Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Satterstrom, F. Kyle; Kosmicki, Jack A.; Wang, Jiebiao; Breen, Michael S.; Rubeis, Silvia De; An, Joon-Yong; Peng, Minshi; Collins, Ryan L.; Grove, Jakob; Klei, Lambertus; Stevens, Christine; Reichert, Jennifer; Mulhern, Maureen; Artomov, Mykyta; Gerges, Sherif; Sheppard, Brooke; Xu, Xiaowei; Bhaduri, Aparna; Norman, Utku; Brand, Harrison; Schwartz, Grace B.; Nguyen, Rachel; Guerrero, Elizabeth E.; Dias, Caroline; Aleksić, Branko; Anney, Richard; Barbosa, Mafalda; Bishop, Somer; Brusco, Alfredo; Bybjerg‐Grauholm, Jonas; Carracedo, Ángel; Chan, Marcus C.Y.; Chiocchetti, Andreas G.; Chung, Brian Hon Yin; Coon, Hilary; Cuccaro, Michael L.; Currò, Aurora; Bernardina, Bernardo Dalla; Doan, Ryan; Domenici, Enrico; Dong, Shan; Fallerini, Chiara; Fernández-Prieto, Montserrat; Ferrero, Giovanni Battista; Freitag, Christine M.; Fromer, Menachem; Gargus, J. Jay; Geschwind, Daniel H.; Giorgio, Elisa; González-Peñas, Javier; Guter, Stephen J.; Halpern, Danielle; Hansen-Kiss, Emily; He, Xin; Herman, Gail E.; Hertz‐Picciotto, Irva; Hougaard, David M.; Hultman, Christina M.; Ionita‐Laza, Iuliana; Jacob, Suma; Jamison, Jesslyn; Jugessur, Astanand; Kaartinen, Miia; Knudsen, Gun Peggy; Kolevzon, Alexander; Kushima, Itaru; Lee, So Lun; Lehtimäki, Terho; Lim, Elaine T.; Lintas, Carla; Lipkin, W. Ian; Lopergolo, Diego; Lopes, Fátima; Ludeña, Yunin; Maciel, Patrı́cia; Magnus, Per; Mahjani, Behrang; Maltman, Nell; Manoach, Dara S.; Meiri, Gal; Menashe, Idan; Miller, Judith; Minshew, Nancy J.; Montenegro, Eduarda Morgana Silva; Moreira, Danielle de Paula; Morrow, Eric M.; Mors, Ole; Mortensen, Preben Bo; Mosconi, Matthew W.; Muglia, Pierandrea; Neale, Benjamin M.; Nordentoft, Merete; Ozaki, Norio; Palotie, Aarno; Parellada, Mara; Passos‐Bueno, Maria Rita; Pericak‐Vance, Margaret A.; Persico, Antonio M.; Pessah, Isaac N.; Puura, Kaija; Reichenberg, Abraham; Renieri, Alessandra; Riberi, Evelise; Robinson, Elise; Samocha, Kaitlin E.; Sandin, Sven; Santangelo, Susan L.; Schellenberg, G D; Scherer, Stephen W.; Schlitt, Sabine; Schmidt, Rebecca Jean; Schmitt, Lauren; Silva, Isabela M.W.; Singh, Tarjinder; Siper, Paige M.; Smith, Moyra; Soares, Gabriela; Stoltenberg, Camilla; Surén, Pål; Süsser, Ezra; Sweeney, John A.; Szatmári, Péter; Tang, Lara; Tassone, Flora; Teufel, Karoline; Trabetti, Elisabetta; Trelles, Maria del Pilar; Walsh, Christopher A.; Weiss, Lauren A.; Werge, Thomas; Werling, Donna M.; Wigdor, Emilie M.; Wilkinson, Emma; Willsey, A. Jeremy; Yu, Timothy W.; Yu, Mullin H.C.; Yuen, Ryan K. C.; Zachi, Elaine Cristina; Agerbo, Esben; Als, Thomas Damm; Appadurai, Vivek; Bækvad‐Hansen, Marie; Belliveau, Rich; Buil, Alfonso; Carey, Caitlin E.; Cerrato, Felecia; Chambert, Kimberly; Churchhouse, Claire; Dalsgaard, Søren; Demontis, Ditte; DuMont, Ashley L.; Goldstein, Jacqueline I.; Hansen, Christine Søholm; Hauberg, Mads E.; Hollegaard, Mads V.; Howrigan, Daniel P.; Huang, Hailiang; Maller, Julian; Martin, Alicia R.; Martin, Joanna; Mattheisen, Manuel; Moran, Jennifer L.; Pallesen, Jonatan; Palmer, Duncan S.; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Poterba, Timothy; Poulsen, Jesper Buchhave; Ripke, Stephan; Schork, Andrew J.; Thompson, Wesley K.; Turley, Patrick; Walters, Raymond; Betancur, Catalina; Cook, Edwin H.; Gallagher, Louise; Gill, Michael; Sutcliffe, James S.; Thurm, Audrey; Zwick, Michael E.; Børglum, Anders; State, Matthew W.; Çiçek, A. Ercüment; Talkowski, Michael E.; Cutler, David J.; Devlin, Bernie; Sanders, Stephan J.; Roeder, Kathryn; Daly, Mark J.; Buxbaum, Joseph D.

doi:10.1016/j.cell.2019.12.036

Cited by 1,675 publications

(1,650 citation statements)

