ORCID Profile
0000-0001-9112-5148
Current Organisations
University of Oxford
,
UCSF Medical Center
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Publisher: Cold Spring Harbor Laboratory
Date: 18-05-2021
DOI: 10.1101/2021.05.17.444514
Abstract: The function of regulatory elements is highly dependent on the cellular context, and thus for understanding the function of elements associated with psychiatric diseases these would ideally be studied in neurons in a living brain. Massively Parallel Reporter Assays (MPRAs) are molecular genetic tools that enable functional screening of hundreds of predefined sequences in a single experiment. These assays have not yet been adapted to query specific cell types in vivo in a complex tissue like the mouse brain. Here, using a test-case 3′UTR MPRA library with genomic elements containing variants from ASD patients, we developed a method to achieve reproducible measurements of element effects in vivo in a cell type-specific manner, using excitatory cortical neurons and striatal medium spiny neurons as test cases. This new technique should enable robust, functional annotation of genetic elements in the cellular contexts most relevant to psychiatric disease.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1038/NG.3529
Publisher: Cold Spring Harbor Laboratory
Date: 07-07-2017
DOI: 10.1101/160499
Abstract: As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 in iduals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.
Publisher: Springer Science and Business Media LLC
Date: 09-2014
DOI: 10.1038/NG.3050
Publisher: Elsevier BV
Date: 2013
Publisher: Elsevier BV
Date: 12-2019
Publisher: Springer Science and Business Media LLC
Date: 22-05-2017
Publisher: Springer Science and Business Media LLC
Date: 28-11-2017
Publisher: Elsevier BV
Date: 07-2017
Publisher: Elsevier BV
Date: 04-2022
Publisher: Springer Science and Business Media LLC
Date: 29-10-2014
DOI: 10.1038/NATURE13772
Publisher: Elsevier BV
Date: 03-2019
Publisher: Elsevier BV
Date: 02-2020
Publisher: Cold Spring Harbor Laboratory
Date: 31-01-2020
DOI: 10.1101/2020.01.31.927665
Abstract: We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs ( RIMS1 , CHD8 , CHD2 , WDFY3 , ASH1L ) causing a common failure of presynaptic homeostatic plasticity (PHP). Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, we find that PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, PDPK1 and PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails an unexpected, maladaptive up-regulation of CREG , a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which erse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.
Publisher: Cold Spring Harbor Laboratory
Date: 18-11-2020
DOI: 10.1101/2020.11.18.389171
Abstract: Genetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of in idual exons in the developing human neocortex. RNA-seq data from 176 human dorsolateral prefrontal cortex s les across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical s les. In the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A a synchronized 5N/5A transition occurs between 24 post-conceptual weeks (2 nd trimester) and six years of age. In mice, the equivalent 5N/5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories. Splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 16-03-2018
DOI: 10.1038/S41593-018-0102-8
Abstract: In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note in fact, only names are given. In all versions of the paper, the corresponding author symbols were attached to A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington and Thomas Lehner they should have been attached, respectively, to Steven E. Hyman, Anjene M. Addington, Thomas Lehner and Nelson B. Freimer. As a result of this shift, the respective contact links in the HTML version did not lead to the indicated in iduals. The errors have been corrected in the HTML and PDF versions of the article.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2021
DOI: 10.1038/S41467-021-24243-0
Abstract: Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer’s disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Cold Spring Harbor Laboratory
Date: 22-03-2019
DOI: 10.1101/585430
Abstract: Variation in gene expression underlies neurotypical development, while genomic variants contribute to neuropsychiatric disorders. BrainVar is a unique resource of paired whole-genome sequencing and bulk-tissue RNA-sequencing from the human dorsolateral prefrontal cortex of 176 neurotypical in iduals across prenatal and postnatal development, providing the opportunity to assay genomic and transcriptomic variation in tandem. Leveraging this resource, we identified rare premature stop codons with commensurate reduced and allele-specific expression of corresponding genes, and common variants that alter gene expression (expression quantitative trait loci, eQTLs). Categorizing eQTLs by prenatal and postnatal effect, genes affected by temporally-specific eQTLs, compared to constitutive eQTLs, are enriched for haploinsufficiency, protein-protein interactions, and neuropsychiatric disorder risk loci. Expression levels of over 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell type specific genes and neuropsychiatric disorder loci, underscoring the importance of cataloguing developmental trajectories in understanding cortical physiology and pathology. Whole-genome and RNA-sequencing across human prefrontal cortex development in BrainVar Gene-specific developmental trajectories characterize the late-fetal transition Identification of constitutive, prenatal-specific, postnatal-specific, and rare eQTLs Integrated analysis reveals genetic and developmental influences on CNS traits and disorders
