, and demonstrates the utility of this approach for prioritization of genes for subsequent functional analysis. Genetic studies have identified dozens of ASDs susceptibility genes, yet the interaction between ASD risk genes are pooly understood. In the aim of identify the molecular mechanisms and potential convergening pathways of ASD risk genes, the last chapter of my research utilizes transcriptome profiling to answer two questions: 1) do these genetic loci converge on specific laminar expression patterns, and 2) where does the phenotypic specificity of ASDs arise, given its genetic overlap with intellectual disability (ID)? To answer these, we mapped ASDs and ID risk genes to non-human primate and human brain transcriptome. We found ASDs genes are enriched in superficial cortical layers and glutamatergic projection neurons at the circuit level. Furthermore, we show that the patterns of ASDs and ID risk genes are distinct, providing a novel biological framework for investigating the pathophysiology of ASDs. In this chapter, we demonstrated the importance of understanding ASD gene interaction with systems biology method. iv The dissertation of Rui Luo is approved. Steve Horvath Matteo Pellegrini Stanley Nelson Daniel Geschwind, Committee Chair University of California, Los Angeles 2014 v To my parents, Kangjin Luo and Jianqing Lu; my husband, Chaochao Cai for their unconditional love and support To my little son, Yuwei Cai your accomplishment will be greater vi TABLE OF CONTENTS Abstract ........................................................................................................................................... i Acknowledgements ......................................................................................................................... v Vita ................................................................................................................................................ xv Introduction ..................................................................................................................................... 1 References ....................................................................................................................................... 5 Chapter 1: Large-scale lymphoblast gene expression profiling of ASD and unaffected controls reveals weak shared signals across cohorts .................................................................................. 11 1.1 Abstract ................................................................................................................................... 11 1.2 Introduction ............................................................................................................................. 12 1.3 Several differentially expressed (DEX) genes in LCLs overlap with DEX genes in autistic brain .............................................................................................................................................. 15 1.4 Prediction of autism using LCLs gene expression signatures ................................................ 17 1.5 Network analysis identifies a neural-related module that is associated with ASDs in AGRE and NIMH cohorts ........................................................................................................................ 17 1.6 eQTL identifies SNPs that are associated with gene expression patterns .............................. 19 1.7 Discussion ............................................................................................................................... 20 1.8 Methods................................................................................................................................... 25 1.9 References ............................................................................................................................... 44 Chapter 2: Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders ...................................................................... 53 2.1 Abstract ................................................................................................................................... 53 2.2 Introduction ............................................................................................................................. 54 2.3 Nerual-related pathways are altered in LCLs of probands, but not siblings ........................... 55 2.4 Copy number variation affects transcript levels in both probands and siblings ..................... 57 2.5 Outlier genes are enriched in large rare de novo CNVs ......................................................... 59 2.6 Transcriptonal data aids prioritization of small and non-recurrent CNV ............................... 61 2.7 Transcriptional alterations in recurrent CNVs 16p11.2 and 7q11.23 ..................................... 62 2.8 Discussion ............................................................................................................................... 65 2.9 Methods................................................................................................................................... 70 2.10 References ........................................................................................................................... 108 Chapter 3: Understand autism risk genes at the transcriptomic
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