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1. Integrative genetic analysis: cornerstone of precision psychiatry

Author: Vorstman, Jacob, Sebat, Jonathan, Bourque, Vincent-Raphaël, and Jacquemont, Sébastien
Published: 2025
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2. Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications

Author: Gur, Ruben C., Bearden, Carrie E., Jacquemont, Sebastien, Swillen, Ann, van Amelsvoort, Therese, van den Bree, Marianne, Vorstman, Jacob, Sebat, Jonathan, Ruparel, Kosha, Gallagher, Robert Sean, McClellan, Emily, White, Lauren, Crowley, Terrence Blaine, Giunta, Victoria, Kushan, Leila, O’Hora, Kathleen, Verbesselt, Jente, Vandensande, Ans, Vingerhoets, Claudia, van Haelst, Mieke, Hall, Jessica, Harwood, Janet, Chawner, Samuel J.R.A., Patel, Nishi, Palad, Katrina, Hong, Oanh, Guevara, James, Martin, Charles Olivier, Jizi, Khadije, Bélanger, Anne-Marie, Scherer, Stephen W., Bassett, Anne S., McDonald-McGinn, Donna M., and Gur, Raquel E.
Published: 2025
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3. A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

Author: de Jong, Tristan V, Pan, Yanchao, Rastas, Pasi, Munro, Daniel, Tutaj, Monika, Akil, Huda, Benner, Chris, Chen, Denghui, Chitre, Apurva S, Chow, William, Colonna, Vincenza, Dalgard, Clifton L, Demos, Wendy M, Doris, Peter A, Garrison, Erik, Geurts, Aron M, Gunturkun, Hakan M, Guryev, Victor, Hourlier, Thibaut, Howe, Kerstin, Huang, Jun, Kalbfleisch, Ted, Kim, Panjun, Li, Ling, Mahaffey, Spencer, Martin, Fergal J, Mohammadi, Pejman, Ozel, Ayse Bilge, Polesskaya, Oksana, Pravenec, Michal, Prins, Pjotr, Sebat, Jonathan, Smith, Jennifer R, Woods, Leah C Solberg, Tabakoff, Boris, Tracey, Alan, Uliano-Silva, Marcela, Villani, Flavia, Wang, Hongyang, Sharp, Burt M, Telese, Francesca, Jiang, Zhihua, Saba, Laura, Wang, Xusheng, Murphy, Terence D, Palmer, Abraham A, Kwitek, Anne E, Dwinell, Melinda R, Williams, Robert W, Li, Jun Z, and Chen, Hao
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, Good Health and Well Being, Rats, Animals, Genome, Molecular Sequence Annotation, Genomics, Whole Genome Sequencing, Genetic Variation, Rnor_6.0, genetic map, heterogeneous stock, hybrid rat diversity panel, inbred strains, mRatBN7.2, phylogenetic tree, rat, recombinant inbred, reference genome
Abstract: The seventh iteration of the reference genome assembly for Rattus norvegicus-mRatBN7.2-corrects numerous misplaced segments and reduces base-level errors by approximately 9-fold and increases contiguity by 290-fold compared with its predecessor. Gene annotations are now more complete, improving the mapping precision of genomic, transcriptomic, and proteomics datasets. We jointly analyzed 163 short-read whole-genome sequencing datasets representing 120 laboratory rat strains and substrains using mRatBN7.2. We defined ∼20.0 million sequence variations, of which 18,700 are predicted to potentially impact the function of 6,677 genes. We also generated a new rat genetic map from 1,893 heterogeneous stock rats and annotated transcription start sites and alternative polyadenylation sites. The mRatBN7.2 assembly, along with the extensive analysis of genomic variations among rat strains, enhances our understanding of the rat genome, providing researchers with an expanded resource for studies involving rats.
Published: 2024

4. Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Author: Maihofer, Adam, Ratanatharathorn, Andrew, Hemmings, Sian, Costenbader, Karen, Michopoulos, Vasiliki, Polimanti, Renato, Rothbaum, Alex, Seedat, Soraya, Mikita, Elizabeth, Smith, Alicia, Salem, Rany, Shaffer, Richard, Wu, Tianying, Sebat, Jonathan, Ressler, Kerry, Stein, Murray, Koenen, Karestan, Wolf, Erika, Sumner, Jennifer, and Nievergelt, Caroline
Subjects: Humans, Stress Disorders, Post-Traumatic, Phenotype, C-Reactive Protein, Autoimmune Diseases, Hashimoto Disease, Biomarkers, Genome-Wide Association Study
Abstract: Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.
Published: 2024

5. Control-independent mosaic single nucleotide variant detection with DeepMosaic

Author: Yang, Xiaoxu, Xu, Xin, Breuss, Martin W, Antaki, Danny, Ball, Laurel L, Chung, Changuk, Shen, Jiawei, Li, Chen, George, Renee D, Wang, Yifan, Bae, Taejeong, Cheng, Yuhe, Abyzov, Alexej, Wei, Liping, Alexandrov, Ludmil B, Sebat, Jonathan L, and Gleeson, Joseph G
Subjects: Genetics, Prevention, Brain Disorders, Human Genome, Underpinning research, 1.1 Normal biological development and functioning, Software, Whole Genome Sequencing, Exome Sequencing, Exome, High-Throughput Nucleotide Sequencing, Polymorphism, Single Nucleotide, Nucleotides, NIMH Brain Somatic Mosaicism Network
Abstract: Mosaic variants (MVs) reflect mutagenic processes during embryonic development and environmental exposure, accumulate with aging and underlie diseases such as cancer and autism. The detection of noncancer MVs has been computationally challenging due to the sparse representation of nonclonally expanded MVs. Here we present DeepMosaic, combining an image-based visualization module for single nucleotide MVs and a convolutional neural network-based classification module for control-independent MV detection. DeepMosaic was trained on 180,000 simulated or experimentally assessed MVs, and was benchmarked on 619,740 simulated MVs and 530 independent biologically tested MVs from 16 genomes and 181 exomes. DeepMosaic achieved higher accuracy compared with existing methods on biological data, with a sensitivity of 0.78, specificity of 0.83 and positive predictive value of 0.96 on noncancer whole-genome sequencing data, as well as doubling the validation rate over previous best-practice methods on noncancer whole-exome sequencing data (0.43 versus 0.18). DeepMosaic represents an accurate MV classifier for noncancer samples that can be implemented as an alternative or complement to existing methods.
Published: 2023

6. Rare copy number variation in posttraumatic stress disorder

Author: Maihofer, Adam X, Engchuan, Worrawat, Huguet, Guillaume, Klein, Marieke, MacDonald, Jeffrey R, Shanta, Omar, Thiruvahindrapuram, Bhooma, Jean-louis, Martineau, Saci, Zohra, Jacquemont, Sebastien, Scherer, Stephen W, Ketema, Elizabeth, Aiello, Allison E, Amstadter, Ananda B, Avdibegović, Esmina, Babic, Dragan, Baker, Dewleen G, Bisson, Jonathan I, Boks, Marco P, Bolger, Elizabeth A, Bryant, Richard A, Bustamante, Angela C, Caldas-de-Almeida, Jose Miguel, Cardoso, Graça, Deckert, Jurgen, Delahanty, Douglas L, Domschke, Katharina, Dunlop, Boadie W, Dzubur-Kulenovic, Alma, Evans, Alexandra, Feeny, Norah C, Franz, Carol E, Gautam, Aarti, Geuze, Elbert, Goci, Aferdita, Hammamieh, Rasha, Jakovljevic, Miro, Jett, Marti, Jones, Ian, Kaufman, Milissa L, Kessler, Ronald C, King, Anthony P, Kremen, William S, Lawford, Bruce R, Lebois, Lauren AM, Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D, Lugonja, Bozo, Luykx, Jurjen J, Lyons, Michael J, Mavissakalian, Matig R, McLaughlin, Katie A, McLean, Samuel A, Mehta, Divya, Mellor, Rebecca, Morris, Charles Phillip, Muhie, Seid, Orcutt, Holly K, Peverill, Matthew, Ratanatharathorn, Andrew, Risbrough, Victoria B, Rizzo, Albert, Roberts, Andrea L, Rothbaum, Alex O, Rothbaum, Barbara O, Roy-Byrne, Peter, Ruggiero, Kenneth J, Rutten, Bart PF, Schijven, Dick, Seng, Julia S, Sheerin, Christina M, Sorenson, Michael A, Teicher, Martin H, Uddin, Monica, Ursano, Robert J, Vinkers, Christiaan H, Voisey, Joanne, Weber, Heike, Winternitz, Sherry, Xavier, Miguel, Yang, Ruoting, McD Young, Ross, Zoellner, Lori A, Salem, Rany M, Shaffer, Richard A, Wu, Tianying, Ressler, Kerry J, Stein, Murray B, Koenen, Karestan C, Sebat, Jonathan, and Nievergelt, Caroline M
Subjects: Post-Traumatic Stress Disorder (PTSD), Mental Health, Human Genome, Genetics, Neurosciences, Brain Disorders, Mental health, Humans, DNA Copy Number Variations, Stress Disorders, Post-Traumatic, Genome, Brain, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Psychiatric Genomics Consortium PTSD Working Group, Psychiatric Genomics Consortium CNV Working Group, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract: Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q
Published: 2022