Publisher: Cold Spring Harbor Laboratory
Date: 13-08-2020
DOI: 10.1101/2020.08.12.248526
Abstract: Current clinical guidelines recommend three genetic tests for the assessment of fetal structural anomalies: karyotype to detect microscopically-visible balanced and unbalanced chromosomal rearrangements, chromosomal microarray (CMA) to detect sub-microscopic copy number variants (CNVs), and exome sequencing (ES) to identify in idual nucleotide changes in coding sequence. Advances in genome sequencing (GS) analysis suggest that it is poised to displace the sequential application of all three conventional tests to become a single diagnostic approach for the assessment of fetal structural anomalies. However, systematic benchmarking is required to assure that GS can capture the full mutational spectrum associated with fetal structural anomalies and to accurately quantify the added diagnostic yield of GS. We applied a novel GS analytic framework that included the discovery, filtration, and interpretation of nine classes of genomic variation to 7,195 in iduals. We assessed the sensitivity of GS to detect diagnostic variants (pathogenic or likely pathogenic) from three standard-of-care tests using 1,612 autism spectrum disorder quartet families (ASD n=6,448) with matched GS, ES, and CMA data, and validated these findings in 46 fetuses with a clinically reportable variant originally identified by karyotype, CMA, or ES. We then assessed the added diagnostic yield of GS in 249 trios (n=747) comprising a fetus with a structural anomaly detected by ultrasound and two unaffected parents that were pre-screened with a combination of all three standard-of-care tests. Across both cohorts, our GS analytic framework identified 98.2% of all diagnostic variants detected by standard-of-care tests, including 100% of those originally detected by CMA (n=88) and ES (n=61), as well as 78.6% (n=11/14) of the chromosomal rearrangements identified by karyotype. The diagnostic yield from GS was 7.8% across all 1,612 ASD probands, almost two-fold more than CMA (4.4%) and three-fold more than ES (3.0%). We also demonstrated that the yield of ES can approach that of GS when CNVs are captured with high sensitivity from exome data (7.4% vs. 7.8%, respectively). In 249 pre-screened fetuses with structural anomalies, GS provided an additional diagnostic yield of 0.4% beyond the combination of all three tests (karyotype, CMA, and ES). Applying our benchmarking results to existing data indicates that GS can achieve an overall diagnostic yield of 46.1% in unselected fetuses with fetal structural anomalies, providing an estimated 17.2% increase in diagnostic yield over karyotype, 14.1% over CMA, and 36.1% over ES when sequence variants are assessed, and 4.1% when CNVs are also identified from exome data. In this study we demonstrate that GS is sensitive to the detection of almost all pathogenic variation captured by karyotype, CMA, and ES, provides a superior diagnostic yield than any in idual test by a wide margin, and contributes a modest increase in diagnostic yield beyond the combination of all three tests. We also outline several strategies to aid the interpretation of GS variants that are cryptic to conventional technologies, which we anticipate will be increasingly encountered as comprehensive variant identification from GS is performed. Taken together, these data suggest GS warrants consideration as a first-tier diagnostic approach for fetal structural anomalies.
Publisher: MDPI AG
Date: 09-02-2023
DOI: 10.3390/IJMS24043509
Abstract: Autism spectrum disorder (ASD) is a common, complex, and highly heritable condition with contributions from both common and rare genetic variations. While disruptive, rare variants in protein-coding regions clearly contribute to symptoms, the role of rare non-coding remains unclear. Variants in these regions, including promoters, can alter downstream RNA and protein quantity however, the functional impacts of specific variants observed in ASD cohorts remain largely uncharacterized. Here, we analyzed 3600 de novo mutations in promoter regions previously identified by whole-genome sequencing of autistic probands and neurotypical siblings to test the hypothesis that mutations in cases have a greater functional impact than those in controls. We leveraged massively parallel reporter assays (MPRAs) to detect transcriptional consequences of these variants in neural progenitor cells and identified 165 functionally high confidence de novo variants (HcDNVs). While these HcDNVs are enriched for markers of active transcription, disruption to transcription factor binding sites, and open chromatin, we did not identify differences in functional impact based on ASD diagnostic status.
