4,464 research outputs found
CNTNAP2 and Autism Spectrum Disorders
No full textAlthough autism was described in the early 1940s as a disorder of affective contact (Kanner, 1943), it was not classified as a neurodevelopmental disorder with a biological basis until the early 1980s, when studies reported its high heritability (Folstein & Rutter, 1977; Ritvo et al., 1985) and co-occurrence with chromosomal abnormalities (Gillberg & Wahlstrom, 1985; Wahlström et al., 1986). Today, autism is considered a heterogeneous neurodevelopmental syndrome and therefore termed autism spectrum disorder (ASD), characterized by variable deficits in social behavior and language, restrictive interests, and repetitive behaviors. Autism spectrum disorder has an estimated prevalence of 1:150–1:200 (Centers for Disease Control and Prevention, 2007), being one of the most common childhood disorders. In addition to the core domains necessary for diagnosis, a number of other behavioral abnormalities are frequently associated with ASD, including epilepsy, sensory abnormalities, hyperactivity, motor abnormalities, sleep disturbances, and gastrointestinal symptoms (Geschwind, 2009).</p
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Analysis of cerebral cortical transcriptome dysregulation in autism and psychiatric disorders
No full textPsychiatric disorders are not well understood. Their diagnosis is based purely on behavioral symptoms and they lack a clearly defined pathology in brain, which challenges our ability to understand their biological roots. However, it is well established that psychiatric disorders are heritable, and large-scale genetic studies have begun to identify now thousands of psychiatric genetic risk variants.1 Discovering how these genetic variants converge within discrete neurobiological pathways is a critical next step for understanding psychiatric disorder mechanisms and identifying new targets for therapeutic development. In search for these convergent pathways, transcriptomic studies have started to identify gene expression changes within human postmortem brain samples from psychiatric patients compared to neurotypical controls. The transcriptome – the set of expressed RNA transcripts present in a given tissue or cellular samples – represents a snapshot of the cell-types and subcellular, molecular processes present and active in sequenced samples. As such, transcriptomic profiling of brain samples from psychiatric cases versus controls may provide increased resolution to identify a molecular pathology of disease not observed via traditional approaches. For example, in ASD, upregulation of microglial, astrocyte, and immune signaling genes, downregulation of specific synaptic genes, and attenuation of regional gene expression differences have been observed with transcriptomic analyses.2,3 While transcriptomic studies have substantially improved our understanding of psychiatric neuropathology, they are limited in scope to single psychiatric disorders and few brain regions. Considering the growing evidence for genetic overlap between distinct psychiatric disorders,4 it is a reasonable next step to determine if these disorders also share biological signatures in the brain. Comparing and contrasting gene expression changes across distinct psychiatric disorders – as well as across the entire cerebral cortex - will provide a fuller picture of the spatial landscape and specificity of molecular dysregulation in the psychiatric disease brain, pinpointing potential regions of particular vulnerability and biological pathways involved in psychiatric disease mechanisms. To obtain this cross-disorder and multi-regional understanding of psychiatric gene expression changes, here I present a comprehensive set of transcriptomic investigations conducted by myself and others, spanning multiple psychiatric disorders and brain regions. In Chapter 2, I share our published mega-analysis of gene expression microarray datasets containing frontal cortex samples from subjects diagnosed with schizophrenia, bipolar disorder, ASD, and major depressive disorder subjects, compared with non-psychiatric controls.5 We find that polygenic overlap parallels transcriptomic overlap, and that psychiatric genetic risk variants are associated with downregulated neuronal genes found in ASD, schizophrenia, and bipolar disorder. In Chapter 3, I present my contributions to our published collaborative work with the PsychENCODE Consortium,6 in which we compiled and uniformly processed genotype and RNA-sequencing data from more than 2,000 postmortem human brain samples to gain an understanding of how the entire transcriptome is impacted in frontal cortex samples from subjects diagnosed with schizophrenia, bipolar disorder, and ASD. Here, I detail my work integrating polygenic risk scores --measures of common genetic burden for psychiatric disease -- with transcriptomic changes to obtain a deeper understanding of how genetic variants directly regulate psychiatric gene expression changes. In Chapter 4, I present our work characterizing ASD transcriptomic across 11 distinct regions spanning the ASD cerebral cortex. We find widespread dysregulation across the cerebral cortex, with this dysregulation exhibiting the greatest magnitude of effect in the occipital region. ASD genetic risk variants are associated with genes downregulated cortex-wide that contribute to neuronal synaptic plasticity pathways, heavily implicating neuronal synaptic plasticity in ASD neuropathology. Together, these transcriptomic analyses expand our understanding of the molecular pathology of psychiatric disorders across distinct disorders and the cerebral cortex, implicating specific genes, cell-types, and biological pathways in psychiatric neuropathology.Abstract Bibliography1. Sullivan, P. F. & Geschwind, D. H. Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders. Cell 177, 162–183 (2019).