7. Genomic architecture of autism from comprehensive whole-genome sequence annotation.

Author: Trost, Brett, Thiruvahindrapuram, Bhooma, Chan, Ada, Engchuan, Worrawat, Higginbotham, Edward, Howe, Jennifer, Loureiro, Livia, Reuter, Miriam, Roshandel, Delnaz, Whitney, Joe, Zarrei, Mehdi, Bookman, Matthew, Somerville, Cherith, Shaath, Rulan, Abdi, Mona, Aliyev, Elbay, Patel, Rohan, Nalpathamkalam, Thomas, Pellecchia, Giovanna, Hamdan, Omar, Kaur, Gaganjot, Wang, Zhuozhi, MacDonald, Jeffrey, Wei, John, Sung, Wilson, Lamoureux, Sylvia, Hoang, Ny, Selvanayagam, Thanuja, Deflaux, Nicole, Geng, Melissa, Ghaffari, Siavash, Bates, John, Young, Edwin, Ding, Qiliang, Shum, Carole, DAbate, Lia, Bradley, Clarrisa, Rutherford, Annabel, Aguda, Vernie, Apresto, Beverly, Chen, Nan, Desai, Sachin, Du, Xiaoyan, Fong, Matthew, Pullenayegum, Sanjeev, Samler, Kozue, Wang, Ting, Ho, Karen, Paton, Tara, Pereira, Sergio, Herbrick, Jo-Anne, Wintle, Richard, Fuerth, Jonathan, Noppornpitak, Juti, Ward, Heather, Magee, Patrick, Al Baz, Ayman, Kajendirarajah, Usanthan, Kapadia, Sharvari, Vlasblom, Jim, Valluri, Monica, Green, Joseph, Seifer, Vicki, Quirbach, Morgan, Rennie, Olivia, Kelley, Elizabeth, Masjedi, Nina, Lord, Catherine, Szego, Michael, Zawati, Man, Lang, Michael, Strug, Lisa, Marshall, Christian, Costain, Gregory, Calli, Kristina, Iaboni, Alana, Yusuf, Afiqah, Ambrozewicz, Patricia, Gallagher, Louise, Amaral, David, Brian, Jessica, Elsabbagh, Mayada, Georgiades, Stelios, Messinger, Daniel, Ozonoff, Sally, Sebat, Jonathan, Sjaarda, Calvin, Smith, Isabel, Szatmari, Peter, Zwaigenbaum, Lonnie, Kushki, Azadeh, Frazier, Thomas, Vorstman, Jacob, Fakhro, Khalid, Fernandez, Bridget, Lewis, M, Weksberg, Rosanna, Fiume, Marc, Yuen, Ryan, and Anagnostou, Evdokia
Subjects: autism spectrum disorder, copy-number variation, neurodevelopmental disorders, phenotype measures, polygenic risk scores, rare variants, structural variation, whole-genome sequencing, Humans, Autism Spectrum Disorder, Autistic Disorder, Genetic Predisposition to Disease, DNA Copy Number Variations, Genomics
Abstract: Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.
Published: 2022

8. Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p.

Author: Weiner, Daniel, Ling, Emi, Erdin, Serkan, Tai, Derek, Yadav, Rachita, Grove, Jakob, Fu, Jack, Nadig, Ajay, Carey, Caitlin, Baya, Nikolas, Bybjerg-Grauholm, Jonas, Berretta, Sabina, Macosko, Evan, Sebat, Jonathan, OConnor, Luke, Hougaard, David, Børglum, Anders, Talkowski, Michael, McCarroll, Steven, and Robinson, Elise
Subjects: Humans, Autistic Disorder, DNA Copy Number Variations, Chromosomes, Chromosome Deletion, Chromosomes, Human, Pair 16
Abstract: The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autisms common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.
Published: 2022

9. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Author: Antaki, Danny, Guevara, James, Maihofer, Adam X, Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E, Hong, Oanh, Arranz, Maria J, Hervas, Amaia, Corsello, Christina, Vaux, Keith K, Muotri, Alysson R, Iakoucheva, Lilia M, Courchesne, Eric, Pierce, Karen, Gleeson, Joseph G, Robinson, Elise B, Nievergelt, Caroline M, and Sebat, Jonathan
Subjects: Biological Sciences, Genetics, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Autism, Mental Health, Neurosciences, Prevention, Pediatric, 2.1 Biological and endogenous factors, 2.4 Surveillance and distribution, Mental health, Autism Spectrum Disorder, Autistic Disorder, Child, Family, Female, Genetic Predisposition to Disease, Humans, Male, Multifactorial Inheritance, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.
Published: 2022

10. Genes To Mental Health (G2MH): A Framework to Map the Combined Effects of Rare and Common Variants on Dimensions of Cognition and Psychopathology

Author: Jacquemont, Sébastien, Huguet, Guillaume, Klein, Marieke, Chawner, Samuel JRA, Donald, Kirsten A, van den Bree, Marianne BM, Sebat, Jonathan, Ledbetter, David H, Constantino, John N, Earl, Rachel K, McDonald-McGinn, Donna M, van Amelsvoort, Therese, Swillen, Ann, O’Donnell-Luria, Anne H, Glahn, David C, Almasy, Laura, Eichler, Evan E, Scherer, Stephen W, Robinson, Elise, Bassett, Anne S, Martin, Christa Lese, Finucane, Brenda, Vorstman, Jacob AS, Bearden, Carrie E, and Gur, Raquel E
Subjects: Clinical and Health Psychology, Biomedical and Clinical Sciences, Clinical Sciences, Psychology, Behavioral and Social Science, Biotechnology, Human Genome, Brain Disorders, Mental Health, Genetics, Basic Behavioral and Social Science, Mental health, Good Health and Well Being, Cognition, Humans, Mental Disorders, Psychiatry, Psychopathology, Genes to Mental Health Network, Autism Spectrum Disorder, Diagnosis and Classification, Genetics/Genomics, Intellectual Disabilities, Neurodevelopmental Disorders, Schizophrenia Spectrum and Other Psychotic Disorders, Medical and Health Sciences, Psychology and Cognitive Sciences, Clinical sciences, Clinical and health psychology
Abstract: Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition, and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes to Mental Health Network (G2MH) is a newly funded National Institute of Mental Health initiative that will collect, share, and analyze large-scale data sets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. The authors present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions and discuss strategies that will be pursued within the G2MH network, as well as how expected results can be translated into clinical practice to improve patient outcomes.
Published: 2022

11. Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism

Author: Urresti, Jorge, Zhang, Pan, Moran-Losada, Patricia, Yu, Nam-Kyung, Negraes, Priscilla D, Trujillo, Cleber A, Antaki, Danny, Amar, Megha, Chau, Kevin, Pramod, Akula Bala, Diedrich, Jolene, Tejwani, Leon, Romero, Sarah, Sebat, Jonathan, Yates III, John R, Muotri, Alysson R, and Iakoucheva, Lilia M
Subjects: Biomedical and Clinical Sciences, Neurosciences, Stem Cell Research - Induced Pluripotent Stem Cell, Pediatric, Mental Health, Intellectual and Developmental Disabilities (IDD), Human Genome, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research, Autism, Brain Disorders, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological, Autism Spectrum Disorder, Autistic Disorder, Brain, Chromosome Deletion, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Humans, Neurogenesis, Organoids, Proteomics, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: Reciprocal deletion and duplication of the 16p11.2 region is the most common copy number variation (CNV) associated with autism spectrum disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV dosage affects neuronal maturation, proliferation, and synapse number, in addition to its effect on organoid size. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with a significant excess of neurons and depletion of neural progenitors observed in deletions. Transcriptomic and proteomic profiling revealed multiple pathways dysregulated by the 16p11.2 CNV, including neuron migration, actin cytoskeleton, ion channel activity, synaptic-related functions, and Wnt signaling. The level of the active form of small GTPase RhoA was increased in both, deletions and duplications. Inhibition of RhoA activity rescued migration deficits, but not neurite outgrowth. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.
Published: 2021

12. Author Correction: Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism

Author: Corominas, Roser, Yang, Xinping, Lin, Guan Ning, Kang, Shuli, Shen, Yun, Ghamsari, Lila, Broly, Martin, Rodriguez, Maria, Tam, Stanley, Wanamaker, Shelly A., Fan, Changyu, Yi, Song, Tasan, Murat, Lemmens, Irma, Kuang, Xingyan, Zhao, Nan, Malhotra, Dheeraj, Michaelson, Jacob J., Vacic, Vladimir, Calderwood, Michael A., Roth, Frederick P., Tavernier, Jan, Horvath, Steve, Salehi-Ashtiani, Kourosh, Korkin, Dmitry, Sebat, Jonathan, Hill, David E., Hao, Tong, Vidal, Marc, and Iakoucheva, Lilia M.
Published: 2023
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13. Developmental and temporal characteristics of clonal sperm mosaicism

Author: Yang, Xiaoxu, Breuss, Martin W, Xu, Xin, Antaki, Danny, James, Kiely N, Stanley, Valentina, Ball, Laurel L, George, Renee D, Wirth, Sara A, Cao, Beibei, Nguyen, An, McEvoy-Venneri, Jennifer, Chai, Guoliang, Nahas, Shareef, Van Der Kraan, Lucitia, Ding, Yan, Sebat, Jonathan, and Gleeson, Joseph G
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Women's Health, Human Genome, Health Disparities, Biotechnology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Adolescent, Aging, Alleles, Clone Cells, Cohort Studies, Growth and Development, Humans, Male, Models, Biological, Mosaicism, Mutation, Risk Factors, Spermatozoa, Time Factors, Young Adult, autism spectrum disorder, clonal mosaicism, congenital disorders, de novo mutation, embryogenesis, mutational signature, somatic, sperm, transmission risk, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.
Published: 2021

14. Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

Author: Amar, Megha, Pramod, Akula Bala, Yu, Nam-Kyung, Herrera, Victor Munive, Qiu, Lily R, Moran-Losada, Patricia, Zhang, Pan, Trujillo, Cleber A, Ellegood, Jacob, Urresti, Jorge, Chau, Kevin, Diedrich, Jolene, Chen, Jiaye, Gutierrez, Jessica, Sebat, Jonathan, Ramanathan, Dhakshin, Lerch, Jason P, Yates, John R, Muotri, Alysson R, and Iakoucheva, Lilia M
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Mental Health, Genetics, Human Genome, Autism, Intellectual and Developmental Disabilities (IDD), Neurosciences, Biotechnology, Brain Disorders, Behavioral and Social Science, Pediatric, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Mental health, Animals, Autism Spectrum Disorder, Autistic Disorder, Cullin Proteins, Cytoskeleton, Germ Cells, Haploinsufficiency, Mice, Neurogenesis, Proteomics, autism spectrum disorder, CRISPR/Cas9 mouse model, Cullin 3 ubiquitin ligase, Cul3, Transcriptomics, TMT quantitative proteomics, neurodevelopmental diseases, brain development, genomics, small GTPase RhoA, cytoskeleton, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.
Published: 2021

15. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author: Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.
Published: 2023
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16. The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study

Author: Maihofer, Adam X., Choi, Karmel W., Coleman, Jonathan R.I., Daskalakis, Nikolaos P., Denckla, Christy A., Ketema, Elizabeth, Morey, Rajendra A., Polimanti, Renato, Ratanatharathorn, Andrew, Torres, Katy, Wingo, Aliza P., Zai, Clement C., Aiello, Allison E., Almli, Lynn M., Amstadter, Ananda B., Andersen, Soren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegovic, Esmina, Borglum, Anders D., Babic, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G., Beckham, Jean C., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Bradley, Bekh, Brashear, Meghan, Breen, Gerome, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Calabrese, Joseph R., Caldas-de-Almeida, Jose Miguel, Chen, Chia-Yen, Dale, Anders M., Dalvie, Shareefa, Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Disner, Seth G., Domschke, Katharina, Duncan, Laramie E., Kulenovic, Alma Dzubur, Erbes, Christopher R., Evans, Alexandra, Farrer, Lindsay A., Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gautam, Aarti, Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles F., Uka, Aferdita Goci, Gordon, Scott D., Guffanti, Guia, Hammamieh, Rasha, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M.J., Hougaard, David Michael, Jakovljevic, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue-Jun, Karstoft, Karen-Inge, Kaufman, Milissa L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kranzler, Henry R., Kremen, William S., Lawford, Bruce R., Lebois, Lauren A.M., Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D., Logue, Mark W., Lori, Adriana, Lugonja, Bozo, Luykx, Jurjen J., Lyons, Michael J., Maples-Keller, Jessica L., Marmar, Charles, Martin, Nicholas G., Maurer, Douglas, Mavissakalian, Matig R., McFarlane, Alexander, McGlinchey, Regina E., McLaughlin, Katie A., McLean, Samuel A., Mehta, Divya, Mellor, Rebecca, Michopoulos, Vasiliki, Milberg, William, Miller, Mark W., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben Bo, Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., O’Donnell, Meaghan, Orcutt, Holly K., Panizzon, Matthew S., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Rice, John P., Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Kenneth J., Rung, Ariane, Rutten, Bart P.F., Saccone, Nancy L., Sanchez, Sixto E., Schijven, Dick, Seedat, Soraya, Seligowski, Antonia V., Seng, Julia S., Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Sponheim, Scott R., Stein, Dan J., Stevens, Jennifer S., Teicher, Martin H., Thompson, Wesley K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., Luella van den Heuvel, Leigh, Van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan, Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Yehuda, Rachel, Young, Keith A., Young, Ross McD., Zhao, Hongyu, Zoellner, Lori A., Haas, Magali, Lasseter, Heather, Provost, Allison C., Salem, Rany M., Sebat, Jonathan, Shaffer, Richard, Wu, Tianying, Ripke, Stephan, Daly, Mark J., Ressler, Kerry J., Koenen, Karestan C., Stein, Murray B., Nievergelt, Caroline M., Wendt, Frank R., Garcia-Argibay, Miguel, Cabrera-Mendoza, Brenda, Valdimarsdóttir, Unnur A., Nivard, Michel G., Larsson, Henrik, Mattheisen, Manuel, and Meier, Sandra M.
Published: 2023
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17. Autism risk in offspring can be assessed through quantification of male sperm mosaicism

Author: Breuss, Martin W, Antaki, Danny, George, Renee D, Kleiber, Morgan, James, Kiely N, Ball, Laurel L, Hong, Oanh, Mitra, Ileena, Yang, Xiaoxu, Wirth, Sara A, Gu, Jing, Garcia, Camila AB, Gujral, Madhusudan, Brandler, William M, Musaev, Damir, Nguyen, An, McEvoy-Venneri, Jennifer, Knox, Renatta, Sticca, Evan, Botello, Martha Cristina Cancino, Uribe Fenner, Javiera, Pérez, Maria Cárcel, Arranz, Maria, Moffitt, Andrea B, Wang, Zihua, Hervás, Amaia, Devinsky, Orrin, Gymrek, Melissa, Sebat, Jonathan, and Gleeson, Joseph G
Subjects: Biomedical and Clinical Sciences, Mental Health, Serious Mental Illness, Autism, Intellectual and Developmental Disabilities (IDD), Genetics, Human Genome, Pediatric, Brain Disorders, Contraception/Reproduction, 2.1 Biological and endogenous factors, Aetiology, Autistic Disorder, Female, Genetic Predisposition to Disease, Humans, Male, Mosaicism, Mutation, Pedigree, Polymorphism, Single Nucleotide, Recurrence, Risk Factors, Spermatozoa, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract: De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.
Published: 2020

18. Common DNA sequence variation influences 3-dimensional conformation of the human genome

Author: Gorkin, David U, Qiu, Yunjiang, Hu, Ming, Fletez-Brant, Kipper, Liu, Tristin, Schmitt, Anthony D, Noor, Amina, Chiou, Joshua, Gaulton, Kyle J, Sebat, Jonathan, Li, Yun, Hansen, Kasper D, and Ren, Bing
Subjects: Cancer, Human Genome, Stem Cell Research, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Base Sequence, Epigenome, Genetic Variation, Genome, Human, Humans, Nucleic Acid Conformation, Quantitative Trait Loci, Transcriptome, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Abstract: BACKGROUND:The 3-dimensional (3D) conformation of chromatin inside the nucleus is integral to a variety of nuclear processes including transcriptional regulation, DNA replication, and DNA damage repair. Aberrations in 3D chromatin conformation have been implicated in developmental abnormalities and cancer. Despite the importance of 3D chromatin conformation to cellular function and human health, little is known about how 3D chromatin conformation varies in the human population, or whether DNA sequence variation between individuals influences 3D chromatin conformation. RESULTS:To address these questions, we perform Hi-C on lymphoblastoid cell lines from 20 individuals. We identify thousands of regions across the genome where 3D chromatin conformation varies between individuals and find that this variation is often accompanied by variation in gene expression, histone modifications, and transcription factor binding. Moreover, we find that DNA sequence variation influences several features of 3D chromatin conformation including loop strength, contact insulation, contact directionality, and density of local cis contacts. We map hundreds of quantitative trait loci associated with 3D chromatin features and find evidence that some of these same variants are associated at modest levels with other molecular phenotypes as well as complex disease risk. CONCLUSION:Our results demonstrate that common DNA sequence variants can influence 3D chromatin conformation, pointing to a more pervasive role for 3D chromatin conformation in human phenotypic variation than previously recognized.
Published: 2019

19. A framework for the investigation of rare genetic disorders in neuropsychiatry

Author: Sanders, Stephan J, Sahin, Mustafa, Hostyk, Joseph, Thurm, Audrey, Jacquemont, Sebastien, Avillach, Paul, Douard, Elise, Martin, Christa L, Modi, Meera E, Moreno-De-Luca, Andres, Raznahan, Armin, Anticevic, Alan, Dolmetsch, Ricardo, Feng, Guoping, Geschwind, Daniel H, Glahn, David C, Goldstein, David B, Ledbetter, David H, Mulle, Jennifer G, Pasca, Sergiu P, Samaco, Rodney, Sebat, Jonathan, Pariser, Anne, Lehner, Thomas, Gur, Raquel E, and Bearden, Carrie E
Subjects: Neurosciences, Mental Health, Genetics, Human Genome, Genomics, Humans, Mental Disorders, Neuropsychiatry, Rare Diseases, Medical and Health Sciences, Immunology
Abstract: De novo and inherited rare genetic disorders (RGDs) are a major cause of human morbidity, frequently involving neuropsychiatric symptoms. Recent advances in genomic technologies and data sharing have revolutionized the identification and diagnosis of RGDs, presenting an opportunity to elucidate the mechanisms underlying neuropsychiatric disorders by investigating the pathophysiology of high-penetrance genetic risk factors. Here we seek out the best path forward for achieving these goals. We think future research will require consistent approaches across multiple RGDs and developmental stages, involving both the characterization of shared neuropsychiatric dimensions in humans and the identification of neurobiological commonalities in model systems. A coordinated and concerted effort across patients, families, researchers, clinicians and institutions, including rapid and broad sharing of data, is now needed to translate these discoveries into urgently needed therapies.
Published: 2019

20. Getting to the Cores of Autism

Author: Iakoucheva, Lilia M, Muotri, Alysson R, and Sebat, Jonathan
Subjects: Biological Sciences, Genetics, Pediatric, Neurosciences, Mental Health, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Autism, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Mental health, Animals, Autism Spectrum Disorder, Cells, Cultured, DNA Copy Number Variations, Disease Models, Animal, Gene Regulatory Networks, Genetic Predisposition to Disease, Humans, Multifactorial Inheritance, Neurogenesis, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: The genetic architecture of autism spectrum disorder (ASD) is itself a diverse allelic spectrum that consists of rare de novo or inherited variants in hundreds of genes and common polygenic risk at thousands of loci. ASD susceptibility genes are interconnected at the level of transcriptional and protein networks, and many function as genetic regulators of neurodevelopment or synaptic proteins that regulate neural activity. So that the core underlying neuropathologies can be further elucidated, we emphasize the importance of first defining subtypes of ASD on the basis of the phenotypic signatures of genes in model systems and humans.
Published: 2019

21. Oligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development

Author: Qiu, Yuqi, Arbogast, Thomas, Lorenzo, Sandra Martin, Li, Hongying, Tang, Shih C, Richardson, Ellen, Hong, Oanh, Cho, Shawn, Shanta, Omar, Pang, Timothy, Corsello, Christina, Deutsch, Curtis K, Chevalier, Claire, Davis, Erica E, Iakoucheva, Lilia M, Herault, Yann, Katsanis, Nicholas, Messer, Karen, and Sebat, Jonathan
Subjects: Biological Sciences, Genetics, Congenital Structural Anomalies, Pediatric, Dental/Oral and Craniofacial Disease, Human Genome, 2.1 Biological and endogenous factors, Autistic Disorder, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 16, Craniofacial Abnormalities, DNA Copy Number Variations, Female, Humans, Intellectual Disability, Male, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract: A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have "mirror" effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes.
Published: 2019

22. Multi-platform discovery of haplotype-resolved structural variation in human genomes.

Author: Chaisson, Mark JP, Sanders, Ashley D, Zhao, Xuefang, Malhotra, Ankit, Porubsky, David, Rausch, Tobias, Gardner, Eugene J, Rodriguez, Oscar L, Guo, Li, Collins, Ryan L, Fan, Xian, Wen, Jia, Handsaker, Robert E, Fairley, Susan, Kronenberg, Zev N, Kong, Xiangmeng, Hormozdiari, Fereydoun, Lee, Dillon, Wenger, Aaron M, Hastie, Alex R, Antaki, Danny, Anantharaman, Thomas, Audano, Peter A, Brand, Harrison, Cantsilieris, Stuart, Cao, Han, Cerveira, Eliza, Chen, Chong, Chen, Xintong, Chin, Chen-Shan, Chong, Zechen, Chuang, Nelson T, Lambert, Christine C, Church, Deanna M, Clarke, Laura, Farrell, Andrew, Flores, Joey, Galeev, Timur, Gorkin, David U, Gujral, Madhusudan, Guryev, Victor, Heaton, William Haynes, Korlach, Jonas, Kumar, Sushant, Kwon, Jee Young, Lam, Ernest T, Lee, Jong Eun, Lee, Joyce, Lee, Wan-Ping, Lee, Sau Peng, Li, Shantao, Marks, Patrick, Viaud-Martinez, Karine, Meiers, Sascha, Munson, Katherine M, Navarro, Fabio CP, Nelson, Bradley J, Nodzak, Conor, Noor, Amina, Kyriazopoulou-Panagiotopoulou, Sofia, Pang, Andy WC, Qiu, Yunjiang, Rosanio, Gabriel, Ryan, Mallory, Stütz, Adrian, Spierings, Diana CJ, Ward, Alistair, Welch, AnneMarie E, Xiao, Ming, Xu, Wei, Zhang, Chengsheng, Zhu, Qihui, Zheng-Bradley, Xiangqun, Lowy, Ernesto, Yakneen, Sergei, McCarroll, Steven, Jun, Goo, Ding, Li, Koh, Chong Lek, Ren, Bing, Flicek, Paul, Chen, Ken, Gerstein, Mark B, Kwok, Pui-Yan, Lansdorp, Peter M, Marth, Gabor T, Sebat, Jonathan, Shi, Xinghua, Bashir, Ali, Ye, Kai, Devine, Scott E, Talkowski, Michael E, Mills, Ryan E, Marschall, Tobias, Korbel, Jan O, Eichler, Evan E, and Lee, Charles
Subjects: Humans, Chromosome Mapping, Genomics, Haplotypes, Genome, Human, Algorithms, Databases, Genetic, INDEL Mutation, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Whole Genome Sequencing, Genome, Human, Databases, Genetic
Abstract: The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (
Published: 2019

23. Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Author: Maihofer, Adam X., Choi, Karmel W., Coleman, Jonathan R.I., Daskalakis, Nikolaos P., Denckla, Christy A., Ketema, Elizabeth, Morey, Rajendra A., Polimanti, Renato, Ratanatharathorn, Andrew, Torres, Katy, Wingo, Aliza P., Zai, Clement C., Aiello, Allison E., Almli, Lynn M., Amstadter, Ananda B., Andersen, Soren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegović, Esmina, Borglum, Anders D., Babić, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G., Beckham, Jean C., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Bradley, Bekh, Brashear, Meghan, Breen, Gerome, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Calabrese, Joseph R., Caldas-de-Almeida, José M., Chen, Chia-Yen, Dale, Anders M., Dalvie, Shareefa, Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Disner, Seth G., Domschke, Katharina, Duncan, Laramie E., Džubur Kulenović, Alma, Erbes, Christopher R., Evans, Alexandra, Farrer, Lindsay A., Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gautam, Aarti, Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles F., Goçi, Aferdita, Gordon, Scott D., Guffanti, Guia, Hammamieh, Rasha, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M.J., Hougaard, David Michael, Jakovljević, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue-Jun, Karstoft, Karen-Inge, Kaufman, Milissa L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kranzler, Henry R., Kremen, William S., Lawford, Bruce R., Lebois, Lauren A.M., Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D., Logue, Mark W., Lori, Adriana, Lugonja, Božo, Luykx, Jurjen J., Lyons, Michael J., Maples-Keller, Jessica L., Marmar, Charles, Martin, Nicholas G., Maurer, Douglas, Mavissakalian, Matig R., McFarlane, Alexander, McGlinchey, Regina E., McLaughlin, Katie A., McLean, Samuel A., Mehta, Divya, Mellor, Rebecca, Michopoulos, Vasiliki, Milberg, William, Miller, Mark W., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben B., Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., O’Donnell, Meaghan, Orcutt, Holly K., Panizzon, Matthew S., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Rice, John P., Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Kenneth J., Rung, Ariane, Rutten, Bart P.F., Saccone, Nancy L., Sanchez, Sixto E., Schijven, Dick, Seedat, Soraya, Seligowski, Antonia V., Seng, Julia S., Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Sponheim, Scott R., Stein, Dan J., Stevens, Jennifer S., Teicher, Martin H., Thompson, Wesley K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., van den Heuvel, Leigh Luella, Van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan H., Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Yehuda, Rachel, Young, Keith A., Young, Ross McD., Zhao, Hongyu, Zoellner, Lori A., Haas, Magali, Lasseter, Heather, Provost, Allison C., Salem, Rany M., Sebat, Jonathan, Shaffer, Richard A., Wu, Tianying, Ripke, Stephan, Daly, Mark J., Ressler, Kerry J., Koenen, Karestan C., Stein, Murray B., and Nievergelt, Caroline M.
Published: 2022
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24. SNPs, short tandem repeats, and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains

Author: Mortazavi, Milad, Ren, Yangsu, Saini, Shubham, Antaki, Danny, St. Pierre, Celine L., Williams, April, Sohni, Abhishek, Wilkinson, Miles F., Gymrek, Melissa, Sebat, Jonathan, and Palmer, Abraham A.
Published: 2022
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25. Paternally inherited cis-regulatory structural variants are associated with autism

Author: Brandler, William M, Antaki, Danny, Gujral, Madhusudan, Kleiber, Morgan L, Whitney, Joe, Maile, Michelle S, Hong, Oanh, Chapman, Timothy R, Tan, Shirley, Tandon, Prateek, Pang, Timothy, Tang, Shih C, Vaux, Keith K, Yang, Yan, Harrington, Eoghan, Juul, Sissel, Turner, Daniel J, Thiruvahindrapuram, Bhooma, Kaur, Gaganjot, Wang, Zhuozhi, Kingsmore, Stephen F, Gleeson, Joseph G, Bisson, Denis, Kakaradov, Boyko, Telenti, Amalio, Venter, J Craig, Corominas, Roser, Toma, Claudio, Cormand, Bru, Rueda, Isabel, Guijarro, Silvina, Messer, Karen S, Nievergelt, Caroline M, Arranz, Maria J, Courchesne, Eric, Pierce, Karen, Muotri, Alysson R, Iakoucheva, Lilia M, Hervas, Amaia, Scherer, Stephen W, Corsello, Christina, and Sebat, Jonathan
Subjects: Biological Sciences, Genetics, Pediatric, Mental Health, Clinical Research, Autism, Intellectual and Developmental Disabilities (IDD), Brain Disorders, 2.1 Biological and endogenous factors, Mental health, Autism Spectrum Disorder, Exons, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Mutation, Paternal Inheritance, Pedigree, Promoter Regions, Genetic, RNA, Untranslated, Selection, Genetic, Sequence Deletion, Transcription Factors, General Science & Technology
Abstract: The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.
Published: 2018

26. Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes

Author: Kimura, Hiroki, Nakatochi, Masahiro, Aleksic, Branko, Guevara, James, Toyama, Miho, Hayashi, Yu, Kato, Hidekazu, Kushima, Itaru, Morikawa, Mako, Ishizuka, Kanako, Okada, Takashi, Tsurusaki, Yoshinori, Fujita, Atsushi, Miyake, Noriko, Ogi, Tomoo, Takata, Atsushi, Matsumoto, Naomichi, Buxbaum, Joseph, Ozaki, Norio, and Sebat, Jonathan
Published: 2022
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27. Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

Author: Huguet, Guillaume, primary, Renne, Thomas, additional, Poulain, Cecile, additional, Dubuc, Alma, additional, Kumar, Kuldeep, additional, Kazem, Sayeh, additional, Engchuan, Worrawat Bank, additional, Shanta, Omar, additional, Douard, Elise, additional, Proulx, Catherine, additional, Jean-Louis, Martineau, additional, Saci, Zohra, additional, Mollon, Josephine, additional, Schultz, Laura M, additional, Knowles, Emma EM, additional, Cox, Simon R, additional, Porteous, David, additional, Davies, Gail, additional, Redmond, Paul, additional, Harris, Sarah E, additional, Schumann, Gunter, additional, Dumas, Guillaume, additional, Labbe, Aurelie, additional, Pausova, Zdenka, additional, Paus, Tomas, additional, Scherer, Stephen W., additional, Sebat, Jonathan, additional, Almasy, Laura, additional, Glahn, David C, additional, and Jacquemont, Sebastien, additional
Published: 2024
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28. Frequency and Complexity of De Novo Structural Mutation in Autism

Author: Brandler, William M, Antaki, Danny, Gujral, Madhusudan, Noor, Amina, Rosanio, Gabriel, Chapman, Timothy R, Barrera, Daniel J, Lin, Guan Ning, Malhotra, Dheeraj, Watts, Amanda C, Wong, Lawrence C, Estabillo, Jasper A, Gadomski, Therese E, Hong, Oanh, Fajardo, Karin V Fuentes, Bhandari, Abhishek, Owen, Renius, Baughn, Michael, Yuan, Jeffrey, Solomon, Terry, Moyzis, Alexandra G, Maile, Michelle S, Sanders, Stephan J, Reiner, Gail E, Vaux, Keith K, Strom, Charles M, Zhang, Kang, Muotri, Alysson R, Akshoomoff, Natacha, Leal, Suzanne M, Pierce, Karen, Courchesne, Eric, Iakoucheva, Lilia M, Corsello, Christina, and Sebat, Jonathan
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Pediatric, Autism, Human Genome, Brain Disorders, Mental Health, Intellectual and Developmental Disabilities (IDD), Biotechnology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Alleles, Amino Acid Sequence, Autism Spectrum Disorder, Base Sequence, Case-Control Studies, Child, DNA Copy Number Variations, Female, Gene Deletion, Gene Duplication, Gene Frequency, Gene Rearrangement, Genetic Loci, Genome, Human, Genotyping Techniques, Humans, INDEL Mutation, Male, Microarray Analysis, Molecular Sequence Data, Pedigree, Reproducibility of Results, Sensitivity and Specificity, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.
Published: 2016

29. The Influence of Microdeletions and Microduplications of 16p11.2 on Global Transcription Profiles

Author: Kusenda, Mary, Vacic, Vladimir, Malhotra, Dheeraj, Rodgers, Linda, Pavon, Kevin, Meth, Jennifer, Kumar, Ravinesh A, Christian, Susan L, Peeters, Hilde, Cho, Shawn S, Addington, Anjene, Rapoport, Judith L, and Sebat, Jonathan
Subjects: Brain Disorders, Human Genome, Neurosciences, Biotechnology, Mental Health, Genetics, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, Autism Spectrum Disorder, Cell Line, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Gene Duplication, Gene Expression, Head, Herpesvirus 4, Human, Humans, Lymph Nodes, Microarray Analysis, Organ Size, Real-Time Polymerase Chain Reaction, Schizophrenia, Sequence Deletion, Transcriptome, 16p11.2, autism spectrum disorders, copy number variation, gene expression, schizophrenia, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract: Copy number variants (CNVs) of a 600 kb region on 16p11.2 are associated with neurodevelopmental disorders and changes in brain volume. The authors hypothesize that abnormal brain development associated with this CNV can be attributed to changes in transcriptional regulation. The authors determined the effects of 16p11.2 dosage on gene expression by transcription profiling of lymphoblast cell lines derived from 6 microdeletion carriers, 15 microduplication carriers and 15 controls. Gene dosage had a significant influence on the transcript abundance of a majority (20/34) of genes within the CNV region. In addition, a limited number of genes were dysregulated in trans. Genes most strongly correlated with patient head circumference included SULT1A, KCTD13, and TMEM242. Given the modest effect of 16p11.2 copy number on global transcriptional regulation in lymphocytes, larger studies utilizing neuronal cell types may be needed in order to elucidate the signaling pathways that influence brain development in this genetic disorder.
Published: 2015

30. An integrated map of structural variation in 2,504 human genomes.

Author: Sudmant, Peter H, Rausch, Tobias, Gardner, Eugene J, Handsaker, Robert E, Abyzov, Alexej, Huddleston, John, Zhang, Yan, Ye, Kai, Jun, Goo, Fritz, Markus Hsi-Yang, Konkel, Miriam K, Malhotra, Ankit, Stütz, Adrian M, Shi, Xinghua, Casale, Francesco Paolo, Chen, Jieming, Hormozdiari, Fereydoun, Dayama, Gargi, Chen, Ken, Malig, Maika, Chaisson, Mark JP, Walter, Klaudia, Meiers, Sascha, Kashin, Seva, Garrison, Erik, Auton, Adam, Lam, Hugo YK, Mu, Xinmeng Jasmine, Alkan, Can, Antaki, Danny, Bae, Taejeong, Cerveira, Eliza, Chines, Peter, Chong, Zechen, Clarke, Laura, Dal, Elif, Ding, Li, Emery, Sarah, Fan, Xian, Gujral, Madhusudan, Kahveci, Fatma, Kidd, Jeffrey M, Kong, Yu, Lameijer, Eric-Wubbo, McCarthy, Shane, Flicek, Paul, Gibbs, Richard A, Marth, Gabor, Mason, Christopher E, Menelaou, Androniki, Muzny, Donna M, Nelson, Bradley J, Noor, Amina, Parrish, Nicholas F, Pendleton, Matthew, Quitadamo, Andrew, Raeder, Benjamin, Schadt, Eric E, Romanovitch, Mallory, Schlattl, Andreas, Sebra, Robert, Shabalin, Andrey A, Untergasser, Andreas, Walker, Jerilyn A, Wang, Min, Yu, Fuli, Zhang, Chengsheng, Zhang, Jing, Zheng-Bradley, Xiangqun, Zhou, Wanding, Zichner, Thomas, Sebat, Jonathan, Batzer, Mark A, McCarroll, Steven A, 1000 Genomes Project Consortium, Mills, Ryan E, Gerstein, Mark B, Bashir, Ali, Stegle, Oliver, Devine, Scott E, Lee, Charles, Eichler, Evan E, and Korbel, Jan O
Subjects: Genomes Project Consortium, Humans, Genetic Predisposition to Disease, Physical Chromosome Mapping, Sequence Analysis, DNA, Genetics, Medical, Genetics, Population, Genomics, Sequence Deletion, Amino Acid Sequence, Genotype, Haplotypes, Homozygote, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Molecular Sequence Data, Genetic Variation, Genome-Wide Association Study, Mutation Rate, Sequence Analysis, DNA, Genetics, Medical, Population, Polymorphism, Single Nucleotide, Genome, Human, General Science & Technology
Abstract: Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.
Published: 2015

31. Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene

Author: Bodkin, J. Alexander, Coleman, Michael J., Godfrey, Laura J., Carvalho, Claudia M.B., Morgan, Charity J., Suckow, Raymond F., Anderson, Thea, Öngür, Dost, Kaufman, Marc J., Lewandowski, Kathryn E., Siegel, Arthur J., Waldstreicher, Elliot, Grochowski, Christopher M., Javitt, Daniel C., Rujescu, Dan, Hebbring, Scott, Weinshilboum, Richard, Rodriguez, Stephanie Burgos, Kirchhoff, Colette, Visscher, Timothy, Vuckovic, Alexander, Fialkowski, Allison, McCarthy, Shane, Malhotra, Dheeraj, Sebat, Jonathan, Goff, Donald C., Hudson, James I., Lupski, James R., Coyle, Joseph T., Rudolph, Uwe, and Levy, Deborah L.
Published: 2019
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32. Publisher Correction: A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Author: Antaki, Danny, Guevara, James, Maihofer, Adam X., Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E., Hong, Oanh, Arranz, Maria J., Hervas, Amaia, Corsello, Christina, Vaux, Keith K., Muotri, Alysson R., Iakoucheva, Lilia M., Courchesne, Eric, Pierce, Karen, Gleeson, Joseph G., Robinson, Elise B., Nievergelt, Caroline M., and Sebat, Jonathan
Published: 2022
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33. Neurocognitive Profiles of 22q11.2 and 16p11.2 Deletions and Duplications

Author: Gur, Ruben, primary, Bearden, Carrie, additional, Jacquemont, Sébastien, additional, Jizi, Khadije, additional, van, Therese Amelsvoort, additional, Bree, Marianne van den, additional, Vorstman, Jacob, additional, Sebat, Jonathan, additional, Ruparel, Kosha, additional, Gallagher, Robert, additional, Swillen, Ann, additional, McClellan, Emily, additional, White, Lauren, additional, Crowley, Terrence, additional, Giunta, Victoria, additional, Kushan, Leila, additional, O’Hora, Kathleen, additional, Verbesselt, Jente, additional, Vandensande, Ans, additional, Vingerhoets, Claudia, additional, Haelst, Mieke van, additional, Hall, Jessica, additional, Harwood, Janet, additional, Chawner, Samuel, additional, Patel, Nishi, additional, Palad, Katrina, additional, Hong, Oanh, additional, Guevara, James, additional, Martin, Charles-Olivier, additional, Bélanger, Anne-Marie, additional, Scherer, Stephen, additional, Bassett, Anne, additional, McDonald-McGinn, Donna, additional, and Gur, Raquel, additional
Published: 2023
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34. Modeling the Interplay Between Neurons and Astrocytes in Autism Using Human Induced Pluripotent Stem Cells

Author: Russo, Fabiele Baldino, Freitas, Beatriz Camille, Pignatari, Graciela Conceição, Fernandes, Isabella Rodrigues, Sebat, Jonathan, Muotri, Alysson Renato, and Beltrão-Braga, Patricia Cristina Baleeiro
Published: 2018
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35. Formation of Chimeric Genes by Copy-Number Variation as a Mutational Mechanism in Schizophrenia

