No abstract

No abstract

Identification of rare inherited variants associated with ASD and 16 new ASD risk genes d Inherited risk reveals both new biological pathways and shared PPI with known genes d We develop and validate a machine learning algorithm (ARC) to remove WGS artifacts d NR3C2 mutations define a novel syndromic form of ASD, which we model in zebrafish

Autoimmunity in Lewy body dementia Lewy body dementia (LBD) is a brain disease that leads to progressive decline in thinking, movement, and independent function. It results from the build-up of microscopic deposits called Lewy bodies, which develop from the aggregation of a misfolded protein called α-synuclein. Gate et al . observed immune cells known as T cells in the brains of LBD patients (see the Perspective by Krot and Rolls). Genomics analysis revealed that T cells traffic to the LBD brain and are associated with neuronal damage. When stimulated with α-synuclein, LBD patient T cells secrete an inflammatory protein known to damage neurons. These findings suggest an unexpected detrimental role of the immune system in LBD. —SMH

Genetic studies of autism spectrum disorder (ASD) have revealed a complex, heterogeneous architecture, in which the contribution of rare inherited variation remains relatively un-explored. We performed whole-genome sequencing (WGS) in 2,308 individuals from families containing multiple affected children, including analysis of single nucleotide variants (SNV) and structural variants (SV). We identified 16 new ASD-risk genes, including many supported by inherited variation, and provide statistical support for 69 genes in total, including previously implicated genes. These risk genes are enriched in pathways involving negative regulation of synaptic transmission and organelle organization. We identify a significant protein-protein interaction (PPI) network seeded by inherited, predicted damaging variants disrupting highly constrained genes, including members of the BAF complex and established ASD risk genes. Analysis of WGS also identified SVs effecting non-coding regulatory regions in developing human brain, implicating NR3C2 and a recurrent 2.5Kb deletion within the promoter of DLG2. These data lend support to studying multiplex families for identifying inherited risk for ASD. We provide these data through the Hartwell Autism Research and Technology Initiative (iHART), an open access cloud-computing repository for ASD genetics research. Main text:Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early deficits in social communication and interaction, together with restricted and repetitive patterns of behavior, interest, or activity(1). Global prevalence is between 1-2%(2), and ASD has a strong genetic component, with heritability estimated between 60% to 90%(3-All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/338855 doi: bioRxiv preprint first posted online Jun. 6, 2018; ! 3! 9). Considerable progress in gene discovery has come from studies in families with only one affected child (simplex families) identifying de novo (DN) copy number variants (CNV)(10-13) and de novo frameshift, splice-acceptor, splice-donor, or nonsense variants (collectively referred to as protein-truncating variants (PTVs))(14-18) that increase ASDrisk and account for an estimated 3-5% of ASD cases (7,8,(19)(20)(21). Despite having identified roughly 90 ASD-risk genes with high confidence (22, 23), it is estimated that between 260 and 1,250 genes confer risk for developing ASD(24), leaving substantial room for gene discovery, especially with regards to inherited variation. To date, several recurrent CNVs have also been associated with increased ASD risk (25)(26)(27). Evidence for inherited risk variants has been drawn primarily from families containing only one affected child (18, 28), which are depleted for inherited risk as compared to families with two or more affected children (multiplex famili...

Background Cerebrospinal fluid (CSF) provides basic mechanical and immunological protection to the brain. Historically, analysis of CSF has focused on protein changes, yet recent studies have shed light on cellular alterations. Evidence now exists for involvement of intrathecal T cells in the pathobiology of neurodegenerative diseases. However, a standardized method for long-term preservation of CSF immune cells is lacking. Further, the functional role of CSF T cells and their cognate antigens in neurodegenerative diseases are largely unknown. Results We present a method for long-term cryopreservation of CSF immune cells for downstream single cell RNA and T cell receptor sequencing (scRNA-TCRseq) analysis. We observe preservation of CSF immune cells, consisting primarily of memory CD4+ and CD8+ T cells. We then utilize unbiased bioinformatics approaches to quantify and visualize TCR sequence similarity within and between disease groups. By this method, we identify clusters of disease-associated, antigen-specific TCRs from clonally expanded CSF T cells of patients with neurodegenerative diseases. Conclusions Here, we provide a standardized approach for long-term storage of CSF immune cells. Additionally, we present unbiased bioinformatic approaches that will facilitate the discovery of target antigens of clonally expanded T cells in neurodegenerative diseases. These novel methods will help improve our understanding of adaptive immunity in the central nervous system.

Background: Cerebrospinal fluid (CSF) provides basic mechanical and immunological protection to the brain. Historically, analysis of CSF has focused on protein changes, yet recent studies have shed light on cellular alterations. Evidence now exists for involvement of intrathecal T cells in the pathobiology of neurodegenerative diseases. However, a standardized method for long-term preservation of CSF immune cells is lacking. Further, the functional role of CSF T cells and their cognate antigens in neurodegenerative diseases are largely unknown. Results: We present a method for long-term cryopreservation of CSF immune cells for downstream single cell RNA and T cell receptor sequencing (scRNA-TCRseq) analysis. We observe preservation of CSF immune cells, consisting primarily of memory CD4 + and CD8 + T cells. We then utilize unbiased bioinformatics approaches to quantify TCR sequence similarity within and between disease groups. By this method, we identify clusters of disease-associated, antigen-specific TCRs from clonally expanded CSF T cells of patients with neurodegenerative diseases. Conclusions: Here, we provide a standardized approach for long-term storage of CSF immune cells. Additionally, we present unbiased bioinformatic approaches that will facilitate the discovery of target antigens of clonally expanded T cells in neurodegenerative diseases. These novel methods will help improve our understanding of adaptive immunity in the central nervous system.

No abstract