Publisher: Springer Science and Business Media LLC
Date: 06-03-2017
Publisher: Springer Science and Business Media LLC
Date: 26-04-2018
Publisher: Springer Science and Business Media LLC
Date: 23-08-2021
DOI: 10.1186/S13073-021-00949-0
Abstract: Genetic variants in the voltage-gated sodium channels SCN1A , SCN2A , SCN3A , and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of in idual exons in the developing human brain. RNA-seq data from 783 human brain s les across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical s les. In the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A , SCN3A , and SCN8A , a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. In SCN8A , over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories. Exon usage in SCN1A , SCN2A , SCN3A , and SCN8A changes dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-12-2018
Abstract: The DNA of protein-coding genes is transcribed into mRNA, which is translated into proteins. The “coding genome” describes the DNA that contains the information to make these proteins and represents ~1.5% of the human genome. Newly arising de novo mutations (variants observed in a child but not in either parent) in the coding genome contribute to numerous childhood developmental disorders, including autism spectrum disorder (ASD). Discovery of these effects is aided by the triplet code that enables the functional impact of many mutations to be readily deciphered. In contrast, the “noncoding genome” covers the remaining ~98.5% and includes elements that regulate when, where, and to what degree protein-coding genes are transcribed. Understanding this noncoding sequence could provide insights into human disorders and refined control of emerging genetic therapies. Yet little is known about the role of mutations in noncoding regions, including whether they contribute to childhood developmental disorders, which noncoding elements are most vulnerable to disruption, and the manner in which information is encoded in the noncoding genome. Whole-genome sequencing (WGS) provides the opportunity to identify the majority of genetic variation in each in idual. By performing WGS on 1902 quartet families including a child affected with ASD, one unaffected sibling control, and their parents, we identified ~67 de novo mutations across each child’s genome. To characterize the functional role of these mutations, we integrated multiple datasets relating to gene function, genes implicated in neurodevelopmental disorders, conservation across species, and epigenetic markers, thereby combinatorially defining 55,143 categories. The scope of the problem—testing for an excess of de novo mutations in cases relative to controls for each category—is challenging because there are more categories than families. Comparing cases to controls, we observed an excess of de novo mutations in cases in in idual categories in the coding genome but not in the noncoding genome. To overcome the challenge of detecting noncoding association, we used machine learning tools to develop a de novo risk score to look for an excess of de novo mutations across multiple categories. This score demonstrated a contribution to ASD risk from coding mutations and a weaker, but significant, contribution from noncoding mutations. This noncoding signal was driven by mutations in the promoter region, defined as the 2000 nucleotides upstream of the transcription start site (TSS) where mRNA synthesis starts. The strongest promoter signals were defined by conservation across species and transcription factor binding sites. Well-defined promoter elements (e.g., TATA-box) are usually observed within 80 nucleotides of the TSS however, the strongest ASD association was observed distally, 750 to 2000 nucleotides upstream of the TSS. We conclude that de novo mutations in the noncoding genome contribute to ASD. The clearest evidence of noncoding ASD association came from mutations at evolutionarily conserved nucleotides in the promoter region. The enrichment for transcription factor binding sites, primarily in the distal promoter, suggests that these mutations may disrupt gene transcription via their interaction with enhancer elements in the promoter region, rather than interfering with transcriptional initiation directly. De novo mutations from 1902 quartet families are assigned to 55,143 annotation categories, which are each assessed for autism spectrum disorder (ASD) association by comparing mutation counts in cases and sibling controls. A de novo risk score demonstrated a noncoding contribution to ASD driven by promoter mutations, especially at sites conserved across species, in the distal promoter or targeted by transcription factors.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2022
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
DOI: 10.1038/NG.3863
Publisher: Springer Science and Business Media LLC
Date: 13-02-2017
DOI: 10.1038/NG.3789
Publisher: Springer Science and Business Media LLC
Date: 11-08-2202
DOI: 10.1038/NG.2711
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Stephan Sanders.