References 109 publications

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“…In contrast to AD in which multiple glial cells are implicated, previous work has indicated neurons as the central cell type for the majority of psychiatric disorders 3,25,44,[56][57][58][59] . However, given the strong genetic overlap between BD and SCZ 49,60 , we do not have much indication about specific biological pathways that are driving one disease versus the other.…”

Section: Discussionmentioning

confidence: 94%

Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders

Won

Mah

et al. 2020

Preprint

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Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks. We integrated genome-wide chromosome conformation in purified human neurons and glia with bulk and single cell transcriptomic and cell type-specific H3K27ac profiles to elucidate the gene regulatory landscape of two major cell classes in the brain. Frequently interacting regions (FIREs) and super-FIREs were strongly associated with cell type-specific gene expression. We linked enhancers in glutamatergic and GABAergic neurons to their cognate genes via neuronal chromatin interaction profiles. These cell-type-specific regulatory landscapes were then leveraged to gain insight into the cellular etiology of several brain disorders. We found that Alzheimer's disease (AD)-associated epigenetic dysregulation was linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia as a central cell type, suggesting that different cell types may confer risk to the disease via different genetic mechanisms. Moreover, neuronal subtype-specific annotation of genetic risk factors for schizophrenia and bipolar disorder identified shared (parvalbumin-expressing interneurons) and distinct cellular etiology (upper layer neurons for bipolar and deeper layer projection neurons for schizophrenia) between these two closely related psychiatric illnesses. Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.

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Section: Discussionmentioning

confidence: 94%

Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders

Won

Mah

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…I hoped that by explaining the science of autism-how it begins in early fetal brain development through the actions of dozens if not hundreds of autism genes and epigenetic mechanisms-it would help make the evidence showing that vaccines did not cause autism easier to grasp. For example, through whole-exome sequencing on Rachel, my wife Ann, and myself, we identified a potentially new autism gene possibly belonging to a larger group of recently published autism genes encoding neuronal cytoskeleton proteins [17].…”

Section: Defending Sciencementioning

confidence: 99%

Combating antiscience: Are we preparing for the 2020s?

Hotez

2020

PLoS Biol

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In the last half of the 2010s, we saw an upswing in antiscience movements and unprecedented attacks on scientists in the United States and elsewhere. All indications suggest that this trend will not slow or reverse anytime soon, and it is now increasingly apparent that it will fall to the scientists themselves to respond, engage a skeptical public, and lead the defense of science. Accordingly, we must recognize opportunities to both reorganize science doctoral and postdoctoral training and incentivize senior scientists as a means to establish a new ecosystem for science public engagement. Such activities may become essential if the assaults on our profession continue or expand. Today, the commitment of young scientists to public service is at an all-time high. However, we must work quickly to capture that enthusiasm and channel it into a social good, lest we lose this opportunity. Potentially, open-access publishers could play a central role.

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“…C4A co-expression partners at FDR q-value < 0.5 were assessed for enrichment of rare variants identified in neurodevelopmental disorders. These included: ~100 high-confidence autism spectrum disorder (ASD) risk genes harboring rare de novo variants 56,57 ; ASD risk genes harboring rare inherited variants 58 ; genes harboring recurrent de novo copy number variants associated with ASD or SCZ, as compiled in ref 21 ; genes harboring an excess of rare exonic variants in ASD, SCZ, intellectual disability (ID), developmental delay (DD), and epilepsy as assessed through an extended version of transmission and de novo association test (extTADA) 59 ; syndromic and highly ranked (1 and 2) genes from SFARI Gene database; genes harboring disruptive and damaging ultra-rare variants (dURVs) in SCZ 60 ; a list of high-confidence epilepsy risk genes compiled in ref 61 ; 321 high-confidence SCZ risk genes identified in ref 18 ; ten high-confidence SCZ risk genes harboring rare exonic variants as identified by the SCHEMA consortium ( https://schema.broadinstitute.org /). For binary gene sets, statistical enrichment analyses were performed using logistic regression, correcting for linear-and log-transformed gene and transcript lengths as well as GC content.…”

Section: Rare Variant Enrichmentmentioning

confidence: 99%

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia

Kim

Haney

Zhang

et al. 2020

Preprint

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Genome-wide association studies have successfully identified hundreds of genomic regions associated with schizophrenia (SCZ). Subsequent fine-mapping of the strongest association signal, which lies in the major histocompatibility complex (MHC) locus, found that risk for SCZ is partially mediated by complex structural variation of the complement component 4 ( C4 ) genes and resulting increased expression of C4A . Although C4A is believed to partake in synaptic pruning, its precise function in the human brain-and its relation to other SCZ risk factors-remains difficult to examine, due to lack of an appropriate experimental system and lack of evolutionary conservation in model organisms. Here we perform a large-scale functional genomic investigation of the human frontal cortex to characterize the systems-level architecture of C4A co-expression and how this network is remodeled with increased C4A copy number. We identify a putative transcriptomic signature of synaptic pruning as well as spatiotemporal and sex differences in C4A co-expression with largest effects observed in frontal cortical brain regions of middle-aged males. We also find that negative, but not positive, co-expression partners of C4A exhibit substantial enrichment for SNP-heritability in SCZ. In line with this finding, there is limited evidence that the complement system is a core SCZ-relevant pathway in comparison to synaptic components. Overall, our results highlight human brain-specific function of C4A and strong and specific convergence of polygenic effects in SCZ pathophysiology.

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Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Cited by 1,675 publications

References 109 publications

Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders

Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders

Combating antiscience: Are we preparing for the 2020s?

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia

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