2. I. Voineagu et al., Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 474, 380–384 (2011).
3. Parikshak, N. N. et al. Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature 540, 423–427 (2016).
4. Bulik-Sullivan, B., Finucane, H., Anttila, V. et al. An atlas of genetic correlations across human diseases and traits. Nat Genet 47, 1236–1241 (2015).
5. Gandal, M. J. et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359, 693–697 (2018).
6. Gandal, M. J. et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362, (2018)
Deutliche und gründliche Erklärung der Adelichen und Ritterlichen freyen Fecht-Kunst : Lectionen auff den stoß/ und deren gebrauchs eigentlicher Nachricht. Auff die rechte Italianische Art und manir, in dieses Tractätlein verfaßt/ und mit nothwendigen Kupfferstücken nach möglichkeit gezieret und vor Augen gestelt / Durch Jeann Daniel L'Ange ...
No full textCorrection for Prusiner et al., Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism
No full textCorrection for “Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism,” by Stanley B. Prusiner, Amanda L. Woerman, Daniel A. Mordes, Joel C. Watts, Ryan Rampersaud, David B. Berry, Smita Patel, Abby Oehler, Jennifer K. Lowe, Stephanie N. Kravitz, Daniel H. Geschwind, David V. Glidden, Glenda M. Halliday, Lefkos T. Middleton, Steve M. Gentleman, Lea T. Grinberg, and Kurt Giles, which was first published August 31, 2015; 10.1073/pnas.1514475112 (Proc. Natl. Acad. Sci. U.S.A. 112, E5308–E5317).
The authors note that Fig. 3 appeared incorrectly. The corrected figure and its legend appear below. The online version has been corrected
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Systematic Characterization of Tauopathy-Associated Genetic Risk Loci using Multiplexed Reporter Assays
No full textThe widespread adoption of genome-wide association studies (GWAS) has revolutionized the detection of genetic loci associated with complex traits. However, the majority of common susceptibility loci reside in poorly annotated noncoding genomic regions and are composed of many correlated polymorphisms due to linkage disequilibrium, obscuring identification of the causal variants and mechanisms underlying trait association. Thus, the functional annotation of noncoding variation is a major impediment to interpretation of genetic risk. Massively Parallel Reporter Assays (MPRA) are a novel experimental approach for the high-throughput functional characterization of noncoding genetic variation, yet remain to be systematically applied to any neurologic disorder. In this dissertation, I utilize MPRA to characterize variation associated with two neurodegenerative disorders that share tau-protein neuropathology, Alzheimer’s disease and Progressive Supranuclear Palsy. First, I describe the design and implementation of an MPRA to screen 5,706 noncoding variants derived from three GWAS for AD and PSP, identifying 320 regulatory polymorphisms comprising 27 of 34 tested loci. These results enable subsequent identification of novel putative risk genes including PLEKHM1 and APOC1 distributed across the complex 17q21.31 and 19q13.32 regions. In Chapter 3, I show that functional predictions from four popular computational algorithms for variant prioritization are discordant both with MPRA results and each other. In Chapter 4, I find that MPRA-defined functional variants preferentially disrupt predicted transcription factor binding sites that converge on enhancers with differential cell-type specific activity in PSP and AD, implicating a neuronal SP1-driven regulatory network in PSP pathogenesis. These analyses support a novel mechanism underlying noncoding genetic risk, whereby common genetic variants drive disease risk via their aggregate activity on specific transcriptional programs. In Chapter 5, I perform genome editing to validate four causal loci, identifying C4 as a novel genetic risk factor for AD. Finally, in Chapter 6, I interrogate technical parameters relevant to assay performance, aiding future studies. Taken together, this work represents a comprehensive characterization of common genetic risk associated with AD and PSP and implicates variants, genes, and transcriptional regulatory networks that represent novel risk factors for neurodegenerative tauopathies
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Informing Genetic Models of Autism via Transcriptional Network Analysis in Brain and Blood
No full textAutism 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 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 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
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Global and Local Regulation of Gene Expression in the Human Brain