Author: Rippey, Caitlin, Walsh, Tom, Gulsuner, Suleyman, Brodsky, Matt, Nord, Alex S, Gasperini, Molly, Pierce, Sarah, Spurrell, Cailyn, Coe, Bradley P, Krumm, Niklas, Lee, Ming K, Sebat, Jonathan, McClellan, Jon M, and King, Mary-Claire
Subjects: Mental Health, Genetics, Neurosciences, Schizophrenia, Biotechnology, Human Genome, Brain Disorders, 1.1 Normal biological development and functioning, Underpinning research, Mental health, Adolescent, Adult, Brain, Case-Control Studies, Cell Line, Child, DNA Copy Number Variations, Gene Deletion, Genes, Duplicate, Genetic Predisposition to Disease, Genome, Human, HEK293 Cells, Humans, Mutant Chimeric Proteins, RNA, Messenger, Young Adult, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Chimeric genes can be caused by structural genomic rearrangements that fuse together portions of two different genes to create a novel gene. We hypothesize that brain-expressed chimeras may contribute to schizophrenia. Individuals with schizophrenia and control individuals were screened genome wide for copy-number variants (CNVs) that disrupted two genes on the same DNA strand. Candidate events were filtered for predicted brain expression and for frequency < 0.001 in an independent series of 20,000 controls. Four of 124 affected individuals and zero of 290 control individuals harbored such events (p = 0.002); a 47 kb duplication disrupted MATK and ZFR2, a 58 kb duplication disrupted PLEKHD1 and SLC39A9, a 121 kb duplication disrupted DNAJA2 and NETO2, and a 150 kb deletion disrupted MAP3K3 and DDX42. Each fusion produced a stable protein when exogenously expressed in cultured cells. We examined whether these chimeras differed from their parent genes in localization, regulation, or function. Subcellular localizations of DNAJA2-NETO2 and MAP3K3-DDX42 differed from their parent genes. On the basis of the expression profile of the MATK promoter, MATK-ZFR2 is likely to be far more highly expressed in the brain during development than the ZFR2 parent gene. MATK-ZFR2 includes a ZFR2-derived isoform that we demonstrate localizes preferentially to neuronal dendritic branch sites. These results suggest that the formation of chimeric genes is a mechanism by which CNVs contribute to schizophrenia and that, by interfering with parent gene function, chimeras may disrupt critical brain processes, including neurogenesis, neuronal differentiation, and dendritic arborization.
Published: 2013

36. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.

Author: Vacic, Vladimir, McCarthy, Shane, Malhotra, Dheeraj, Murray, Fiona, Chou, Hsun-Hua, Peoples, Aine, Makarov, Vladimir, Yoon, Seungtai, Bhandari, Abhishek, Corominas, Roser, Iakoucheva, Lilia M, Krastoshevsky, Olga, Krause, Verena, Larach-Walters, Verónica, Welsh, David K, Craig, David, Kelsoe, John R, Gershon, Elliot S, Leal, Suzanne M, Dell Aquila, Marie, Morris, Derek W, Gill, Michael, Corvin, Aiden, Insel, Paul A, McClellan, Jon, King, Mary-Claire, Karayiorgou, Maria, Levy, Deborah L, DeLisi, Lynn E, and Sebat, Jonathan
Subjects: Cell Line, Chromosomes, Human, Pair 7, Humans, Genetic Predisposition to Disease, Cyclic AMP, Cohort Studies, Reproducibility of Results, Pedigree, Schizophrenia, Signal Transduction, Transcription, Genetic, Gene Dosage, Inheritance Patterns, Genes, Duplicate, Female, Male, Receptors, Vasoactive Intestinal Peptide, Type II, Genome-Wide Association Study, DNA Copy Number Variations, General Science & Technology
Abstract: Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.
Published: 2011

37. Mapping copy number variation by population-scale genome sequencing.

Author: Mills, Ryan, Walter, Klaudia, Stewart, Chip, Handsaker, Robert, Chen, Ken, Alkan, Can, Abyzov, Alexej, Yoon, Seungtai, Ye, Kai, Cheetham, R, Chinwalla, Asif, Conrad, Donald, Fu, Yutao, Grubert, Fabian, Hajirasouliha, Iman, Hormozdiari, Fereydoun, Iakoucheva, Lilia, Iqbal, Zamin, Kang, Shuli, Kidd, Jeffrey, Konkel, Miriam, Korn, Joshua, Khurana, Ekta, Kural, Deniz, Lam, Hugo, Leng, Jing, Li, Ruiqiang, Li, Yingrui, Lin, Chang-Yun, Luo, Ruibang, Mu, Xinmeng, Nemesh, James, Peckham, Heather, Rausch, Tobias, Scally, Aylwyn, Shi, Xinghua, Stromberg, Michael, Stütz, Adrian, Urban, Alexander, Walker, Jerilyn, Wu, Jiantao, Zhang, Yujun, Zhang, Zhengdong, Batzer, Mark, Ding, Li, Marth, Gabor, McVean, Gil, Sebat, Jonathan, Snyder, Michael, Wang, Jun, Ye, Kenny, Eichler, Evan, Gerstein, Mark, Hurles, Matthew, Lee, Charles, McCarroll, Steven, and Korbel, Jan
Subjects: DNA Copy Number Variations, Gene Duplication, Genetic Predisposition to Disease, Genetics, Population, Genome, Human, Genomics, Genotype, Humans, Mutagenesis, Insertional, Reproducibility of Results, Sequence Analysis, DNA, Sequence Deletion
Abstract: Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.
Published: 2011

38. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

Author: Girirajan, Santhosh, Rosenfeld, Jill A, Cooper, Gregory M, Antonacci, Francesca, Siswara, Priscillia, Itsara, Andy, Vives, Laura, Walsh, Tom, McCarthy, Shane E, Baker, Carl, Mefford, Heather C, Kidd, Jeffrey M, Browning, Sharon R, Browning, Brian L, Dickel, Diane E, Levy, Deborah L, Ballif, Blake C, Platky, Kathryn, Farber, Darren M, Gowans, Gordon C, Wetherbee, Jessica J, Asamoah, Alexander, Weaver, David D, Mark, Paul R, Dickerson, Jennifer, Garg, Bhuwan P, Ellingwood, Sara A, Smith, Rosemarie, Banks, Valerie C, Smith, Wendy, McDonald, Marie T, Hoo, Joe J, French, Beatrice N, Hudson, Cindy, Johnson, John P, Ozmore, Jillian R, Moeschler, John B, Surti, Urvashi, Escobar, Luis F, El-Khechen, Dima, Gorski, Jerome L, Kussmann, Jennifer, Salbert, Bonnie, Lacassie, Yves, Biser, Alisha, McDonald-McGinn, Donna M, Zackai, Elaine H, Deardorff, Matthew A, Shaikh, Tamim H, Haan, Eric, Friend, Kathryn L, Fichera, Marco, Romano, Corrado, Gécz, Jozef, DeLisi, Lynn E, Sebat, Jonathan, King, Mary-Claire, Shaffer, Lisa G, and Eichler, Evan E
Subjects: Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Neurosciences, Brain Disorders, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Adult, Case-Control Studies, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Developmental Disabilities, Family, Gene Frequency, Humans, Infant, Models, Genetic, Oligonucleotide Array Sequence Analysis, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Recurrence, Severity of Illness Index, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.
Published: 2010

39. Large-Scale Copy Number Polymorphism in the Human Genome

Author: Sebat, Jonathan, Lakshmi, B., Troge, Jennifer, Alexander, Joan, Young, Janet, Lundin, Pär, Månér, Susanne, Massa, Hillary, Walker, Megan, Chi, Maoyen, Navin, Nicholas, Lucito, Robert, Healy, John, Hicks, James, Ye, Kenny, Reiner, Andrew, Gilliam, T. Conrad, Trask, Barbara, Patterson, Nick, Zetterberg, Anders, and Wigler, Michael
Published: 2004

40. Distribution of Short Paired Duplications in Mammalian Genomes

Author: Thomas, Elizabeth E., Srebro, Nathan, Sebat, Jonathan, Navin, Nicholas, Healy, John, Mishra, Bud, and Wigler, Michael
Published: 2004

41. Microduplications of 16p11.2 are associated with schizophrenia

Author: McCarthy, Shane E, Makarov, Vladimir, Kirov, George, Addington, Anjene M, McClellan, Jon, Yoon, Seungtai, Perkins, Diana O, Dickel, Diane E, Kusenda, Mary, Krastoshevsky, Olga, Krause, Verena, Kumar, Ravinesh A, Grozeva, Detelina, Malhotra, Dheeraj, Walsh, Tom, Zackai, Elaine H, Kaplan, Paige, Ganesh, Jaya, Krantz, Ian D, Spinner, Nancy B, Roccanova, Patricia, Bhandari, Abhishek, Pavon, Kevin, Lakshmi, B, Leotta, Anthony, Kendall, Jude, Lee, Yoon-ha, Vacic, Vladimir, Gary, Sydney, Iakoucheva, Lilia M, Crow, Timothy J, Christian, Susan L, Lieberman, Jeffrey A, Stroup, T Scott, Lehtimäki, Terho, Puura, Kaija, Haldeman-Englert, Chad, Pearl, Justin, Goodell, Meredith, Willour, Virginia L, DeRosse, Pamela, Steele, Jo, Kassem, Layla, Wolff, Jessica, Chitkara, Nisha, McMahon, Francis J, Malhotra, Anil K, Potash, James B, Schulze, Thomas G, Nöthen, Markus M, Cichon, Sven, Rietschel, Marcella, Leibenluft, Ellen, Kustanovich, Vlad, Lajonchere, Clara M, Sutcliffe, James S, Skuse, David, Gill, Michael, Gallagher, Louise, Mendell, Nancy R, Craddock, Nick, Owen, Michael J, O'Donovan, Michael C, Shaikh, Tamim H, Susser, Ezra, DeLisi, Lynn E, Sullivan, Patrick F, Deutsch, Curtis K, Rapoport, Judith, Levy, Deborah L, King, Mary-Claire, and Sebat, Jonathan
Subjects: Mental health, Chromosomes, Human, Pair 16, Gene Duplication, Genetic Predisposition to Disease, Humans, Risk Factors, Schizophrenia, Wellcome Trust Case Control Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
Published: 2009

42. 70. GENE-BASED ANALYSIS OF RARE CNVS ACROSS SIX PSYCHIATRIC DISORDERS IDENTIFIES COMMON BIOLOGICAL COMPONENTS BUT DISTINCTLY DIFFERENT GENETIC EFFECTS IN AUTISM AND SCHIZOPHRENIA

Author: Engchuan, Worrawat, primary, Thiruvahindrapuram, Bhooma, additional, MacDonald, Jeffrey R., additional, Shanta, Omar, additional, Kumar, Kuldeep, additional, Klein, Marieke, additional, Huguet, Guillaume, additional, Wang, Zhuozhi, additional, Pellecchia, Giovanna, additional, Yuen, Ryan KC, additional, Merico, Daniele, additional, Jacquemont, Sebastien, additional, Scherer, Stephen W., additional, and Sebat, Jonathan, additional
Published: 2023
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43. W56. UNRAVELING THE IMPACT OF GENOMIC VARIATIONS ON COGNITIVE ABILITY ACROSS THE HUMAN CORTEX: INSIGHTS FROM GENE EXPRESSION AND COPY NUMBER VARIANTS

Author: Kumar, Kuldeep, primary, Kazem, Sayeh, additional, Huguet, Guillaume, additional, Renne, Thomas, additional, Engchuan, Bank, additional, Shanta, Omar, additional, Thiruvahindrapuram, Bhooma, additional, MacDonald, Jeff, additional, Klein, Marieke, additional, Scherer, Stephen, additional, Almasy, Laura, additional, Sebat, Jonathan, additional, Glahn, David, additional, Dumas, Guillaume, additional, and Jacquemont, Sébastien, additional
Published: 2023
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44. 69. GENOME-WIDE ASSOCIATION OF COPY NUMBER VARIANTS ACROSS SIX MAJOR PSYCHIATRIC DISORDERS REVEALS GENOTYPE-PHENOTYPE RELATIONSHIPS OF RARE VARIANTS

Author: Shanta, Omar, primary, Enghuan, Worrawat, additional, MacDonald, Jeffrey Jeffrey, additional, Thiruvahindrapuram, Bhooma, additional, Klein, Marieke, additional, Maihofer, Adam, additional, Jacquemont, Sebastien, additional, Kendall, Kimberley, additional, Sonderby, Ida, additional, Huguet, Guillaume, additional, Kumar, Kuldeep, additional, Schmilovich, Zoe, additional, Scherer, Stephen, additional, and Sebat, Jonathan, additional
Published: 2023
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45. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author: Maury, Eduardo A., primary, Sherman, Maxwell A., additional, Genovese, Giulio, additional, Gilgenast, Thomas G., additional, Kamath, Tushar, additional, Burris, S.J., additional, Rajarajan, Prashanth, additional, Flaherty, Erin, additional, Akbarian, Schahram, additional, Chess, Andrew, additional, McCarroll, Steven A., additional, Loh, Po-Ru, additional, Phillips-Cremins, Jennifer E., additional, Brennand, Kristen J., additional, Macosko, Evan Z., additional, Walters, James T.R., additional, O’Donovan, Michael, additional, Sullivan, Patrick, additional, Sebat, Jonathan, additional, Lee, Eunjung A., additional, Walsh, Christopher A., additional, Marshall, Christian R., additional, Merico, Daniele, additional, Thiruvahindrapuram, Bhooma, additional, Wang, Zhouzhi, additional, Scherer, Stephen W., additional, Howrigan, Daniel P, additional, Ripke, Stephan, additional, Bulik-Sullivan, Brendan, additional, Farh, Kai-How, additional, Fromer, Menachem, additional, Goldstein, Jacqueline I., additional, Huang, Hailiang, additional, Lee, Phil, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Belliveau, Richard A., additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Chambert, Kimberley D., additional, O'Dushlaine, Colm, additional, Scolnick, Edward M., additional, Smoller, Jordan W., additional, Moran, Jennifer L., additional, Palotie, Aarno, additional, Petryshen, Tracey L., additional, Wu, Wenting, additional, Greer, Douglas S., additional, Antaki, Danny, additional, Shetty, Aniket, additional, Gujral, Madhusudan, additional, Brandler, William M., additional, Malhotra, Dheeraj, additional, Fuentes Fajarado, Karin V., additional, Maile, Michelle S., additional, Holmans, Peter A., additional, Carrera, Noa, additional, Craddock, Nick, additional, Escott-Price, Valentina, additional, Georgieva, Lyudmila, additional, Hamshere, Marian L., additional, Kavanagh, David, additional, Legge, Sophie E., additional, Pocklington, Andrew J., additional, Richards, Alexander L., additional, Ruderfer, Douglas M., additional, Williams, Nigel M., additional, Kirov, George, additional, Owen, Michael J., additional, Pinto, Dalila, additional, Cai, Guiqing, additional, Davis, Kenneth L., additional, Drapeau, Elodie, additional, Friedman, Joseph I, additional, Haroutunian, Vahram, additional, Parkhomenko, Elena, additional, Reichenberg, Abraham, additional, Silverman, Jeremy M., additional, Buxbaum, Joseph D., additional, Domenici, Enrico, additional, Agartz, Ingrid, additional, Djurovic, Srdjan, additional, Mattingsdal, Morten, additional, Melle, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Söderman, Erik, additional, Albus, Margot, additional, Alexander, Madeline, additional, Laurent, Claudine, additional, Levinson, Douglas F., additional, Amin, Farooq, additional, Atkins, Joshua, additional, Cairns, Murray J., additional, Scott, Rodney J., additional, Tooney, Paul A., additional, Wu, Jing Qin, additional, Bacanu, Silviu A., additional, Bigdeli, Tim B., additional, Reimers, Mark A., additional, Webb, Bradley T., additional, Wolen, Aaron R., additional, Wormley, Brandon K., additional, Kendler, Kenneth S., additional, Riley, Brien P., additional, Kähler, Anna K., additional, Magnusson, Patrik K.E., additional, Hultman, Christina M., additional, Bertalan, Marcelo, additional, Hansen, Thomas, additional, Olsen, Line, additional, Rasmussen, Henrik B., additional, Werge, Thomas, additional, Mattheisen, Manuel, additional, Black, Donald W., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Roffman, Joshua L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Kahn, René S, additional, Strengman, Eric, additional, Ophoff, Roel A., additional, Carr, Vaughan J., additional, Catts, Stanley V., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Michie, Patricia T., additional, Pantelis, Christos, additional, Schall, Ulrich, additional, Jablensky, Assen V., additional, Kelly, Brian J., additional, Campion, Dominique, additional, Cantor, Rita M., additional, Cheng, Wei, additional, Cloninger, C. Robert, additional, Svrakic, Dragan M, additional, Cohen, David, additional, Cormican, Paul, additional, Donohoe, Gary, additional, Morris, Derek W., additional, Corvin, Aiden, additional, Gill, Michael, additional, Crespo-Facorro, Benedicto, additional, Crowley, James J., additional, Farrell, Martilias S., additional, Giusti-Rodríguez, Paola, additional, Kim, Yunjung, additional, Szatkiewicz, Jin P., additional, Williams, Stephanie, additional, Curtis, David, additional, Pimm, Jonathan, additional, Gurling, Hugh, additional, McQuillin, Andrew, additional, Davidson, Michael, additional, Weiser, Mark, additional, Degenhardt, Franziska, additional, Forstner, Andreas J., additional, Herms, Stefan, additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Cichon, Sven, additional, Nöthen, Markus M., additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, McCarley, Robert W., additional, Levy, Deborah L., additional, Mesholam-Gately, Raquelle I., additional, Seidman, Larry J., additional, Dikeos, Dimitris, additional, Papadimitriou, George N., additional, Dinan, Timothy, additional, Duan, Jubao, additional, Sanders, Alan R., additional, Gejman, Pablo V., additional, Gershon, Elliot S., additional, Dudbridge, Frank, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Salomaa, Veikko, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Knowles, James A., additional, Pato, Michele T., additional, Pato, Carlos N., additional, Frank, Josef, additional, Meier, Sandra, additional, Schulze, Thomas G., additional, Strohmaier, Jana, additional, Witt, Stephanie H., additional, Rietschel, Marcella, additional, Franke, Lude, additional, Karjalainen, Juha, additional, Freedman, Robert, additional, Olincy, Ann, additional, Freimer, Nelson B., additional, Purcell, Shaun M., additional, Roussos, Panos, additional, Stahl, Eli A., additional, Sklar, Pamela, additional, Giegling, Ina, additional, Hartmann, Annette M., additional, Konte, Bettina, additional, Rujescu, Dan, additional, Godard, Stephanie, additional, Hirschhorn, Joel N., additional, Pers, Tune H., additional, Price, Alkes, additional, Esko, Tõnu, additional, Gratten, Jacob, additional, Lee, S. Hong, additional, Visscher, Peter M., additional, Wray, Naomi R., additional, Mowry, Bryan J., additional, de Haan, Lieuwe, additional, Meijer, Carin J., additional, Hansen, Mark, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Joa, Inge, additional, Kalaydjieva, Luba, additional, Keller, Matthew C., additional, Kennedy, James L., additional, Zai, Clement C., additional, Knight, Jo, additional, Lerer, Bernard, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Stroup, T. Scott, additional, Lönnqvist, Jouko, additional, Suvisaari, Jaana, additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, McDonald, Colm, additional, McIntosh, Andrew M., additional, Blackwood, Douglas H.R., additional, Metspalu, Andres, additional, Milani, Lili, additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Collier, David A., additional, Müller-Myhsok, Bertram, additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Powell, John, additional, Myin-Germeys, Inez, additional, Van Os, Jim, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Pulver, Ann E., additional, Nicodemus, Kristin K., additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, Adolfsson, Rolf, additional, O'Callaghan, Eadbhard, additional, Oh, Sang-Yun, additional, O'Neill, F. Anthony, additional, Paunio, Tiina, additional, Pietiläinen, Olli, additional, Perkins, Diana O., additional, Quested, Digby, additional, Savitz, Adam, additional, Li, Qingqin S., additional, Schwab, Sibylle G., additional, Shi, Jianxin, additional, Spencer, Chris C.A., additional, Thirumalai, Srinivas, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wildenauer, Dieter B., additional, Bramon, Elvira, additional, Darvasi, Ariel, additional, Posthuma, Danielle, additional, St. Clair, David, additional, Shanta, Omar, additional, Klein, Marieke, additional, Park, Peter J., additional, Weinberger, Daniel, additional, Moran, John V., additional, Gage, Fred H., additional, Vaccarino, Flora M., additional, Gleeson, Joseph, additional, Mathern, Gary, additional, Courchesne, Eric, additional, Roy, Subhojit, additional, Bizzotto, Sara, additional, Coulter, Michael, additional, Dias, Caroline, additional, D'Gama, Alissa, additional, Ganz, Javier, additional, Hill, Robert, additional, Huang, August Yue, additional, Khoshkhoo, Sattar, additional, Kim, Sonia, additional, Lodato, Michael, additional, Miller, Michael, additional, Borges-Monroy, Rebeca, additional, Rodin, Rachel, additional, Zhou, Zinan, additional, Bohrson, Craig, additional, Chu, Chong, additional, Cortes-Ciriano, Isidro, additional, Dou, Yanmei, additional, Galor, Alon, additional, Gulhan, Doga, additional, Kwon, Minseok, additional, Luquette, Joe, additional, Viswanadham, Vinay, additional, Jones, Attila, additional, Rosenbluh, Chaggai, additional, Cho, Sean, additional, Langmead, Ben, additional, Thorpe, Jeremy, additional, Erwin, Jennifer, additional, Jaffe, Andrew, additional, McConnell, Michael, additional, Narurkar, Rujuta, additional, Paquola, Apua, additional, Shin, Jooheon, additional, Straub, Richard, additional, Abyzov, Alexej, additional, Bae, Taejeong, additional, Jang, Yeongjun, additional, Wang, Yifan, additional, Gage, Fred, additional, Linker, Sara, additional, Reed, Patrick, additional, Wang, Meiyan, additional, Urban, Alexander, additional, Zhou, Bo, additional, Zhu, Xiaowei, additional, Pattni, Reenal, additional, Amero, Aitor Serres, additional, Juan, David, additional, Lobon, Irene, additional, Marques-Bonet, Tomas, additional, Moruno, Manuel Solis, additional, Perez, Raquel Garcia, additional, Povolotskaya, Inna, additional, Soriano, Eduardo, additional, Averbuj, Dan, additional, Ball, Laurel, additional, Breuss, Martin, additional, Yang, Xiaoxu, additional, Chung, Changuk, additional, Emery, Sarah B., additional, Flasch, Diane A., additional, Kidd, Jeffrey M., additional, Kopera, Huira C., additional, Kwan, Kenneth Y., additional, Mills, Ryan E., additional, Moldovan, John B., additional, Sun, Chen, additional, Zhao, Xuefang, additional, Zhou, Weichen, additional, Frisbie, Trenton J., additional, Cherskov, Adriana, additional, Fasching, Liana, additional, Jourdon, Alexandre, additional, Pochareddy, Sirisha, additional, Scuderi, Soraya, additional, and Sestan, Nenad, additional
Published: 2023
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46. Inferring the molecular and phenotypic impact of amino acid variants with MutPred2

Author: Pejaver, Vikas, Urresti, Jorge, Lugo-Martinez, Jose, Pagel, Kymberleigh A., Lin, Guan Ning, Nam, Hyun-Jun, Mort, Matthew, Cooper, David N., Sebat, Jonathan, Iakoucheva, Lilia M., Mooney, Sean D., and Radivojac, Predrag
Published: 2020
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47. Current progress and future direction in the genetics of PTSD: Focus on the development and contributions of the PGC-PTSD working group

Author: Junglen, Angela G., primary, Sheerin, Christina, additional, Delahanty, Douglas L., additional, Hauser, Michael A., additional, Lori, Adriana, additional, Morey, Rajendra A., additional, Nievergelt, Caroline M., additional, Nugent, Nicole R., additional, Sebat, Jonathan, additional, Smith, Alicia K., additional, Sumner, Jennifer A., additional, Uddin, Monica, additional, and Amstadter, Ananda B., additional
Published: 2020
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48. Correction: Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism

Author: Urresti, Jorge, Zhang, Pan, Moran-Losada, Patricia, Yu, Nam-Kyung, Negraes, Priscilla D., Trujillo, Cleber A., Antaki, Danny, Amar, Megha, Chau, Kevin, Pramod, Akula Bala, Diedrich, Jolene, Tejwani, Leon, Romero, Sarah, Sebat, Jonathan, Yates III, John R., Muotri, Alysson R., and Iakoucheva, Lilia M.
Published: 2021
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49. Contributors

Author: Abbott, Ryan, primary, Ahmed, Ahmed T., additional, Alda, Martin, additional, Amstadter, Ananda B., additional, Andreassen, Ole A., additional, Arnet, Victoria K., additional, Bardy, Cedric, additional, Barta, Csaba, additional, Baune, Bernhard T., additional, Becker, Elisabeth R.B., additional, Bewernick, Bettina H., additional, Biernacka, Joanna M., additional, Bleich, Stefan, additional, Blumenthal, Marissa S., additional, Bonvicini, Cristian, additional, Bousman, Chad A., additional, Brown, Lisa C., additional, Burton, Christie L., additional, Cao, Han, additional, Carpenter, Joanne S., additional, Cath, Danielle, additional, Cearns, Micah, additional, Chang, Donald D., additional, Charney, Alexander, additional, Ching, Christopher R.K., additional, Chitty, Kate M., additional, Ciobanu, Liliana G., additional, Clark, Scott R., additional, Cole, A.M., additional, Collinson, Jane L., additional, Colodro-Conde, Lucía, additional, Corvin, A., additional, Cotter, David R., additional, Cross, Shane P.M., additional, Crouse, Jacob J., additional, Cryan, John F, additional, Czamara, Darina, additional, Dalvie, Shareefa, additional, Degenhardt, Franziska, additional, Delahanty, Douglas L., additional, Dinan, Timothy G, additional, Eapen, Valsamma, additional, Eyre, Harris A., additional, Forstner, Andreas J., additional, Frieling, Helge, additional, Frye, Mark A., additional, Gehue, Lillian J., additional, Geller, Daniel, additional, Glozier, Nicholas, additional, Godlewska, Beata R., additional, Goldstein-Piekarski, Andrea N., additional, Gorbovskaya, Ilona, additional, Grabe, Hans Jörgen, additional, Grande, Iria, additional, Grant, Paul, additional, Greenberg, Zarina, additional, Grünblatt, Edna, additional, Guastella, Adam J., additional, Gururajan, Anand, additional, Hahn, Tim, additional, Hall, Alisha S.M., additional, Hamilton, Blake A., additional, Hamm, Alfons O., additional, Harmer, Catherine J., additional, Hartmann, Jessica, additional, Hauser, Michael A., additional, Hermens, Daniel F., additional, Hickie, Ian B., additional, Iorfino, Frank, additional, Jahanshad, Neda, additional, Jansen, Iris E., additional, Junglen, Angela G., additional, Karim, Helmet T., additional, Kaur, Manreena, additional, Koen, Nastassja, additional, Koethe, Dagmar, additional, Lagopoulos, Jim, additional, Lee, Rico S.Z., additional, Legge, Sophie E., additional, Levinson, Douglas F., additional, Leweke, F. Markus, additional, Licinio, Julio, additional, Linden, David E.J., additional, Liu, Jonathan C.W., additional, Lo, Anita, additional, Lohoff, Falk W., additional, Lori, Adriana, additional, Lueken, Ulrike, additional, Maj, Carlo, additional, McGorry, Patrick D., additional, McIntyre, Roger S., additional, McMahon, Agnes B., additional, Mehta, Divya, additional, Mei, Cristina, additional, Morey, Rajendra A., additional, Müller, Daniel J., additional, Naismith, Sharon L., additional, Nelson, Barnaby, additional, Neyazi, Alexandra, additional, Nichles, Alissa, additional, Nievergelt, Caroline M., additional, Nugent, Nicole R., additional, Ormond, C., additional, Pardiñas, Antonio F., additional, Perry, Seth W., additional, Pisanu, Claudia, additional, Posthuma, Danielle, additional, Ragguett, Renee-Marie, additional, Raji, Cyrus, additional, Raygada, Margarita, additional, Rennert, Owen M., additional, Reynolds, Charles F., additional, Sabherwal, Sophie, additional, Salagre, Estela, additional, Saunders, Pamela H., additional, Scassellati, Catia, additional, Schlaepfer, Thomas E., additional, Schmaal, Lianne, additional, Schubert, Klaus Oliver, additional, Schwarz, Emanuel, additional, Scott, Elizabeth M., additional, Scott, Jan, additional, Sebat, Jonathan, additional, Severino, Giovanni, additional, Sheerin, Christina, additional, Singh, Ajeet B., additional, Singh, Balwinder, additional, Smagula, Stephen F., additional, Smeland, Olav B., additional, Smith, Alicia K., additional, Sorcher, Jill L., additional, Spooner, Rachael, additional, Squassina, Alessio, additional, Stahl, Eli A., additional, Stein, Dan J., additional, Streit, Fabian, additional, Sullivan, Patrick F., additional, Sumner, Jennifer A., additional, Thompson, Paul M., additional, Tickell, Ashleigh M., additional, Toben, Catherine, additional, Uddin, Monica, additional, Vahabzadeh, Arshya, additional, Van, Linh K., additional, van de Weijer, Margot P., additional, van den Heuvel, Odile A., additional, Van der Auwera, Sandra, additional, Verboven, Anouk H.A., additional, Vieta, Eduard, additional, Wainer, Zoe, additional, Walters, James T.R., additional, Watson, Hunna J., additional, White, Django, additional, Williams, Leanne M., additional, Witt, Stephanie H., additional, Yao, Yin, additional, Yilmaz, Zeynep, additional, Zai, Gwyneth, additional, and Zmicerevska, Natalia, additional
Published: 2019
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50. Ranking of non-coding pathogenic variants and putative essential regions of the human genome

Author: Wells, Alex, Heckerman, David, Torkamani, Ali, Yin, Li, Sebat, Jonathan, Ren, Bing, Telenti, Amalio, and di Iulio, Julia
Published: 2019
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