Author: "Willsey, A Jeremy" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Willsey, A Jeremy"' showing total 375 results

Start Over Author "Willsey, A Jeremy"

375 results on '"Willsey, A Jeremy"'

1. Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Author: Barr, Cathy L., Batterson, James R., Berlin, Cheston, Budman, Cathy L., Coppola, Giovanni, Cox, Nancy J., Darrow, Sabrina, Dion, Yves, Freimer, Nelson B., Grados, Marco A., Greenberg, Erica, Hirschtritt, Matthew E., Huang, Alden Y., Illmann, Cornelia, King, Robert A., Kurlan, Roger, Leckman, James F., Lyon, Gholson J., Malaty, Irene A., McMahon, William M., Neale, Benjamin M., Okun, Michael S., Osiecki, Lisa, Robertson, Mary M., Rouleau, Guy A., Sandor, Paul, Singer, Harvey S., Smit, Jan H., Sul, Jae Hoon, Androutsos, Christos, Basha, Entela, Farkas, Luca, Fichna, Jakub, Janik, Piotr, Kapisyzi, Mira, Karagiannidis, Iordanis, Koumoula, Anastasia, Nagy, Peter, Puchala, Joanna, Szejko, Natalia, Szymanska, Urszula, Tsironi, Vaia, Apter, Alan, Ball, Juliane, Bodmer, Benjamin, Bognar, Emese, Buse, Judith, Vela, Marta Correa, Fremer, Carolin, Garcia-Delgar, Blanca, Gulisano, Mariangela, Hagen, Annelieke, Hagstrøm, Julie, Madruga-Garrido, Marcos, Pellico, Alessandra, Ruhrman, Daphna, Schnell, Jaana, Silvestri, Paola Rosaria, Skov, Liselotte, Steinberg, Tamar, Gloor, Friederike Tagwerker, Turner, Victoria L., Weidinger, Elif, Alexander, John, Aranyi, Tamas, Buisman, Wim R., Buitelaar, Jan K., Driessen, Nicole, Drineas, Petros, Fan, Siyan, Forde, Natalie J., Gerasch, Sarah, van den Heuvel, Odile A., Jespersgaard, Cathrine, Kanaan, Ahmad S., Möller, Harald E., Nawaz, Muhammad S., Nespoli, Ester, Pagliaroli, Luca, Poelmans, Geert, Pouwels, Petra J.W., Rizzo, Francesca, Veltman, Dick J., van der Werf, Ysbrand D., Widomska, Joanna, Zilhäo, Nuno R., Brown, Lawrence W., Cheon, Keun-Ah, Coffey, Barbara J., Fernandez, Thomas V., Gilbert, Donald L., Hong, Hyun Ju, Ibanez-Gomez, Laura, Kim, Eun-Joo, Kim, Young Key, Kim, Young-Shin, Koh, Yun-Joo, Kook, Sodahm, Kuperman, Samuel, Leventhal, Bennett L., Maras, Athanasios, Murphy, Tara L., Shin, Eun-Young, Song, Dong-Ho, Song, Jungeun, State, Matthew W., Visscher, Frank, Wang, Sheng, Zinner, Samuel H., Tsetsos, Fotis, Topaloudi, Apostolia, Jain, Pritesh, Yang, Zhiyu, Yu, Dongmei, Kolovos, Petros, Tumer, Zeynep, Rizzo, Renata, Hartmann, Andreas, Depienne, Christel, Worbe, Yulia, Müller-Vahl, Kirsten R., Cath, Danielle C., Boomsma, Dorret I., Wolanczyk, Tomasz, Zekanowski, Cezary, Barta, Csaba, Nemoda, Zsofia, Tarnok, Zsanett, Padmanabhuni, Shanmukha S., Buxbaum, Joseph D., Grice, Dorothy, Glennon, Jeffrey, Stefansson, Hreinn, Hengerer, Bastian, Yannaki, Evangelia, Stamatoyannopoulos, John A., Benaroya-Milshtein, Noa, Cardona, Francesco, Hedderly, Tammy, Heyman, Isobel, Huyser, Chaim, Mir, Pablo, Morer, Astrid, Mueller, Norbert, Munchau, Alexander, Plessen, Kerstin J., Porcelli, Cesare, Roessner, Veit, Walitza, Susanne, Schrag, Anette, Martino, Davide, Tischfield, Jay A., Heiman, Gary A., Willsey, A. Jeremy, Dietrich, Andrea, Davis, Lea K., Crowley, James J., Mathews, Carol A., Scharf, Jeremiah M., Georgitsi, Marianthi, Hoekstra, Pieter J., and Paschou, Peristera
Published: 2024
Full Text: View/download PDF

2. A convergent molecular network underlying autism and congenital heart disease

Author: Rosenthal, Sara Brin, Willsey, Helen Rankin, Xu, Yuxiao, Mei, Yuan, Dea, Jeanselle, Wang, Sheng, Curtis, Charlotte, Sempou, Emily, Khokha, Mustafa K, Chi, Neil C, Willsey, Arthur Jeremy, Fisch, Kathleen M, and Ideker, Trey
Subjects: Biological Sciences, Genetics, Pediatric, Heart Disease, Autism, Intellectual and Developmental Disabilities (IDD), Mental Health, Genetic Testing, Rare Diseases, Congenital Heart Disease, Brain Disorders, Cardiovascular, Neurosciences, Congenital Structural Anomalies, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Autism Spectrum Disorder, Autistic Disorder, Heart Defects, Congenital, Humans, Subject areas: systems biology, autism, congenital heart disease, network genetics, Biochemistry and Cell Biology, Biochemistry and cell biology
Abstract: Patients with neurodevelopmental disorders, including autism, have an elevated incidence of congenital heart disease, but the extent to which these conditions share molecular mechanisms remains unknown. Here, we use network genetics to identify a convergent molecular network underlying autism and congenital heart disease. This network is impacted by damaging genetic variants from both disorders in multiple independent cohorts of patients, pinpointing 101 genes with shared genetic risk. Network analysis also implicates risk genes for each disorder separately, including 27 previously unidentified genes for autism and 46 for congenital heart disease. For 7 genes with shared risk, we create engineered disruptions in Xenopus tropicalis, confirming both heart and brain developmental abnormalities. The network includes a family of ion channels, such as the sodium transporter SCN2A, linking these functions to early heart and brain development. This study provides a road map for identifying risk genes and pathways involved in co-morbid conditions.
Published: 2021

3. Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD

Author: Wang, Sheng, Wang, Belinda, Drury, Vanessa, Drake, Sam, Sun, Nawei, Alkhairo, Hasan, Arbelaez, Juan, Duhn, Clif, Bal, Vanessa H., Langley, Kate, Martin, Joanna, Hoekstra, Pieter J., Dietrich, Andrea, Xing, Jinchuan, Heiman, Gary A., Tischfield, Jay A., Fernandez, Thomas V., Owen, Michael J., O’Donovan, Michael C., Thapar, Anita, State, Matthew W., and Willsey, A. Jeremy
Published: 2023
Full Text: View/download PDF

4. Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience

Author: Willsey, Helen Rankin, Exner, Cameron RT, Xu, Yuxiao, Everitt, Amanda, Sun, Nawei, Wang, Belinda, Dea, Jeanselle, Schmunk, Galina, Zaltsman, Yefim, Teerikorpi, Nia, Kim, Albert, Anderson, Aoife S, Shin, David, Seyler, Meghan, Nowakowski, Tomasz J, Harland, Richard M, Willsey, A Jeremy, and State, Matthew W
Subjects: Autism, Mental Health, Brain Disorders, Neurosciences, Biotechnology, Estrogen, Intellectual and Developmental Disabilities (IDD), Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research - Nonembryonic - Human, Pediatric, Genetics, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, Neurological, Animals, Autism Spectrum Disorder, Cerebral Cortex, Drug Evaluation, Preclinical, Estrogens, Female, Gene Expression Regulation, Developmental, Humans, Male, Neurogenesis, Risk Factors, Signal Transduction, Xenopus, CRISPR, Xenopus tropicalis, autism spectrum disorders, brain development, convergent, estrogen, genetics, neural progenitor cells, neurogenesis, sonic hedgehog, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract: Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.
Published: 2021

5. De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette’s Disorder and Autism

Author: Cappi, Carolina, Oliphant, Melody E, Péter, Zsanett, Zai, Gwyneth, Conceição do Rosário, Maria, Sullivan, Catherine AW, Gupta, Abha R, Hoffman, Ellen J, Virdee, Manmeet, Olfson, Emily, Abdallah, Sarah B, Willsey, A Jeremy, Shavitt, Roseli G, Miguel, Euripedes C, Kennedy, James L, Richter, Margaret A, and Fernandez, Thomas V
Subjects: Biological Sciences, Genetics, Mental Health, Pediatric, Brain Disorders, Human Genome, Neurosciences, Clinical Research, Biotechnology, Prevention, Intellectual and Developmental Disabilities (IDD), Serious Mental Illness, Autism, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Autistic Disorder, Calcium-Binding Proteins, Child, DNA, DNA-Binding Proteins, Humans, Mutation, Obsessive-Compulsive Disorder, Tourette Syndrome, Transcription Factors, CHD8, Obsessive-compulsive disorder, SCUBE1, Tourette, Whole-exome sequencing, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract: BackgroundObsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. In recent years, risk gene discovery in other complex psychiatric disorders has been achieved by studying rare de novo (DN) coding variants.MethodsWe performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), comparing DN variant frequencies with 777 previously sequenced unaffected trios. We estimated the contribution of DN mutations to OCD risk and the number of genes involved. Finally, we looked for gene enrichment in other datasets and canonical pathways.ResultsDN likely gene disrupting and predicted damaging missense variants are enriched in OCD probands (rate ratio, 1.52; p = .0005) and contribute to risk. We identified 2 high-confidence risk genes, each containing 2 DN damaging variants in unrelated probands: CHD8 and SCUBE1. We estimate that 34% of DN damaging variants in OCD contribute to risk and that DN damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring DN damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly Tourette's disorder and autism spectrum disorder. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways, biological processes, and disease networks.ConclusionsOur findings show a pathway toward systematic gene discovery in OCD via identification of DN damaging variants. Sequencing larger cohorts of OCD parent-child trios will reveal more OCD risk genes and will provide needed insights into underlying disease biology.
Published: 2020

6. Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in Tbr1 Mutants.