No full textNeuropsychiatric disorders are behavioral conditions marked by intellectual, social, or emotional deficits that can be linked to diseases of the nervous system. Autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BP), major depressive disorder (MDD), and attention deficit and hyperactivity disorder (ADHD) are common, heritable diseases each with a prevalence exceeding 1% of the population, none of which can be characterized by discernable anatomical or neurological pathologies. Genetic association studies have identified mutations in hundreds of genes that contribute to risk for at least one of these disorders, and have shown that a substantial fraction of the genetic liability is shared between many of these neuropsychiatric diseases. It has long been hoped that with enough genetic evidence we will identify the biological pathways, developmental time points, and brain regions that, when disrupted, give rise to neuropsychiatric disorders. However, the cellular and functional complexity of the human brain, as well as the genetic complexity of neuropsychiatric disease, make it difficult to search for such convergence. In this thesis, I investigate global and local transcriptional regulation within and across 12 regions of the human brain in order to investigate the regional specificity of neuropsychiatric disorders. I develop novel bioinformatics methods – ranging from data processing to network construction – to identify whether the transcriptional regulation of a set of genes is shared or specific. I hypothesize that local, region-specific transcriptional regulation corresponds directly to cell types and processes that are specific to, or far more prevalent in, a given region; that cross-regional transcriptional regulation corresponds to cell types that show little heterogeneity across brain regions; and that genetic disruption of region-specific transcriptional programs results in regional susceptibility. I use a systems-biology approach to summarize transcriptional regulation into reproducibly co-expressed gene sets (“co-expression modules”), which can be analyzed statistically to identify common functions, pathways, and cell types. I then integrate data from genetic association studies to ascertain gene sets conferring outsized risk for neuropsychiatric disorders, thereby implicating the corresponding pathways for further investigation in disease etiology. Finally, I use the network structure itself to investigate the genetic architecture of ASD and SCZ in terms of omnigenics and network polygenics. Chapter 1 presents the biological background for the studies and summarizes some of the major studies of neuropsychiatric disorders along with their principal methods and conclusions. In chapter 2, utilizing my multi-regional co-expression approach, I identify 12 brain-wide, 114 region-specific, and 50 cross-regional co-expression modules. Nearly 40% of expressed genes fall into brain-wide modules and correspond to major cell classes and conserved biological processes, while region-specific modules comprise 25% of expressed genes and correspond to region-specific cell types. The detailed study in chapter 3 demonstrates that neuropsychiatric risk concentrates in both brain wide and multi-regional modules, implicating major core cell types in disease etiology but not region-specific susceptibility. Chapter 4 presents a new and more general framework for defining genetic networks. Using this framework, I show that the network pattern of ASD-associated rare loss-of-function mutations, as well as the large number of significant targets for trans master regulators in BP and SCZ, support a classical polygenic architecture with thousands of directly causal genes. These results suggest that a nontrivial component of risk for neuropsychiatric disease comes from the global polygenic disruption of neuronal function and neuronal maturation
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Cross-Species Single-Cell Analysis of Maternal Immune Activation and its Translatability to Schizophrenia
No full textMaternal immune activation (MIA) is a well-known risk factor for neurodevelopmental disorders such as schizophrenia. This thesis presents a single-cell RNA sequencing analysis of MIA across brain regions (dorsal and ventral striatum and frontal cortex), developmental stages (adult and adolescent), and species (mouse and nonhuman primate (NHP)). After evaluating preprocessing pipelines, we assessed cell-type conservation and MIA effects across species via marker gene expression, hierarchical clustering, Pearson correlation, and reference mapping. While cell-type identities were largely conserved, MIA-induced gene expression changes were species-specific and showed weak cross-species correlation. Medium spiny neurons displayed the most consistent cross-species gene expression and MIA response. Comparison of NHP MIA effects to human schizophrenia data revealed little global similarity, though several differentially expressed genes associated with neurodevelopmental disorders showed consistent dysregulation. These findings highlight limitations in the transcriptomic translatability of animal MIA models to human schizophrenia but identify promising shared targets for future study
Defender: the life of Daniel H. Wells
No full textIncludes bibliographical references and index.Defender is the first and only scholarly biography of Daniel H. Wells, one of the important yet historically neglected leaders among the nineteenth-century Mormons—leaders like Heber C. Kimball, George Q. Cannon, and Jedediah M. Grant. An adult convert to the Mormon faith during the Mormons’ Nauvoo period, Wells developed relationships with men at the highest levels of the church hierarchy, emigrated to Utah with the Mormon pioneers, and served in a series of influential posts in both church and state. Wells was known especially as a military leader in both Nauvoo and Utah—he led the territorial militia in four Indian conflicts and a confrontation with the US Army (the Utah War). But he was also the territorial attorney general and obtained title to all the land in Salt Lake City from the federal government during his tenure as the mayor of Salt Lake City. He was Second Counselor to Brigham Young in the LDS Church's First Presidency and twice served as president of the Mormon European mission. Among these and other accomplishments, he ran businesses in lumbering, coal mining, manufacturing, and gas production; developed roads, ferries, railroads, and public buildings; and presided over a family of seven wives and thirty-seven children. Wells witnessed and influenced a wide range of consequential events that shaped the culture, politics, and society of Utah in the latter half of the nineteenth century. Using research from relevant collections, sources in public records, references to Wells in the Joseph Smith papers, other contemporaneous journals and letters, and the writings of Brigham Young, Quentin Thomas Wells has created a serious and significant contribution to Mormon history scholarship.--Provided by publisher.1634-1814, a Puritan family's progress: the Wells' migration from England to America -- 1814-1838, Daniel H. Wells: from a brief childhood in New York to frontier life in Illinois -- 1839-1841, a bachelor farmer in commerce becomes a married entrepreneur and civic leader in Nauvoo -- 1841-1844, the Mormon hegemony: civic controversy, court cases and family conflict -- 1843-1846, the Mormon hegemony: disaffection and libel leads to mayhem and murder -- 1844-1846, the decline of Nauvoo: Daniel becomes a Mormon and leads in the battle of Nauvoo -- 1846-1848, the cost of conversion: travels to winter quarters and the trail to great Salt Lake City -- 1848-1851, desert home and new callings: the superintendent, the general and the attorney general -- 1851-1855, six additional wives: a dozen children and many enterprises to support the family -- 1855-1857, fighting Indians or feeding them: family matters and Brigham's new counselor -- 1857-1858, the Utah Expedition: causes and consequences, a war of lies and egos, but no casualties -- 1858-1859, the Peace Commission and war by other means: church, territorial and federal politics in Utah -- 1860-1864, family, business, church, and politics in Utah while the Civil War ravages the nation -- 1860-1864, the Wells family grows and prospers during the Civil War -- 1864-1865, Daniel's first (incomplete) term as European Mission president -- 1865-1868, Utah's Black Hawk War -- 1868-1870, mayor of Salt Lake City: defending the faith, fighting crime, and obtaining the deed to the city -- 1870-1878, Mormon versus gentile in railroads, business, government and religion -- 1875-1878, Daniel opposes the Glu, defends Brigham, escapes drowning and dedicates a temple -- 1877-1879, from counselor to assistant, trapped in court, imprisoned and paraded home -- 1880-1885, Wells family marriages, the anti-polygamy crusade, and a second mission in Europe -- 1886-1888, defending against opposition in England while tragedy unfolds at home -- 1887-1891, preparing for his passing, president of the temple, death while still in harness -- Appendix A: the Wells family in England and America, 1484-1814 -- Appendix B: the Chapin family in England and America,1484-1814
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Investigation of sex-differential genetic risk factors for autism spectrum disorders
No full textAutism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders that affect more males than females, and the mechanisms responsible for increasing males' risk or protecting females are not understood. This sex biased prevalence is consistent across time and populations, suggesting that an understanding of the processes driving sex-differential risk would likely be informative of fundamental pathophysiology in ASD. One known component of ASD risk is genetic variation. Thus, here I apply several approaches that leverage current knowledge of ASD genetics to investigate the role and mechanisms of sex-differential biology in ASD risk. First, I evaluate a cohort of families with more than one autistic child for evidence of sex-differential, familial risk variation. Second, I use genetic linkage analysis to identify sex-differential risk loci in families from the same multiplex cohort. Third, I characterize gene expression patterns in typical human neocortex to identify points of interaction between typical sexual dimorphism and genes known to carry risk variants for ASD.I find that recurrence rates for ASD diagnoses in multiplex families are consistent with a female protective model, in which females require more deleterious genetic variation to be affected with ASD and this greater genetic load is shared with females' siblings. I also identify several chromosomal loci with evidence of genetic linkage in families either with (chromosome 8p21.2 and 8p12), or without (chromosome 1p31.3), an autistic female. No significant common variants are found in either region that can account for this linkage; these loci will be further investigated by targeted sequencing to identify rare risk variants. Gene expression analyses show that known ASD risk genes are not differentially expressed in males or females in the prenatal or adult human neocortex. However, astrocyte markers and gene sets implicated in immune function and inflammatory processes are expressed at higher levels in males. This suggests that sex-differential factors may operate downstream from, or interact with, ASD risk genes, as opposed to directly regulating the expression of these genes. Overall, findings from these multiple approaches provide valuable context for the function of sex-differential biology in ASD etiology, and suggest promising directions for future research
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