Author: Fazel Darbandi, Siavash, Robinson Schwartz, Sarah E, Pai, Emily Ling-Lin, Everitt, Amanda, Turner, Marc L, Cheyette, Benjamin NR, Willsey, A Jeremy, State, Matthew W, Sohal, Vikaas S, and Rubenstein, John LR
Subjects: Thalamus, Neurons, Dendritic Spines, Synapses, Animals, Mice, Inbred C57BL, Mice, Transgenic, Humans, Mice, DNA-Binding Proteins, T-Box Domain Proteins, Female, Male, Neurogenesis, HEK293 Cells, Wnt Signaling Pathway, Autism Spectrum Disorder, ASD, LiCl treatment, Tbr1, WNT-signaling, cortex, excitatory neuron, social deficit, spine maturation, synaptogenesis, Intellectual and Developmental Disabilities (IDD), Biotechnology, Neurosciences, Autism, Mental Health, Brain Disorders, Genetics, Pediatric, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Biochemistry and Cell Biology, Medical Physiology
Abstract: Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b). Furthermore, Tbr1 mutant corticothalamic neurons have reduced thalamic axonal arborization. LiCl and a GSK3β inhibitor, two WNT-signaling agonists, robustly rescue the dendritic spines and the synaptic and axonal defects, suggesting that this could have relevance for therapeutic approaches in some forms of ASD.
Published: 2020

7. Human 3D cellular model of hypoxic brain injury of prematurity.

Author: Pașca, Anca M, Park, Jin-Young, Shin, Hyun-Woo, Qi, Qihao, Revah, Omer, Krasnoff, Rebecca, O'Hara, Ruth, Willsey, A Jeremy, Palmer, Theo D, and Pașca, Sergiu P
Subjects: Cerebral Cortex, Organoids, Humans, Brain Injuries, Hypoxia, Brain, T-Box Domain Proteins, Cell Hypoxia, Models, Neurological, Infant, Newborn, Neurogenesis, Unfolded Protein Response, Neural Stem Cells, Infant, Extremely Premature, Hypoxia, Brain, Models, Neurological, Infant, Newborn, Extremely Premature, Immunology, Medical and Health Sciences
Abstract: Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.
Published: 2019

8. Interrogating the Genetic Determinants of Tourette’s Syndrome and Other Tic Disorders Through Genome-Wide Association Studies

Author: Yu, Dongmei, Sul, Jae Hoon, Tsetsos, Fotis, Nawaz, Muhammad S, Huang, Alden Y, Zelaya, Ivette, Illmann, Cornelia, Osiecki, Lisa, Darrow, Sabrina M, Hirschtritt, Matthew E, Greenberg, Erica, Muller-Vahl, Kirsten R, Stuhrmann, Manfred, Dion, Yves, Rouleau, Guy, Aschauer, Harald, Stamenkovic, Mara, Schlögelhofer, Monika, Sandor, Paul, Barr, Cathy L, Grados, Marco, Singer, Harvey S, Nöthen, Markus M, Hebebrand, Johannes, Hinney, Anke, King, Robert A, Fernandez, Thomas V, Barta, Csaba, Tarnok, Zsanett, Nagy, Peter, Depienne, Christel, Worbe, Yulia, Hartmann, Andreas, Budman, Cathy L, Rizzo, Renata, Lyon, Gholson J, McMahon, William M, Batterson, James R, Cath, Danielle C, Malaty, Irene A, Okun, Michael S, Berlin, Cheston, Woods, Douglas W, Lee, Paul C, Jankovic, Joseph, Robertson, Mary M, Gilbert, Donald L, Brown, Lawrence W, Coffey, Barbara J, Dietrich, Andrea, Hoekstra, Pieter J, Kuperman, Samuel, Zinner, Samuel H, Luðvigsson, Pétur, Sæmundsen, Evald, Thorarensen, Ólafur, Atzmon, Gil, Barzilai, Nir, Wagner, Michael, Moessner, Rainald, Ophoff, Roel, Pato, Carlos N, Pato, Michele T, Knowles, James A, Roffman, Joshua L, Smoller, Jordan W, Buckner, Randy L, Willsey, A Jeremy, Tischfield, Jay A, Heiman, Gary A, Stefansson, Hreinn, Stefansson, Kári, Posthuma, Danielle, Cox, Nancy J, Pauls, David L, Freimer, Nelson B, Neale, Benjamin M, Davis, Lea K, Paschou, Peristera, Coppola, Giovanni, Mathews, Carol A, and Scharf, Jeremiah M
Subjects: Mental Health, Prevention, Brain Disorders, Human Genome, Neurosciences, Neurodegenerative, Serious Mental Illness, Tourette Syndrome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Risk Factors, Severity of Illness Index, Tic Disorders, fms-Like Tyrosine Kinase 3, Tourette Association of America International Consortium for Genetics, the Gilles de la Tourette GWAS Replication Initiative, the Tourette International Collaborative Genetics Study, and the Psychiatric Genomics Consortium Tourette Syndrome Working Group, Child Psychiatry, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract: ObjectiveTourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity.MethodsGWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined.ResultsGWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects.ConclusionsModulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.
Published: 2019

9. Genomics, convergent neuroscience and progress in understanding autism spectrum disorder

Author: Willsey, Helen Rankin, Willsey, A. Jeremy, Wang, Belinda, and State, Matthew W.
Published: 2022
Full Text: View/download PDF

10. Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder

Author: An, Joon-Yong, Lin, Kevin, Zhu, Lingxue, Werling, Donna M, Dong, Shan, Brand, Harrison, Wang, Harold Z, Zhao, Xuefang, Schwartz, Grace B, Collins, Ryan L, Currall, Benjamin B, Dastmalchi, Claudia, Dea, Jeanselle, Duhn, Clif, Gilson, Michael C, Klei, Lambertus, Liang, Lindsay, Markenscoff-Papadimitriou, Eirene, Pochareddy, Sirisha, Ahituv, Nadav, Buxbaum, Joseph D, Coon, Hilary, Daly, Mark J, Kim, Young Shin, Marth, Gabor T, Neale, Benjamin M, Quinlan, Aaron R, Rubenstein, John L, Sestan, Nenad, State, Matthew W, Willsey, A Jeremy, Talkowski, Michael E, Devlin, Bernie, Roeder, Kathryn, and Sanders, Stephan J
Subjects: Human Genome, Genetics, Biotechnology, Intellectual and Developmental Disabilities (IDD), Mental Health, Brain Disorders, Autism, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Binding Sites, Conserved Sequence, DNA Mutational Analysis, Genetic Loci, Genetic Variation, Humans, Mutation, Pedigree, Promoter Regions, Genetic, Risk, Transcription Factors, General Science & Technology
Abstract: Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.
Published: 2018

11. Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Author: Li, Mingfeng, Santpere, Gabriel, Imamura Kawasawa, Yuka, Evgrafov, Oleg V, Gulden, Forrest O, Pochareddy, Sirisha, Sunkin, Susan M, Li, Zhen, Shin, Yurae, Zhu, Ying, Sousa, André MM, Werling, Donna M, Kitchen, Robert R, Kang, Hyo Jung, Pletikos, Mihovil, Choi, Jinmyung, Muchnik, Sydney, Xu, Xuming, Wang, Daifeng, Lorente-Galdos, Belen, Liu, Shuang, Giusti-Rodríguez, Paola, Won, Hyejung, de Leeuw, Christiaan A, Pardiñas, Antonio F, Hu, Ming, Jin, Fulai, Li, Yun, Owen, Michael J, O’Donovan, Michael C, Walters, James TR, Posthuma, Danielle, Reimers, Mark A, Levitt, Pat, Weinberger, Daniel R, Hyde, Thomas M, Kleinman, Joel E, Geschwind, Daniel H, Hawrylycz, Michael J, State, Matthew W, Sanders, Stephan J, Sullivan, Patrick F, Gerstein, Mark B, Lein, Ed S, Knowles, James A, Sestan, Nenad, Willsey, A Jeremy, Oldre, Aaron, Szafer, Aaron, Camarena, Adrian, Cherskov, Adriana, Charney, Alexander W, Abyzov, Alexej, Kozlenkov, Alexey, Safi, Alexias, Jones, Allan R, Ashley-Koch, Allison E, Ebbert, Amanda, Price, Amanda J, Sekijima, Amanda, Kefi, Amira, Bernard, Amy, Amiri, Anahita, Sboner, Andrea, Clark, Andrew, Jaffe, Andrew E, Tebbenkamp, Andrew TN, Sodt, Andy J, Guillozet-Bongaarts, Angie L, Nairn, Angus C, Carey, Anita, Huttner, Anita, Chervenak, Ann, Szekely, Anna, Shieh, Annie W, Harmanci, Arif, Lipska, Barbara K, Carlyle, Becky C, Gregor, Ben W, Kassim, Bibi S, Sheppard, Brooke, Bichsel, Candace, Hahn, Chang-Gyu, Lee, Chang-Kyu, Chen, Chao, Kuan, Chihchau L, Dang, Chinh, Lau, Chris, Cuhaciyan, Christine, Armoskus, Christoper, Mason, Christopher E, Liu, Chunyu, Slaughterbeck, Cliff R, Bennet, Crissa, Pinto, Dalila, Polioudakis, Damon, Franjic, Daniel, Miller, Daniel J, Bertagnolli, Darren, and Lewis, David A
Subjects: Human Genome, Genetics, Neurosciences, Biotechnology, Pediatric, Mental Health, Brain, Epigenesis, Genetic, Epigenomics, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Humans, Mental Disorders, Nervous System Diseases, Neurogenesis, Single-Cell Analysis, Transcriptome, BrainSpan Consortium, PsychENCODE Consortium, PsychENCODE Developmental Subgroup, General Science & Technology
Abstract: To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.
Published: 2018

12. Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Author: Shah, Priya S, Link, Nichole, Jang, Gwendolyn M, Sharp, Phillip P, Zhu, Tongtong, Swaney, Danielle L, Johnson, Jeffrey R, Von Dollen, John, Ramage, Holly R, Satkamp, Laura, Newton, Billy, Hüttenhain, Ruth, Petit, Marine J, Baum, Tierney, Everitt, Amanda, Laufman, Orly, Tassetto, Michel, Shales, Michael, Stevenson, Erica, Iglesias, Gabriel N, Shokat, Leila, Tripathi, Shashank, Balasubramaniam, Vinod, Webb, Laurence G, Aguirre, Sebastian, Willsey, A Jeremy, Garcia-Sastre, Adolfo, Pollard, Katherine S, Cherry, Sara, Gamarnik, Andrea V, Marazzi, Ivan, Taunton, Jack, Fernandez-Sesma, Ana, Bellen, Hugo J, Andino, Raul, and Krogan, Nevan J
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Vector-Borne Diseases, Biodefense, Infectious Diseases, Emerging Infectious Diseases, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Animals, Cell Line, Tumor, Culicidae, Dengue, Dengue Virus, HEK293 Cells, Humans, Membrane Proteins, Nuclear Proteins, Protein Interaction Mapping, Viral Nonstructural Proteins, Zika Virus, Zika Virus Infection, ANKLE2, Drosophila, PAF1C, Sec61, Zika virus, dengue virus, endoplasmic reticulum, flavivirus, interferon stimulated genes, microcephaly, proteomics, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms.
Published: 2018

13. Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity

Author: Darbandi, Siavash Fazel, Schwartz, Sarah E Robinson, Qi, Qihao, Catta-Preta, Rinaldo, Pai, Emily Ling-Lin, Mandell, Jeffrey D, Everitt, Amanda, Rubin, Anna, Krasnoff, Rebecca A, Katzman, Sol, Tastad, David, Nord, Alex S, Willsey, A Jeremy, Chen, Bin, State, Matthew W, Sohal, Vikaas S, and Rubenstein, John LR
Subjects: Biomedical and Clinical Sciences, Neurosciences, Mental Health, Biotechnology, Brain Disorders, Pediatric, Genetics, Intellectual and Developmental Disabilities (IDD), Human Genome, Autism, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Animals, Newborn, Cells, Cultured, DNA-Binding Proteins, Gene Dosage, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neocortex, Nerve Net, T-Box Domain Proteins, ASD, Tbr1, aggression, anxiety-like behavior, cortical development, development, layer 6, synapses, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract: An understanding of how heterozygous loss-of-function mutations in autism spectrum disorder (ASD) risk genes, such as TBR1, contribute to ASD remains elusive. Conditional Tbr1 deletion during late mouse gestation in cortical layer 6 neurons (Tbr1layer6 mutants) provides novel insights into its function, including dendritic patterning, synaptogenesis, and cell-intrinsic physiology. These phenotypes occur in heterozygotes, providing insights into mechanisms that may underlie ASD pathophysiology. Restoring expression of Wnt7b largely rescues the synaptic deficit in Tbr1layer6 mutant neurons. Furthermore, Tbr1layer6 heterozygotes have increased anxiety-like behavior, a phenotype seen ASD. Integrating TBR1 chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data from layer 6 neurons and activity of TBR1-bound candidate enhancers provides evidence for how TBR1 regulates layer 6 properties. Moreover, several putative TBR1 targets are ASD risk genes, placing TBR1 in a central position both for ASD risk and for regulating transcriptional circuits that control multiple steps in layer 6 development essential for the assembly of neural circuits.
Published: 2018

14. De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.

Author: Wang, Sheng, Mandell, Jeffrey D, Kumar, Yogesh, Sun, Nawei, Morris, Montana T, Arbelaez, Juan, Nasello, Cara, Dong, Shan, Duhn, Clif, Zhao, Xin, Yang, Zhiyu, Padmanabhuni, Shanmukha S, Yu, Dongmei, King, Robert A, Dietrich, Andrea, Khalifa, Najah, Dahl, Niklas, Huang, Alden Y, Neale, Benjamin M, Coppola, Giovanni, Mathews, Carol A, Scharf, Jeremiah M, Tourette International Collaborative Genetics Study (TIC Genetics), Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE), Tourette Association of America International Consortium for Genetics (TAAICG), Fernandez, Thomas V, Buxbaum, Joseph D, De Rubeis, Silvia, Grice, Dorothy E, Xing, Jinchuan, Heiman, Gary A, Tischfield, Jay A, Paschou, Peristera, Willsey, A Jeremy, and State, Matthew W
Subjects: Tourette International Collaborative Genetics Study, Tourette Syndrome Genetics Southern and Eastern Europe Initiative, Tourette Association of America International Consortium for Genetics, Humans, Tourette Syndrome, Cadherins, Receptors, Cell Surface, Pedigree, Cell Polarity, Adult, Child, Female, Male, DNA Copy Number Variations, TIC Genetics, Tourette disorder, cell polarity, copy number variants, de novo variants, gene discovery, microarray genotyping, multiplex, simplex, whole exome sequencing, Clinical Research, Pediatric, Biotechnology, Genetics, Brain Disorders, Human Genome, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Biochemistry and Cell Biology, Medical Physiology
Abstract: We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.
Published: 2018

15. The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders

Author: Willsey, A Jeremy, Morris, Montana T, Wang, Sheng, Willsey, Helen R, Sun, Nawei, Teerikorpi, Nia, Baum, Tierney B, Cagney, Gerard, Bender, Kevin J, Desai, Tejal A, Srivastava, Deepak, Davis, Graeme W, Doudna, Jennifer, Chang, Edward, Sohal, Vikaas, Lowenstein, Daniel H, Li, Hao, Agard, David, Keiser, Michael J, Shoichet, Brian, von Zastrow, Mark, Mucke, Lennart, Finkbeiner, Steven, Gan, Li, Sestan, Nenad, Ward, Michael E, Huttenhain, Ruth, Nowakowski, Tomasz J, Bellen, Hugo J, Frank, Loren M, Khokha, Mustafa K, Lifton, Richard P, Kampmann, Martin, Ideker, Trey, State, Matthew W, and Krogan, Nevan J
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Schizophrenia, Rare Diseases, Mental Illness, Biotechnology, Neurosciences, Mental Health, Intellectual and Developmental Disabilities (IDD), 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Mental health, Neurological, Good Health and Well Being, Chromosome Mapping, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Neurobiology, Neurodevelopmental Disorders, Neuropsychiatry, Systems Biology, convergence, genetics, interactome, network, neurodevelopmental disorder, pathway, proteomics, psychiatric cell map initiative, psychiatric disorder, psychiatry, systems biology, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.
Published: 2018

16. Publisher Correction: Whole genome sequencing in psychiatric disorders: the WGSPD consortium.

Author: Sanders, Stephan J, Neale, Benjamin M, Huang, Hailiang, Werling, Donna M, An, Joon-Yong, Dong, Shan, Abecasis, Goncalo, Arguello, P Alexander, Blangero, John, Boehnke, Michael, Daly, Mark J, Eggan, Kevin, Geschwind, Daniel H, Glahn, David C, Goldstein, David B, Gur, Raquel E, Handsaker, Robert E, McCarroll, Steven A, Ophoff, Roel A, Palotie, Aarno, Pato, Carlos N, Sabatti, Chiara, State, Matthew W, Willsey, A Jeremy, Hyman, Steven E, Addington, Anjene M, Lehner, Thomas, Freimer, Nelson B, and Whole Genome Sequencing for Psychiatric Disorders (WGSPD)
Subjects: Whole Genome Sequencing for Psychiatric Disorders, Mental Health, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract: In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author; it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note; in fact, only names are given. In all versions of the paper, the corresponding author symbols were attached to A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington and Thomas Lehner; they should have been attached, respectively, to Steven E. Hyman, Anjene M. Addington, Thomas Lehner and Nelson B. Freimer. As a result of this shift, the respective contact links in the HTML version did not lead to the indicated individuals. The errors have been corrected in the HTML and PDF versions of the article.
Published: 2018

17. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

Author: Werling, Donna M, Brand, Harrison, An, Joon-Yong, Stone, Matthew R, Zhu, Lingxue, Glessner, Joseph T, Collins, Ryan L, Dong, Shan, Layer, Ryan M, Markenscoff-Papadimitriou, Eirene, Farrell, Andrew, Schwartz, Grace B, Wang, Harold Z, Currall, Benjamin B, Zhao, Xuefang, Dea, Jeanselle, Duhn, Clif, Erdman, Carolyn A, Gilson, Michael C, Yadav, Rachita, Handsaker, Robert E, Kashin, Seva, Klei, Lambertus, Mandell, Jeffrey D, Nowakowski, Tomasz J, Liu, Yuwen, Pochareddy, Sirisha, Smith, Louw, Walker, Michael F, Waterman, Matthew J, He, Xin, Kriegstein, Arnold R, Rubenstein, John L, Sestan, Nenad, McCarroll, Steven A, Neale, Benjamin M, Coon, Hilary, Willsey, A Jeremy, Buxbaum, Joseph D, Daly, Mark J, State, Matthew W, Quinlan, Aaron R, Marth, Gabor T, Roeder, Kathryn, Devlin, Bernie, Talkowski, Michael E, and Sanders, Stephan J
Subjects: Biological Sciences, Genetics, Human Genome, Biotechnology, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Mental Health, Autism, 2.1 Biological and endogenous factors, Autism Spectrum Disorder, Female, Genetic Predisposition to Disease, Genome, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Polymorphism, Single Nucleotide, Protein Isoforms, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.
Published: 2018

18. Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility

Author: McCluskey, Kate E, primary, Stovell, Katherine M, additional, Law, Karen, additional, Kostyanovskaya, Elina, additional, Schmidt, James, additional, Exner, Cameron RT, additional, Dea, Jeanselle, additional, Brimble, Elise, additional, State, Matthew W, additional, Willsey, A Jeremy, additional, and Willsey, Helen Rankin, additional
Published: 2024
Full Text: View/download PDF

19. Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders

Author: Xia, Yan, primary, Xia, Cuihua, additional, Jiang, Yi, additional, Chen, Yu, additional, Zhou, Jiaqi, additional, Dai, Rujia, additional, Han, Cong, additional, Mao, Zhongzheng, additional, Consortium, PsychENCODE, additional, Liu, Chunyu, additional, Chen, Chao, additional, Akbarian, Schahram, additional, Abyzov, Alexej, additional, Ahituv, Nadav, additional, Arasappan, Dhivya, additional, Almagro Armenteros, Jose Juan, additional, Beliveau, Brian J., additional, Bendl, Jaroslav, additional, Berretta, Sabina, additional, Bharadwaj, Rahul A., additional, Bhattacharya, Arjun, additional, Bicks, Lucy, additional, Brennand, Kristen, additional, Capauto, Davide, additional, Champagne, Frances A., additional, Chatterjee, Tanima, additional, Chatzinakos, Chris, additional, Chen, Yuhang, additional, Chen, H. Isaac, additional, Cheng, Yuyan, additional, Cheng, Lijun, additional, Chess, Andrew, additional, Chien, Jo-fan, additional, Chu, Zhiyuan, additional, Clarke, Declan, additional, Clement, Ashley, additional, Collado-Torres, Leonardo, additional, Cooper, Gregory M., additional, Crawford, Gregory E., additional, Daskalakis, Nikolaos P., additional, Davila-Velderrain, Jose, additional, Deep-Soboslay, Amy, additional, Deng, Chengyu, additional, DiPietro, Christopher P., additional, Dracheva, Stella, additional, Drusinsky, Shiron, additional, Duan, Ziheng, additional, Duong, Duc, additional, Dursun, Cagatay, additional, Eagles, Nicholas J., additional, Edelstein, Jonathan, additional, Emani, Prashant S., additional, Fullard, John F., additional, Galani, Kiki, additional, Galeev, Timur, additional, Gandal, Michael J., additional, Gaynor, Sophia, additional, Gerstein, Mark, additional, Geschwind, Daniel H., additional, Girdhar, Kiran, additional, Goes, Fernando S., additional, Greenleaf, William, additional, Grundman, Jennifer, additional, Guo, Hanmin, additional, Guo, Qiuyu, additional, Gupta, Chirag, additional, Hadas, Yoav, additional, Hallmayer, Joachim, additional, Han, Xikun, additional, Haroutunian, Vahram, additional, Hawken, Natalie, additional, He, Chuan, additional, Henry, Ella, additional, Hicks, Stephanie C., additional, Ho, Marcus, additional, Ho, Li-Lun, additional, Hoffman, Gabriel E., additional, Huang, Yiling, additional, Huuki-Myers, Louise A., additional, Hwang, Ahyeon, additional, Hyde, Thomas M., additional, Iatrou, Artemis, additional, Inoue, Fumitaka, additional, Jajoo, Aarti, additional, Jensen, Matthew, additional, Jiang, Lihua, additional, Jin, Peng, additional, Jin, Ting, additional, Jops, Connor, additional, Jourdon, Alexandre, additional, Kawaguchi, Riki, additional, Kellis, Manolis, additional, Khullar, Saniya, additional, Kleinman, Joel E., additional, Kleopoulos, Steven P., additional, Kozlenkov, Alex, additional, Kriegstein, Arnold, additional, Kundaje, Anshul, additional, Kundu, Soumya, additional, Lee, Cheyu, additional, Lee, Donghoon, additional, Li, Junhao, additional, Li, Mingfeng, additional, Lin, Xiao, additional, Liu, Shuang, additional, Liu, Jason, additional, Liu, Jianyin, additional, Lou, Shaoke, additional, Loupe, Jacob M., additional, Lu, Dan, additional, Ma, Shaojie, additional, Ma, Liang, additional, Margolis, Michael, additional, Mariani, Jessica, additional, Martinowich, Keri, additional, Maynard, Kristen R., additional, Mazariegos, Samantha, additional, Meng, Ran, additional, Myers, Richard M., additional, Micallef, Courtney, additional, Mikhailova, Tatiana, additional, Ming, Guo-li, additional, Mohammadi, Shahin, additional, Monte, Emma, additional, Montgomery, Kelsey S., additional, Moore, Jill E., additional, Moran, Jennifer R., additional, Mukamel, Eran A., additional, Nairn, Angus C., additional, Nemeroff, Charles B., additional, Ni, Pengyu, additional, Norton, Scott, additional, Nowakowski, Tomasz, additional, Omberg, Larsson, additional, Page, Stephanie C., additional, Park, Saejeong, additional, Patowary, Ashok, additional, Pattni, Reenal, additional, Pertea, Geo, additional, Peters, Mette A., additional, Phalke, Nishigandha, additional, Pinto, Dalila, additional, Pjanic, Milos, additional, Pochareddy, Sirisha, additional, Pollard, Katherine S., additional, Pollen, Alex, additional, Pratt, Henry, additional, Przytycki, Pawel F., additional, Purmann, Carolin, additional, Qin, Zhaohui S., additional, Qu, Ping-Ping, additional, Quintero, Diana, additional, Raj, Towfique, additional, Rajagopalan, Ananya S., additional, Reach, Sarah, additional, Reimonn, Thomas, additional, Ressler, Kerry J., additional, Ross, Deanna, additional, Roussos, Panos, additional, Rozowsky, Joel, additional, Ruth, Misir, additional, Ruzicka, W. Brad, additional, Sanders, Stephan J., additional, Schneider, Juliane M., additional, Scuderi, Soraya, additional, Sebra, Robert, additional, Sestan, Nenad, additional, Seyfried, Nicholas, additional, Shao, Zhiping, additional, Shedd, Nicole, additional, Shieh, Annie W., additional, Shin, Joo Heon, additional, Skarica, Mario, additional, Snijders, Clara, additional, Song, Hongjun, additional, State, Matthew W., additional, Stein, Jason, additional, Steyert, Marilyn, additional, Subburaju, Sivan, additional, Sudhof, Thomas, additional, Snyder, Michael, additional, Tao, Ran, additional, Therrien, Karen, additional, Tsai, Li-Huei, additional, Urban, Alexander E., additional, Vaccarino, Flora M., additional, van Bake, Harm, additional, Vo, Daniel, additional, Voloudakis, Georgios, additional, Wamsley, Brie, additional, Wang, Tao, additional, Wang, Sidney H., additional, Wang, Daifeng, additional, Wang, Yifan, additional, Warrell, Jonathan, additional, Wei, Yu, additional, Weimer, Annika K., additional, Weinberger, Daniel R., additional, Wen, Cindy, additional, Weng, Zhiping, additional, Whalen, Sean, additional, White, Kevin P., additional, Willsey, A. Jeremy, additional, Won, Hyejung, additional, Wong, Wing, additional, Wu, Hao, additional, Wu, Feinan, additional, Wuchty, Stefan, additional, Wylie, Dennis, additional, Xu, Siwei, additional, Yap, Chloe X., additional, Zeng, Biao, additional, Zhang, Pan, additional, Zhang, Chunling, additional, Zhang, Bin, additional, Zhang, Jing, additional, Zhang, Yanqiong, additional, Zhou, Xiao, additional, Ziffra, Ryan, additional, Zeier, Zane R., additional, and Zintel, Trisha M., additional
Published: 2024
Full Text: View/download PDF

20. Whole genome sequencing in psychiatric disorders: the WGSPD consortium.

Author: Sanders, Stephan J, Neale, Benjamin M, Huang, Hailiang, Werling, Donna M, An, Joon-Yong, Dong, Shan, Whole Genome Sequencing for Psychiatric Disorders (WGSPD), Abecasis, Goncalo, Arguello, P Alexander, Blangero, John, Boehnke, Michael, Daly, Mark J, Eggan, Kevin, Geschwind, Daniel H, Glahn, David C, Goldstein, David B, Gur, Raquel E, Handsaker, Robert E, McCarroll, Steven A, Ophoff, Roel A, Palotie, Aarno, Pato, Carlos N, Sabatti, Chiara, State, Matthew W, Willsey, A Jeremy, Hyman, Steven E, Addington, Anjene M, Lehner, Thomas, and Freimer, Nelson B
Subjects: Whole Genome Sequencing for Psychiatric Disorders, Humans, Mental Disorders, Biological Psychiatry, Genome, Human, Genetic Variation, Whole Genome Sequencing, Genetics, Human Genome, Autism, Serious Mental Illness, Schizophrenia, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Health, Biotechnology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Mental health, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract: As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.
Published: 2017

21. Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder

Author: Bishop, Somer L, Farmer, Cristan, Bal, Vanessa, Robinson, Elise B, Willsey, A Jeremy, Werling, Donna M, Havdahl, Karoline Alexandra, Sanders, Stephan J, and Thurm, Audrey
Subjects: Biological Psychology, Psychology, Genetic Testing, Clinical Research, Mental Health, Behavioral and Social Science, Brain Disorders, Autism, Pediatric Research Initiative, Intellectual and Developmental Disabilities (IDD), Genetics, Basic Behavioral and Social Science, Pediatric, 2.3 Psychological, social and economic factors, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Autism Spectrum Disorder, Case-Control Studies, Child, Child, Preschool, DNA Copy Number Variations, DNA Mutational Analysis, Developmental Disabilities, Female, Genotype, Humans, Intelligence, Language Development Disorders, Likelihood Functions, Male, Phenotype, Prognosis, Reference Values, De Novo Mutations, Idiopathic ASD, Simons Simplex Collection, Syndromic ASD, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract: ObjectiveAside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes or loci.MethodAnalyses preemptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains.ResultsChildren with de novo mutations (N=112) had a greater likelihood of motor delay during early development (later age at walking), but they were less impaired on certain measures of ASD core symptoms (parent-rated social communication abnormalities and clinician-rated diagnostic certainty about ASD) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language (i.e., regular use of complex sentences).ConclusionsChildren with ASD with de novo mutations may exhibit a "muted" symptom profile with respect to social communication and language deficits relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental and demographic variables are properly accounted for first.
Published: 2017

22. De Novo Coding Variants Are Strongly Associated with Tourette Disorder.

Author: Willsey, A Jeremy, Fernandez, Thomas V, Yu, Dongmei, King, Robert A, Dietrich, Andrea, Xing, Jinchuan, Sanders, Stephan J, Mandell, Jeffrey D, Huang, Alden Y, Richer, Petra, Smith, Louw, Dong, Shan, Samocha, Kaitlin E, Tourette International Collaborative Genetics (TIC Genetics), Tourette Syndrome Association International Consortium for Genetics (TSAICG), Neale, Benjamin M, Coppola, Giovanni, Mathews, Carol A, Tischfield, Jay A, Scharf, Jeremiah M, State, Matthew W, and Heiman, Gary A
Subjects: Tourette International Collaborative Genetics, Tourette Syndrome Association International Consortium for Genetics, Humans, Tourette Syndrome, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins, Proteins, Cell Cycle Proteins, Fibronectins, Cadherins, Receptors, Cell Surface, Phosphoproteins, Odds Ratio, Cohort Studies, Sequence Analysis, DNA, Parents, Mutation, Adult, Child, Female, Male, Genetic Variation, TIC Genetics, TSAICG, Tourette disorder, Tourette syndrome, de novo variants, gene discovery, whole-exome sequencing, Biotechnology, Brain Disorders, Human Genome, Neurosciences, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Aetiology, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract: Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT.
Published: 2017

23. De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

Author: Abdulkadir, Mohamed, Arbelaez, Juan, Bodmer, Benjamin, Bromberg, Yana, Brown, Lawrence W., Cheon, Keun-Ah, Coffey, Barbara J., Deng, Li, Dietrich, Andrea, Dong, Shan, Duhn, Clif, Elzerman, Lonneke, Fernandez, Thomas V., Fremer, Carolin, Garcia-Delgar, Blanca, Gilbert, Donald L., Grice, Dorothy E., Hagstrøm, Julie, Hedderly, Tammy, Heiman, Gary A., Heyman, Isobel, Hoekstra, Pieter J., Hong, Hyun Ju, Huyser, Chaim, Kim, Eun-Joo, Kim, Young Key, Kim, Young-Shin, King, Robert A., Koh, Yun-Joo, Kook, Sodahm, Kuperman, Samuel, Leventhal, Bennett L, Ludolph, Andrea G., Madruga-Garrido, Marcos, Mandell, Jeffrey D., Maras, Athanasios, Mir, Pablo, Morer, Astrid, Morris, Montana T, Müller-Vahl, Kirsten, Münchau, Alexander, Murphy, Tara L., Nasello, Cara, Plessen, Kerstin J., Poisner, Hannah, Roessner, Veit, Sanders, Stephan J., Shin, Eun-Young, Song, Dong-Ho, Song, Jungeun, State, Matthew W., Sun, Nawei, Thackray, Joshua K., Tischfield, Jay A., Tübing, Jennifer, Visscher, Frank, Wanderer, Sina, Wang, Sheng, Willsey, A Jeremy, Woods, Martin, Xing, Jinchuan, Zhang, Yeting, Zhao, Xin, Zinner, Samuel H., Androutsos, Christos, Barta, Csaba, Farkas, Luca, Fichna, Jakub, Georgitsi, Marianthi, Janik, Piotr, Karagiannidis, Iordanis, Koumoula, Anastasia, Nagy, Peter, Paschou, Peristera, Puchala, Joanna, Rizzo, Renata, Szejko, Natalia, Szymanska, Urszula, Tarnok, Zsanett, Tsironi, Vaia, Wolanczyk, Tomasz, Zekanowski, Cezary, Barr, Cathy L., Batterson, James R., Berlin, Cheston, Bruun, Ruth D., Budman, Cathy L., Cath, Danielle C., Chouinard, Sylvain, Coppola, Giovanni, Cox, Nancy J., Darrow, Sabrina, Davis, Lea K., Dion, Yves, Freimer, Nelson B., Grados, Marco A., Hirschtritt, Matthew E., Huang, Alden Y., Illmann, Cornelia, Kurlan, Roger, Leckman, James F., Lyon, Gholson J., Malaty, Irene A., Mathews, Carol A., MacMahon, William M., Neale, Benjamin M., Okun, Michael S., Osiecki, Lisa, Pauls, David L., Posthuma, Danielle, Ramensky, Vasily, Robertson, Mary M., Rouleau, Guy A., Sandor, Paul, Scharf, Jeremiah M., Singer, Harvey S., Smit, Jan, Sul, Jae-Hoon, Yu, Dongmei, Kumar, Yogesh, Morris, Montana T., Yang, Zhiyu, Padmanabhuni, Shanmukha S., Khalifa, Najah, Dahl, Niklas, Buxbaum, Joseph D., De Rubeis, Silvia, and Willsey, A. Jeremy
Published: 2018
Full Text: View/download PDF

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

Author: Aleksic, Branko, Anney, Richard, Barbosa, Mafalda, Bishop, Somer, Brusco, Alfredo, Bybjerg-Grauholm, Jonas, Carracedo, Angel, Chan, Marcus C.Y., Chiocchetti, Andreas G., Chung, Brian H.Y., Coon, Hilary, Cuccaro, Michael L., Curró, Aurora, Dalla Bernardina, Bernardo, Doan, Ryan, Domenici, Enrico, Dong, Shan, Fallerini, Chiara, Fernández-Prieto, Montserrat, Ferrero, Giovanni Battista, Freitag, Christine M., Fromer, Menachem, Gargus, J. Jay, Geschwind, Daniel, Giorgio, Elisa, González-Peñas, Javier, Guter, Stephen, Halpern, Danielle, Hansen-Kiss, Emily, He, Xin, Herman, Gail E., Hertz-Picciotto, Irva, Hougaard, David M., Hultman, Christina M., Ionita-Laza, Iuliana, Jacob, Suma, Jamison, Jesslyn, Jugessur, Astanand, Kaartinen, Miia, Knudsen, Gun Peggy, Kolevzon, Alexander, Kushima, Itaru, Lee, So Lun, Lehtimäki, Terho, Lim, Elaine T., Lintas, Carla, Lipkin, W. Ian, Lopergolo, Diego, Lopes, Fátima, Ludena, Yunin, Maciel, Patricia, Magnus, Per, Mahjani, Behrang, Maltman, Nell, Manoach, Dara S., Meiri, Gal, Menashe, Idan, Miller, Judith, Minshew, Nancy, Montenegro, Eduarda M.S., Moreira, Danielle, Morrow, Eric M., Mors, Ole, Mortensen, Preben Bo, Mosconi, Matthew, Muglia, Pierandrea, Neale, Benjamin M., Nordentoft, Merete, Ozaki, Norio, Palotie, Aarno, Parellada, Mara, Passos-Bueno, Maria Rita, Pericak-Vance, Margaret, Persico, Antonio M., Pessah, Isaac, Puura, Kaija, Reichenberg, Abraham, Renieri, Alessandra, Riberi, Evelise, Robinson, Elise B., Samocha, Kaitlin E., Sandin, Sven, Santangelo, Susan L., Schellenberg, Gerry, Scherer, Stephen W., Schlitt, Sabine, Schmidt, Rebecca, Schmitt, Lauren, Silva, Isabela M.W., Singh, Tarjinder, Siper, Paige M., Smith, Moyra, Soares, Gabriela, Stoltenberg, Camilla, Suren, Pål, Susser, Ezra, Sweeney, John, Szatmari, Peter, Tang, Lara, Tassone, Flora, Teufel, Karoline, Trabetti, Elisabetta, Trelles, Maria del Pilar, Walsh, Christopher A., Weiss, Lauren A., Werge, Thomas, Werling, Donna M., Wigdor, Emilie M., Wilkinson, Emma, Willsey, A. Jeremy, Yu, Timothy W., Yu, Mullin H.C., Yuen, Ryan, Zachi, Elaine, Agerbo, Esben, Als, Thomas Damm, Appadurai, Vivek, Bækvad-Hansen, Marie, Belliveau, Rich, Buil, Alfonso, Carey, Caitlin E., Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dalsgaard, Søren, Demontis, Ditte, Dumont, Ashley, Goldstein, Jacqueline, Hansen, Christine S., Hauberg, Mads Engel, Hollegaard, Mads V., Howrigan, Daniel P., Huang, Hailiang, Maller, Julian, Martin, Alicia R., Martin, Joanna, Mattheisen, Manuel, Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Poterba, Timothy, Poulsen, Jesper Buchhave, Ripke, Stephan, Schork, Andrew J., Thompson, Wesley K., Turley, Patrick, Walters, Raymond K., Satterstrom, F. Kyle, Kosmicki, Jack A., Wang, Jiebiao, Breen, Michael S., De Rubeis, Silvia, An, Joon-Yong, Peng, Minshi, Collins, Ryan, Grove, Jakob, Klei, Lambertus, Stevens, Christine, Reichert, Jennifer, Mulhern, Maureen S., Artomov, Mykyta, Gerges, Sherif, Sheppard, Brooke, Xu, Xinyi, Bhaduri, Aparna, Norman, Utku, Brand, Harrison, Schwartz, Grace, Nguyen, Rachel, Guerrero, Elizabeth E., Dias, Caroline, Betancur, Catalina, Cook, Edwin H., Gallagher, Louise, Gill, Michael, Sutcliffe, James S., Thurm, Audrey, Zwick, Michael E., Børglum, Anders D., State, Matthew W., Cicek, A. Ercument, Talkowski, Michael E., Cutler, David J., Devlin, Bernie, Sanders, Stephan J., Roeder, Kathryn, Daly, Mark J., and Buxbaum, Joseph D.
Published: 2020
Full Text: View/download PDF

25. Localized JNK signaling regulates organ size during development.

Author: Willsey, Helen Rankin, Zheng, Xiaoyan, Carlos Pastor-Pareja, José, Willsey, A Jeremy, Beachy, Philip A, and Xu, Tian
Subjects: Extremities, Animals, Drosophila, MAP Kinase Signaling System, Gene Expression Regulation, Developmental, Organogenesis, Arthropod Antennae, Wings, Animal, D. melanogaster, Hedgehog, Hippo, JNK, TRAF4, development, developmental biology, size control, stem cells, Gene Expression Regulation, Developmental, Wings, Animal, Biochemistry and Cell Biology
Abstract: A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control.
Published: 2016

26. The Genetic Etiology of Tourette Syndrome: Large-Scale Collaborative Efforts on the Precipice of Discovery.

Author: Georgitsi, Marianthi, Willsey, A Jeremy, Mathews, Carol A, State, Matthew, Scharf, Jeremiah M, and Paschou, Peristera
Subjects: GWAS, Gilles de la Tourette syndrome, collaborative studies, gene-environment interactions, genetics of complex disorders, neurodevelopmental disorders, next generation sequencing, Clinical Research, Neurodegenerative, Pediatric, Tourette Syndrome, Brain Disorders, Genetics, Neurosciences, Rare Diseases, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Psychology, Cognitive Sciences
Abstract: Gilles de la Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder that is characterized by multiple motor and phonic tics. It has a complex etiology with multiple genes likely interacting with environmental factors to lead to the onset of symptoms. The genetic basis of the disorder remains elusive. However, multiple resources and large-scale projects are coming together, launching a new era in the field and bringing us on the verge of discovery. The large-scale efforts outlined in this report are complementary and represent a range of different approaches to the study of disorders with complex inheritance. The Tourette Syndrome Association International Consortium for Genetics (TSAICG) has focused on large families, parent-proband trios and cases for large case-control designs such as genomewide association studies (GWAS), copy number variation (CNV) scans, and exome/genome sequencing. TIC Genetics targets rare, large effect size mutations in simplex trios, and multigenerational families. The European Multicentre Tics in Children Study (EMTICS) seeks to elucidate gene-environment interactions including the involvement of infection and immune mechanisms in TS etiology. Finally, TS-EUROTRAIN, a Marie Curie Initial Training Network, aims to act as a platform to unify large-scale projects in the field and to educate the next generation of experts. Importantly, these complementary large-scale efforts are joining forces to uncover the full range of genetic variation and environmental risk factors for TS, holding great promise for identifying definitive TS susceptibility genes and shedding light into the complex pathophysiology of this disorder.
Published: 2016

27. The PsychENCODE project

Author: Akbarian, Schahram, Liu, Chunyu, Knowles, James A, Vaccarino, Flora M, Farnham, Peggy J, Crawford, Gregory E, Jaffe, Andrew E, Pinto, Dalila, Dracheva, Stella, Geschwind, Daniel H, Mill, Jonathan, Nairn, Angus C, Abyzov, Alexej, Pochareddy, Sirisha, Prabhakar, Shyam, Weissman, Sherman, Sullivan, Patrick F, State, Matthew W, Weng, Zhiping, Peters, Mette A, White, Kevin P, Gerstein, Mark B, Amiri, Anahita, Armoskus, Chris, Ashley-Koch, Allison E, Bae, Taejeong, Beckel-Mitchener, Andrea, Berman, Benjamin P, Coetzee, Gerhard A, Coppola, Gianfilippo, Francoeur, Nancy, Fromer, Menachem, Gao, Robert, Grennan, Kay, Herstein, Jennifer, Kavanagh, David H, Ivanov, Nikolay A, Jiang, Yan, Kitchen, Robert R, Kozlenkov, Alexey, Kundakovic, Marija, Li, Mingfeng, Li, Zhen, Liu, Shuang, Mangravite, Lara M, Mattei, Eugenio, Markenscoff-Papadimitriou, Eirene, Navarro, Fábio CP, North, Nicole, Omberg, Larsson, Panchision, David, Parikshak, Neelroop, Poschmann, Jeremie, Price, Amanda J, Purcaro, Michael, Reddy, Timothy E, Roussos, Panos, Schreiner, Shannon, Scuderi, Soraya, Sebra, Robert, Shibata, Mikihito, Shieh, Annie W, Skarica, Mario, Sun, Wenjie, Swarup, Vivek, Thomas, Amber, Tsuji, Junko, van Bakel, Harm, Wang, Daifeng, Wang, Yongjun, Wang, Kai, Werling, Donna M, Willsey, A Jeremy, Witt, Heather, Won, Hyejung, Wong, Chloe CY, Wray, Gregory A, Wu, Emily Y, Xu, Xuming, Yao, Lijing, Senthil, Geetha, Lehner, Thomas, Sklar, Pamela, and Sestan, Nenad
Subjects: Biotechnology, Human Genome, Brain Disorders, Genetics, Mental Health, Serious Mental Illness, Neurosciences, Schizophrenia, Intellectual and Developmental Disabilities (IDD), Autism, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, Mental health, Animals, Brain, Chromosome Mapping, Epigenesis, Genetic, Genetic Code, Humans, Mental Disorders, Transcriptome, PsychENCODE Consortium, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract: Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. We are beginning with a focus on autism spectrum disorder, bipolar disorder and schizophrenia, and expect that this knowledge will apply to a wide variety of psychiatric disorders. This paper outlines the motivation and design of PsychENCODE.
Published: 2015

28. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Author: Sanders, Stephan J, He, Xin, Willsey, A Jeremy, Ercan-Sencicek, A Gulhan, Samocha, Kaitlin E, Cicek, A Ercument, Murtha, Michael T, Bal, Vanessa H, Bishop, Somer L, Dong, Shan, Goldberg, Arthur P, Jinlu, Cai, Keaney, John F, Klei, Lambertus, Mandell, Jeffrey D, Moreno-De-Luca, Daniel, Poultney, Christopher S, Robinson, Elise B, Smith, Louw, Solli-Nowlan, Tor, Su, Mack Y, Teran, Nicole A, Walker, Michael F, Werling, Donna M, Beaudet, Arthur L, Cantor, Rita M, Fombonne, Eric, Geschwind, Daniel H, Grice, Dorothy E, Lord, Catherine, Lowe, Jennifer K, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Talkowski, Michael E, Sutcliffe, James S, Walsh, Christopher A, Yu, Timothy W, Consortium, Autism Sequencing, Ledbetter, David H, Martin, Christa Lese, Cook, Edwin H, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, and State, Matthew W
Subjects: Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Pediatric, Prevention, Biotechnology, Brain Disorders, Genetics, Mental Health, Intellectual and Developmental Disabilities (IDD), Human Genome, Autism, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Female, Genetic Loci, Genetic Variation, Humans, Male, Protein Interaction Maps, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract: Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).
Published: 2015

29. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Author: Chaste, Pauline, Klei, Lambertus, Sanders, Stephan J, Hus, Vanessa, Murtha, Michael T, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, Lese Martin, Christa, Beaudet, Arthur L, Lord, Catherine, State, Matthew W, Cook, Edwin H, and Devlin, Bernie
Subjects: Humans, Genetic Predisposition to Disease, Family, Autistic Disorder, Phenotype, Polymorphism, Single Nucleotide, Female, Male, Genetic Variation, Genome-Wide Association Study, Autism Spectrum Disorder, Autism, GWAS, Genetics, Heterogeneity, Power, Genetic Testing, Pediatric, Intellectual and Developmental Disabilities (IDD), Mental Health, Human Genome, Brain Disorders, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract: BackgroundPhenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.MethodsGenome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.ResultsAssociation analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.ConclusionsIn genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.
Published: 2015

30. Autism spectrum disorders: from genes to neurobiology

Author: Willsey, A Jeremy and State, Matthew W
Subjects: Biomedical and Clinical Sciences, Neurosciences, Intellectual and Developmental Disabilities (IDD), Clinical Research, Brain Disorders, Mental Health, Pediatric, Human Genome, Genetics, Biotechnology, Autism, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, Mental health, Brain, Child Development Disorders, Pervasive, Genetic Predisposition to Disease, Humans, Neurobiology, Cognitive Sciences
Abstract: Advances in genome-wide technology, coupled with the availability of large cohorts, are finally yielding a steady stream of autism spectrum disorder (ASD) genes carrying mutations of large effect. These findings represent important molecular clues, but at the same time present notable challenges to traditional strategies for moving from genes to neurobiology. A remarkable degree of genetic heterogeneity, the biological pleiotropy of ASD genes, and the tremendous complexity of the human brain are prompting the development of new strategies for translating genetic discoveries into therapeutic targets. Recent developments in systems biology approaches that 'contextualize' these genetic findings along spatial, temporal, and cellular axes of human brain development are beginning to bridge the gap between high-throughput gene discovery and testable pathophysiological hypotheses.
Published: 2015

31. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author: Lee, Phil H., Anttila, Verneri, Won, Hyejung, Feng, Yen-Chen A., Rosenthal, Jacob, Zhu, Zhaozhong, Tucker-Drob, Elliot M., Nivard, Michel G., Grotzinger, Andrew D., Posthuma, Danielle, Wang, Meg M.-J., Yu, Dongmei, Stahl, Eli A., Walters, Raymond K., Anney, Richard J.L., Duncan, Laramie E., Ge, Tian, Adolfsson, Rolf, Banaschewski, Tobias, Belangero, Sintia, Cook, Edwin H., Coppola, Giovanni, Derks, Eske M., Hoekstra, Pieter J., Kaprio, Jaakko, Keski-Rahkonen, Anna, Kirov, George, Kranzler, Henry R., Luykx, Jurjen J., Rohde, Luis A., Zai, Clement C., Agerbo, Esben, Arranz, M.J., Asherson, Philip, Bækvad-Hansen, Marie, Baldursson, Gísli, Bellgrove, Mark, Belliveau, Richard A., Jr., Buitelaar, Jan, Burton, Christie L., Bybjerg-Grauholm, Jonas, Casas, Miquel, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Cormand, Bru, Crosbie, Jennifer, Dalsgaard, Søren, Demontis, Ditte, Doyle, Alysa E., Dumont, Ashley, Elia, Josephine, Grove, Jakob, Gudmundsson, Olafur O., Haavik, Jan, Hakonarson, Hakon, Hansen, Christine S., Hartman, Catharina A., Hawi, Ziarih, Hervás, Amaia, Hougaard, David M., Howrigan, Daniel P., Huang, Hailiang, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Leung, Patrick W.L., Loo, Sandra K., Martin, Joanna, Martin, Alicia R., McGough, James J., Medland, Sarah E., Moran, Jennifer L., Mors, Ole, Mortensen, Preben B., Oades, Robert D., Palmer, Duncan S., Pedersen, Carsten B., Pedersen, Marianne G., Peters, Triinu, Poterba, Timothy, Poulsen, Jesper B., Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Rothenberger, Aribert, Rovira, Paula, Sánchez-Mora, Cristina, Satterstrom, F. Kyle, Schachar, Russell, Artigas, Maria Soler, Steinberg, Stacy, Stefansson, Hreinn, Turley, Patrick, Walters, G. Bragi, Werge, Thomas, Zayats, Tetyana, Arking, Dan E., Bettella, Francesco, Buxbaum, Joseph D., Christensen, Jane H., Collins, Ryan L., Coon, Hilary, De Rubeis, Silvia, Delorme, Richard, Grice, Dorothy E., Hansen, Thomas F., Holmans, Peter A., Hope, Sigrun, Hultman, Christina M., Klei, Lambertus, Ladd-Acosta, Christine, Magnusson, Pall, Nærland, Terje, Nyegaard, Mette, Pinto, Dalila, Qvist, Per, Rehnström, Karola, Reichenberg, Abraham, Reichert, Jennifer, Roeder, Kathryn, Rouleau, Guy A., Saemundsen, Evald, Sanders, Stephan J., Sandin, Sven, St Pourcain, Beate, Stefansson, Kari, Sutcliffe, James S., Talkowski, Michael E., Weiss, Lauren A., Willsey, A. Jeremy, Agartz, Ingrid, Akil, Huda, Albani, Diego, Alda, Martin, Als, Thomas D., Anjorin, Adebayo, Backlund, Lena, Bass, Nicholas, Bauer, Michael, Baune, Bernhard T., Bellivier, Frank, Bergen, Sarah E., Berrettini, Wade H., Biernacka, Joanna M., Blackwood, Douglas H.R., Bøen, Erlend, Budde, Monika, Bunney, William, Burmeister, Margit, Byerley, William, Byrne, Enda M., Cichon, Sven, Clarke, Toni-Kim, Coleman, Jonathan R.I., Craddock, Nicholas, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna, Elvsåshagen, Torbjørn, Etain, Bruno, Fischer, Sascha B., Forstner, Andreas J., Forty, Liz, Frank, Josef, Frye, Mark, Fullerton, Janice M., Gade, Katrin, Gaspar, Héléna A., Gershon, Elliot S., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Gordon-Smith, Katherine, Green, Melissa J., Greenwood, Tiffany A., Grigoroiu-Serbanescu, Maria, Guzman-Parra, José, Hauser, Joanna, Hautzinger, Martin, Heilbronner, Urs, Herms, Stefan, Hoffmann, Per, Holland, Dominic, Jamain, Stéphane, Jones, Ian, Jones, Lisa A., Kandaswamy, Radhika, Kelsoe, John R., Kennedy, James L., Joachim, Oedegaard Ketil, Kittel-Schneider, Sarah, Kogevinas, Manolis, Koller, Anna C., Lavebratt, Catharina, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Loohuis, Loes M.O., Lucae, Susanne, Maaser, Anna, Malt, Ulrik F., Martin, Nicholas G., Martinsson, Lina, McElroy, Susan L., McMahon, Francis J., McQuillin, Andrew, Melle, Ingrid, Metspalu, Andres, Millischer, Vincent, Mitchell, Philip B., Montgomery, Grant W., Morken, Gunnar, Morris, Derek W., Müller-Myhsok, Bertram, Mullins, Niamh, Myers, Richard M., Nievergelt, Caroline M., Nordentoft, Merete, Adolfsson, Annelie Nordin, Nöthen, Markus M., Ophoff, Roel A., Owen, Michael J., Paciga, Sara A., Pato, Carlos N., Pato, Michele T., Perlis, Roy H., Perry, Amy, Potash, James B., Reinbold, Céline S., Rietschel, Marcella, Rivera, Margarita, Roberson, Mary, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Sigurdsson, Engilbert, Smeland, Olav B., Stordal, Eystein, Streit, Fabian, Strohmaier, Jana, Thorgeirsson, Thorgeir E., Treutlein, Jens, Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Wang, Yunpeng, Witt, Stephanie H., Zandi, Peter, Adan, Roger A.H., Alfredsson, Lars, Ando, Tetsuya, Aschauer, Harald, Baker, Jessica H., Bencko, Vladimir, Bergen, Andrew W., Birgegård, Andreas, Perica, Vesna Boraska, Brandt, Harry, Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Clementi, Maurizio, Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, James J., Danner, Unna N., Davis, Oliver S.P., Degortes, Daniela, DeSocio, Janiece E., Dick, Danielle M., Dina, Christian, Docampo, Elisa, Egberts, Karin, Ehrlich, Stefan, Espeseth, Thomas, Fernández-Aranda, Fernando, Fichter, Manfred M., Foretova, Lenka, Forzan, Monica, Gambaro, Giovanni, Giegling, Ina, Gonidakis, Fragiskos, Gorwood, Philip, Mayora, Monica Gratacos, Guo, Yiran, Halmi, Katherine A., Hatzikotoulas, Konstantinos, Hebebrand, Johannes, Helder, Sietske G., Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Imgart, Hartmut, Jiménez-Murcia, Susana, Johnson, Craig, Jordan, Jennifer, Julià, Antonio, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J.H., Kaye, Walter H., Kennedy, Martin A., Kim, Youl-Ri, Klareskog, Lars, Klump, Kelly L., Knudsen, Gun Peggy S., Landén, Mikael, Le Hellard, Stephanie, Levitan, Robert D., Li, Dong, Lichtenstein, Paul, Maj, Mario, Marsal, Sara, McDevitt, Sara, Mitchell, James, Monteleone, Palmiero, Monteleone, Alessio Maria, Munn-Chernoff, Melissa A., Nacmias, Benedetta, Navratilova, Marie, O’Toole, Julie K., Padyukov, Leonid, Pantel, Jacques, Papezova, Hana, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Roberts, Marion, Rujescu, Dan, Rybakowski, Filip, Scherag, André, Schmidt, Ulrike, Seitz, Jochen, Slachtova, Lenka, Slof-Op‘t Landt, Margarita C.T., Slopien, Agnieszka, Sorbi, Sandro, Southam, Lorraine, Strober, Michael, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tziouvas, Konstantinos, van Elburg, Annemarie A., Wade, Tracey D., Wagner, Gudrun, Walton, Esther, Watson, Hunna J., Wichmann, H-Erich, Woodside, D. Blake, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Adams, Mark J., Andlauer, Till F.M., Berger, Klaus, Binder, Elisabeth B., Boomsma, Dorret I., Castelao, Enrique, Colodro-Conde, Lucía, Direk, Nese, Docherty, Anna R., Domenici, Enrico, Domschke, Katharina, Dunn, Erin C., Foo, Jerome C., de. Geus, E.J.C., Grabe, Hans J., Hamilton, Steven P., Horn, Carsten, Hottenga, Jouke-Jan, Howard, David, Ising, Marcus, Kloiber, Stefan, Levinson, Douglas F., Lewis, Glyn, Magnusson, Patrik K.E., Mbarek, Hamdi, Middeldorp, Christel M., Mostafavi, Sara, Nyholt, Dale R., Penninx, Brenda WJH., Peterson, Roseann E., Pistis, Giorgio, Porteous, David J., Preisig, Martin, Quiroz, Jorge A., Schaefer, Catherine, Schulte, Eva C., Shi, Jianxin, Smith, Daniel J., Thomson, Pippa A., Tiemeier, Henning, Uher, Rudolf, van der Auwera, Sandra, Weissman, Myrna M., Alexander, Madeline, Begemann, Martin, Bramon, Elvira, Buccola, Nancy G., Cairns, Murray J., Campion, Dominique, Carr, Vaughan J., Cloninger, C. Robert, Cohen, David, Collier, David A., Corvin, Aiden, DeLisi, Lynn E., Donohoe, Gary, Dudbridge, Frank, Duan, Jubao, Freedman, Robert, Gejman, Pablo V., Golimbet, Vera, Godard, Stephanie, Ehrenreich, Hannelore, Hartmann, Annette M., Henskens, Frans A., Ikeda, Masashi, Iwata, Nakao, Jablensky, Assen V., Joa, Inge, Jönsson, Erik G., Kelly, Brian J., Knight, Jo, Konte, Bettina, Laurent-Levinson, Claudine, Lee, Jimmy, Lencz, Todd, Lerer, Bernard, Loughland, Carmel M., Malhotra, Anil K., Mallet, Jacques, McDonald, Colm, Mitjans, Marina, Mowry, Bryan J., Murphy, Kieran C., Murray, Robin M., O’Neill, F. Anthony, Oh, Sang-Yun, Palotie, Aarno, Pantelis, Christos, Pulver, Ann E., Petryshen, Tracey L., Quested, Digby J., Riley, Brien, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Scott, Rodney J., Sham, Pak C., Silverman, Jeremy M., Sim, Kang, Steixner, Agnes A., Tooney, Paul A., van Os, Jim, Vawter, Marquis P., Walsh, Dermot, Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Wormley, Brandon K., Zhang, Fuquan, Androutsos, Christos, Arnold, Paul D., Barr, Cathy L., Barta, Csaba, Bey, Katharina, Bienvenu, O. Joseph, Black, Donald W., Brown, Lawrence W., Budman, Cathy, Cath, Danielle, Cheon, Keun-Ah, Ciullo, Valentina, Coffey, Barbara J., Cusi, Daniele, Davis, Lea K., Denys, Damiaan, Depienne, Christel, Dietrich, Andrea, Eapen, Valsamma, Falkai, Peter, Fernandez, Thomas V., Garcia-Delgar, Blanca, Geller, Daniel A., Gilbert, Donald L., Grados, Marco A., Greenberg, Erica, Grünblatt, Edna, Hagstrøm, Julie, Hanna, Gregory L., Hartmann, Andreas, Hedderly, Tammy, Heiman, Gary A., Heyman, Isobel, Hong, Hyun Ju, Huang, Alden, Huyser, Chaim, Ibanez-Gomez, Laura, Khramtsova, Ekaterina A., Kim, Young Key, Kim, Young-Shin, King, Robert A., Koh, Yun-Joo, Konstantinidis, Anastasios, Kook, Sodahm, Kuperman, Samuel, Leventhal, Bennett L., Lochner, Christine, Ludolph, Andrea G., Madruga-Garrido, Marcos, Malaty, Irene, Maras, Athanasios, McCracken, James T., Meijer, Inge A., Mir, Pablo, Morer, Astrid, Müller-Vahl, Kirsten R., Münchau, Alexander, Murphy, Tara L., Naarden, Allan, Nagy, Peter, Nestadt, Gerald, Nestadt, Paul S., Nicolini, Humberto, Nurmi, Erika L., Okun, Michael S., Paschou, Peristera, Piras, Fabrizio, Piras, Federica, Pittenger, Christopher, Plessen, Kerstin J., Richter, Margaret A., Rizzo, Renata, Robertson, Mary, Roessner, Veit, Ruhrmann, Stephan, Samuels, Jack F., Sandor, Paul, Schlögelhofer, Monika, Shin, Eun-Young, Singer, Harvey, Song, Dong-Ho, Song, Jungeun, Spalletta, Gianfranco, Stein, Dan J., Stewart, S Evelyn, Storch, Eric A., Stranger, Barbara, Stuhrmann, Manfred, Tarnok, Zsanett, Tischfield, Jay A., Tübing, Jennifer, Visscher, Frank, Vulink, Nienke, Wagner, Michael, Walitza, Susanne, Wanderer, Sina, Woods, Martin, Worbe, Yulia, Zai, Gwyneth, Zinner, Samuel H., Sullivan, Patrick F., Franke, Barbara, Daly, Mark J., Bulik, Cynthia M., McIntosh, Andrew M., O’Donovan, Michael C., Zheutlin, Amanda, Andreassen, Ole A., Børglum, Anders D., Breen, Gerome, Edenberg, Howard J., Fanous, Ayman H., Faraone, Stephen V., Gelernter, Joel, Mathews, Carol A., Mattheisen, Manuel, Mitchell, Karen S., Neale, Michael C., Nurnberger, John I., Ripke, Stephan, Santangelo, Susan L., Scharf, Jeremiah M., Stein, Murray B., Thornton, Laura M., Walters, James T.R., Wray, Naomi R., Geschwind, Daniel H., Neale, Benjamin M., Kendler, Kenneth S., and Smoller, Jordan W.
Published: 2019
Full Text: View/download PDF

32. Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data

Author: Glessner, Joseph T, Bick, Alexander G, Ito, Kaoru, Homsy, Jason, Rodriguez-Murillo, Laura, Fromer, Menachem, Mazaika, Erica, Vardarajan, Badri, Italia, Michael, Leipzig, Jeremy, DePalma, Steven R, Golhar, Ryan, Sanders, Stephan J, Yamrom, Boris, Ronemus, Michael, Iossifov, Ivan, Willsey, A Jeremy, State, Matthew W, Kaltman, Jonathan R, White, Peter S, Shen, Yufeng, Warburton, Dorothy, Brueckner, Martina, Seidman, Christine, Goldmuntz, Elizabeth, Gelb, Bruce D, Lifton, Richard, Seidman, Jonathan, Hakonarson, Hakon, and Chung, Wendy K
Subjects: Human Genome, Pediatric, Congenital Structural Anomalies, Genetics, Cardiovascular, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Cohort Studies, DNA Copy Number Variations, Exome, Gene Frequency, Gene Regulatory Networks, Heart Defects, Congenital, Humans, Molecular Sequence Data, Polymorphism, Single Nucleotide, DNA copy number variations, genomics, microarray analysis, polymorphism, single nucleotide, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract: RationaleCongenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.ObjectiveTo determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD.Methods and resultsWe studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6×10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.ConclusionsWe demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.
Published: 2014

33. De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

Author: Dong, Shan, Walker, Michael F, Carriero, Nicholas J, DiCola, Michael, Willsey, A Jeremy, Ye, Adam Y, Waqar, Zainulabedin, Gonzalez, Luis E, Overton, John D, Frahm, Stephanie, Keaney, John F, Teran, Nicole A, Dea, Jeanselle, Mandell, Jeffrey D, Bal, Vanessa Hus, Sullivan, Catherine A, DiLullo, Nicholas M, Khalil, Rehab O, Gockley, Jake, Yuksel, Zafer, Sertel, Sinem M, Ercan-Sencicek, A Gulhan, Gupta, Abha R, Mane, Shrikant M, Sheldon, Michael, Brooks, Andrew I, Roeder, Kathryn, Devlin, Bernie, State, Matthew W, Wei, Liping, and Sanders, Stephan J
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Autism, Human Genome, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Health, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Mental health, Child, Child Development Disorders, Pervasive, DNA, DNA-Binding Proteins, Female, Fragile X Mental Retardation Protein, Frameshift Mutation, GTP-Binding Proteins, Humans, Male, Nerve Tissue Proteins, Pedigree, Phenotype, Sequence Deletion, Sex Factors, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract: Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
Published: 2014

34. Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2.

Author: Chaste, Pauline, Sanders, Stephan J, Mohan, Kommu N, Klei, Lambertus, Song, Youeun, Murtha, Michael T, Hus, Vanessa, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Lord, Catherine, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, State, Matthew W, Martin, Christa Lese, Devlin, Bernie, Beaudet, Arthur L, Cook, Edwin H, and Kim, Soo-Jeong
Subjects: Chromosomes, Human, Pair 15, Humans, Chromosome Deletion, Genetic Predisposition to Disease, Child Development Disorders, Pervasive, Adult, Child, Female, Male, DNA Copy Number Variations, 15q11.2, autism, deletion, duplication, penetrance, Developmental & Child Psychology, Clinical Sciences, Neurosciences, Psychology
Abstract: The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.
Published: 2014

35. The developmental transcriptome of the human brain

Author: Tebbenkamp, Andrew TN, Willsey, A Jeremy, State, Matthew W, and Šestan, Nenad
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Autism, Mental Health, Human Genome, Genetics, Pediatric, Intellectual and Developmental Disabilities (IDD), Brain Disorders, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, Neurological, Mental health, Brain, Brain Diseases, Child Development Disorders, Pervasive, Developmental Disabilities, Gene Expression Regulation, Developmental, Humans, Schizophrenia, Transcriptome, Williams Syndrome, autism spectrum disorder, gene co-expression analysis, genetics, psychiatric and neurologic disorders, schizophrenia, Williams syndrome, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract: Purpose of reviewRecent characterizations of the transcriptome of the developing human brain by several groups have generated comprehensive datasets on coding and noncoding RNAs that will be instrumental for illuminating the underlying biology of complex neurodevelopmental disorders. This review summarizes recent studies successfully utilizing these data to increase our understanding of the molecular mechanisms of pathogenesis.Recent findingsSeveral approaches have successfully integrated developmental transcriptome data with gene discovery to generate testable hypotheses about when and where in the developing human brain disease-associated genes converge. Specifically, these include the projection neurons in the prefrontal and primary motor--somatosensory cortex during mid-fetal development in autism spectrum disorder and the frontal cortex during fetal development in schizophrenia.SummaryDevelopmental transcriptome data is a key to interpreting disease-associated mutations and transcriptional changes. Novel approaches integrating the spatial and temporal dimensions of these data have increased our understanding of when and where disease occurs. Refinement of spatial and temporal properties and expanding these findings to other neurodevelopmental disorders will provide critical insights for understanding disease biology.
Published: 2014

36. Single-Nucleotide Polymorphism

Author: Willsey, A. Jeremy, primary and Morris, Montana T., additional
Published: 2021
Full Text: View/download PDF

37. Next-Generation Sequencing

Author: Willsey, A. Jeremy, primary and Morris, Montana T., additional
Published: 2021
Full Text: View/download PDF

38. Copy Number Variation

Author: Willsey, A. Jeremy, primary and Morris, Montana T., additional
Published: 2021
Full Text: View/download PDF

39. Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis

Author: Sun, Nawei, primary, Teyssier, Noam, additional, Wang, Belinda, additional, Drake, Sam, additional, Seyler, Meghan, additional, Zaltsman, Yefim, additional, Everitt, Amanda, additional, Teerikorpi, Nia, additional, Willsey, Helen Rankin, additional, Goodarzi, Hani, additional, Tian, Ruilin, additional, Kampmann, Martin, additional, and Willsey, A. Jeremy, additional
Published: 2023
Full Text: View/download PDF

40. A foundational atlas of autism protein interactions reveals molecular convergence

Author: Wang, Belinda, primary, Vartak, Rasika, additional, Zaltsman, Yefim, additional, Naing, Zun Zar Chi, additional, Hennick, Kelsey M., additional, Polacco, Benjamin J., additional, Bashir, Ali, additional, Eckhardt, Manon, additional, Bouhaddou, Mehdi, additional, Xu, Jiewei, additional, Sun, Nawei, additional, Lasser, Micaela C., additional, Zhou, Yuan, additional, McKetney, Justin, additional, Guiley, Keelan Z., additional, Chan, Una, additional, Kaye, Julia A., additional, Chadha, Nishant, additional, Cakir, Merve, additional, Gordon, Martin, additional, Khare, Prachi, additional, Drake, Sam, additional, Drury, Vanessa, additional, Burke, David F., additional, Gonzalez, Silvano, additional, Alkhairy, Sahar, additional, Thomas, Reuben, additional, Lam, Stephanie, additional, Morris, Montana, additional, Bader, Ethel, additional, Seyler, Meghan, additional, Baum, Tierney, additional, Krasnoff, Rebecca, additional, Wang, Sheng, additional, Pham, Presley, additional, Arbalaez, Juan, additional, Pratt, Dexter, additional, Chag, Shivali, additional, Mahmood, Nadir, additional, Rolland, Thomas, additional, Bourgeron, Thomas, additional, Finkbeiner, Steven, additional, Swaney, Danielle L., additional, Bandyopadhay, Sourav, additional, Ideker, Trey, additional, Beltrao, Pedro, additional, Willsey, Helen Rankin, additional, Obernier, Kirsten, additional, Nowakowski, Tomasz J., additional, Hüttenhain, Ruth, additional, State, Matthew W., additional, Willsey, A. Jeremy, additional, and Krogan, Nevan J., additional
Published: 2023
Full Text: View/download PDF

41. Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity

Author: Fazel Darbandi, Siavash, Robinson Schwartz, Sarah E., Qi, Qihao, Catta-Preta, Rinaldo, Pai, Emily Ling-Lin, Mandell, Jeffrey D., Everitt, Amanda, Rubin, Anna, Krasnoff, Rebecca A., Katzman, Sol, Tastad, David, Nord, Alex S., Willsey, A. Jeremy, Chen, Bin, State, Matthew W., Sohal, Vikaas S., and Rubenstein, John L.R.
Published: 2018
Full Text: View/download PDF

42. Coexpression Networks Implicate Human Midfetal Deep Cortical Projection Neurons in the Pathogenesis of Autism

Author: Willsey, A Jeremy, Sanders, Stephan J, Li, Mingfeng, Dong, Shan, Tebbenkamp, Andrew T, Muhle, Rebecca A, Reilly, Steven K, Lin, Leon, Fertuzinhos, Sofia, Miller, Jeremy A, Murtha, Michael T, Bichsel, Candace, Niu, Wei, Cotney, Justin, Ercan-Sencicek, A Gulhan, Gockley, Jake, Gupta, Abha R, Han, Wenqi, He, Xin, Hoffman, Ellen J, Klei, Lambertus, Lei, Jing, Liu, Wenzhong, Liu, Li, Lu, Cong, Xu, Xuming, Zhu, Ying, Mane, Shrikant M, Lein, Ed S, Wei, Liping, Noonan, James P, Roeder, Kathryn, Devlin, Bernie, Sestan, Nenad, and State, Matthew W
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Mental Health, Intellectual and Developmental Disabilities (IDD), Pediatric, Brain Disorders, Clinical Research, Autism, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Neurological, Mental health, Animals, Brain, Child Development Disorders, Pervasive, Exome, Female, Fetus, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mice, Mutation, Neurons, Prefrontal Cortex, Sequence Analysis, DNA, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.
Published: 2013

43. Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait.

Author: Chaste, Pauline, Klei, Lambertus, Sanders, Stephan J, Murtha, Michael T, Hus, Vanessa, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Lord, Catherine, Mane, Shrikant M, Lese Martin, Christa, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, State, Matthew W, Devlin, Bernie, Cook, Edwin H, and Kim, Soo-Jeong
Subjects: Head, Humans, Body Weights and Measures, Intelligence, Family, Autistic Disorder, Quantitative Trait, Heritable, Adult, Child, Female, Male, ASD, IQ, autism spectrum disorder, body metrics, genetic ancestry, head circumference, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract: BackgroundBrain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort.MethodsWe used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters.ResultsGender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC.ConclusionsMeasured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.
Published: 2013

44. De Novo Coding Variants Are Strongly Associated with Tourette Disorder

Author: Abdulkadir, Mohamed, Bohnenpoll, Julia, Bromberg, Yana, Brown, Lawrence W., Cheon, Keun-Ah, Coffey, Barbara J., Deng, Li, Dietrich, Andrea, Dong, Shan, Elzerman, Lonneke, Fernandez, Thomas V., Fründt, Odette, Garcia-Delgar, Blanca, Gedvilaite, Erika, Gilbert, Donald L., Grice, Dorothy E., Hagstrøm, Julie, Hedderly, Tammy, Heiman, Gary A., Heyman, Isobel, Hoekstra, Pieter J., Hong, Hyun Ju, Huyser, Chaim, Ibanez-Gomez, Laura, Kim, Young Key, Kim, Young-Shin, King, Robert A., Koh, Yun-Joo, Kook, Sodahm, Kuperman, Samuel, Lamerz, Andreas, Leventhal, Bennett, Ludolph, Andrea G., Lühr da Silva, Claudia, Madruga-Garrido, Marcos, Mandell, Jeffrey D., Maras, Athanasios, Mir, Pablo, Morer, Astrid, Münchau, Alexander, Murphy, Tara L., Nasello, Cara, Openneer, Thaïra J.C., Plessen, Kerstin J., Richer, Petra, Roessner, Veit, Sanders, Stephan, Shin, Eun-Young, Sival, Deborah A., Smith, Louw, Song, Dong-Ho, Song, Jungeun, State, Matthew W., Stolte, Anne Marie, Sun, Nawei, Tischfield, Jay A., Tübing, Jennifer, Visscher, Frank, Walker, Michael F., Wanderer, Sina, Wang, Shuoguo, Willsey, A. Jeremy, Woods, Martin, Xing, Jinchuan, Zhang, Yeting, Zhou, Anbo, Zinner, Samuel H., Barr, Cathy L., Batterson, James R., Berlin, Cheston, Bruun, Ruth D., Budman, Cathy L., Cath, Danielle C., Chouinard, Sylvain, Coppola, Giovanni, Cox, Nancy J., Darrow, Sabrina, Davis, Lea K., Dion, Yves, Freimer, Nelson B., Grados, Marco A., Hirschtritt, Matthew E., Huang, Alden Y., Illmann, Cornelia, Kurlan, Roger, Leckman, James F., Lyon, Gholson J., Malaty, Irene A., Mathews, Carol A., MaMahon, William M., Neale, Benjamin M., Okun, Michael S., Osiecki, Lisa, Pauls, David L., Posthuma, Danielle, Ramensky, Vasily, Robertson, Mary M., Rouleau, Guy A., Sandor, Paul, Scharf, Jeremiah M., Singer, Harvey S., Smit, Jan, Sul, Jae-Hoon, Yu, Dongmei, Sanders, Stephan J., and Samocha, Kaitlin E.
Published: 2017
Full Text: View/download PDF

45. Single-Nucleotide Polymorphism

Author: Willsey, A. Jeremy, primary and Morris, Montana T., additional
Published: 2020
Full Text: View/download PDF

46. Copy Number Variation

Author: Willsey, A. Jeremy, primary and Morris, Montana T., additional
Published: 2020
Full Text: View/download PDF

47. Next-Generation Sequencing

Author: Willsey, A. Jeremy, primary and Morris, Montana T., additional
Published: 2020
Full Text: View/download PDF

48. Pleiotropy of autism-associated chromatin regulators

Author: Lasser, Micaela, primary, Sun, Nawei, additional, Xu, Yuxiao, additional, Wang, Sheng, additional, Drake, Sam, additional, Law, Karen, additional, Gonzalez, Silvano, additional, Wang, Belinda, additional, Drury, Vanessa, additional, Castillo, Octavio, additional, Zaltsman, Yefim, additional, Dea, Jeanselle, additional, Bader, Ethel, additional, McCluskey, Kate E., additional, State, Matthew W., additional, Willsey, A. Jeremy, additional, and Willsey, Helen Rankin, additional
Published: 2023
Full Text: View/download PDF

49. Adrenomedullin promotes interneuron migration in a dual human model for hypoxic interneuronopathy of prematurity

Author: Michno, Wojciech P., primary, Puno, Alyssa, additional, Li, Li, additional, Everitt, Amanda, additional, McCluskey, Kate, additional, Birey, Fikri, additional, Htun, Saw, additional, Nagar, Dhriti, additional, Dai, Yuqin, additional, Gurwitz, Emily, additional, Willsey, A. Jeremy, additional, and Pasca, Anca M., additional
Published: 2023
Full Text: View/download PDF

50. Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD

Author: National Institute of Mental Health (US), Tourette Association of America, Human Genetics Institute of New Jersey, Tourette Syndrome Association of New Jersey, Wang, Sheng, Wang, Belinda, Drury, Vanessa, Drake, Sam, Sun, Nawei, Alkhairo, Hasan, Arbelaez, Juan, Duhn, Clif, Tourette International Collaborative Genetics (TIC Genetics), Madruga, Marcos, Mir, Pablo, Bal, Vanessa H., Langley, Kate, Martin, Joanna, Hoekstra, Pieter J., Dietrich, Andrea, Xing, Jinchuan, Heiman, Gary A., Tischfield, Jay A., Fernández, Thomas V., Owen, Michael J., O’Donovan, Michael C., Thapar, Anita, State, Matthew W., Willsey, A. Jeremy, National Institute of Mental Health (US), Tourette Association of America, Human Genetics Institute of New Jersey, Tourette Syndrome Association of New Jersey, Wang, Sheng, Wang, Belinda, Drury, Vanessa, Drake, Sam, Sun, Nawei, Alkhairo, Hasan, Arbelaez, Juan, Duhn, Clif, Tourette International Collaborative Genetics (TIC Genetics), Madruga, Marcos, Mir, Pablo, Bal, Vanessa H., Langley, Kate, Martin, Joanna, Hoekstra, Pieter J., Dietrich, Andrea, Xing, Jinchuan, Heiman, Gary A., Tischfield, Jay A., Fernández, Thomas V., Owen, Michael J., O’Donovan, Michael C., Thapar, Anita, State, Matthew W., and Willsey, A. Jeremy
Abstract: Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of “male vulnerability”, rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of “idiopathic” ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.
Published: 2023

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

375 results on '"Willsey, A Jeremy"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources