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1. Single-cell genomics and regulatory networks for 388 human brains.

Author

Emani, Prashant, Liu, Jason, Clarke, Declan, Jensen, Matthew, Warrell, Jonathan, Gupta, Chirag, Meng, Ran, Lee, Che Yu, Xu, Siwei, Dursun, Cagatay, Lou, Shaoke, Chen, Yuhang, Chu, Zhiyuan, Galeev, Timur, Hwang, Ahyeon, Li, Yunyang, Ni, Pengyu, Zhou, Xiao, Bakken, Trygve, Bendl, Jaroslav, Bicks, Lucy, Chatterjee, Tanima, Cheng, Lijun, Cheng, Yuyan, Dai, Yi, Duan, Ziheng, Flaherty, Mary, Fullard, John, Gancz, Michael, Garrido-Martín, Diego, Gaynor-Gillett, Sophia, Grundman, Jennifer, Hawken, Natalie, Henry, Ella, Hoffman, Gabriel, Huang, Ao, Jiang, Yunzhe, Jin, Ting, Jorstad, Nikolas, Kawaguchi, Riki, Khullar, Saniya, Liu, Jianyin, Liu, Junhao, Liu, Shuang, Ma, Shaojie, Margolis, Michael, Mazariegos, Samantha, Moore, Jill, Moran, Jennifer, Nguyen, Eric, Phalke, Nishigandha, Pjanic, Milos, Pratt, Henry, Quintero, Diana, Rajagopalan, Ananya, Riesenmy, Tiernon, Shedd, Nicole, Shi, Manman, Spector, Megan, Terwilliger, Rosemarie, Travaglini, Kyle, Wamsley, Brie, Wang, Gaoyuan, Xia, Yan, Xiao, Shaohua, Yang, Andrew, Zheng, Suchen, Gandal, Michael, Lee, Donghoon, Lein, Ed, Roussos, Panos, Sestan, Nenad, Weng, Zhiping, White, Kevin, Won, Hyejung, Girgenti, Matthew, Zhang, Jing, Wang, Daifeng, Geschwind, Daniel, and Gerstein, Mark

Subjects
Humans, Aging, Brain, Cell Communication, Chromatin, Gene Regulatory Networks, Genomics, Mental Disorders, Prefrontal Cortex, Quantitative Trait Loci, Single-Cell Analysis
Abstract

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Published
2024

2. Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

Author

Wen, Cindy, Margolis, Michael, Dai, Rujia, Zhang, Pan, Przytycki, Pawel F, Vo, Daniel D, Bhattacharya, Arjun, Matoba, Nana, Tang, Miao, Jiao, Chuan, Kim, Minsoo, Tsai, Ellen, Hoh, Celine, Aygün, Nil, Walker, Rebecca L, Chatzinakos, Christos, Clarke, Declan, Pratt, Henry, Peters, Mette A, Gerstein, Mark, Daskalakis, Nikolaos P, Weng, Zhiping, Jaffe, Andrew E, Kleinman, Joel E, Hyde, Thomas M, Weinberger, Daniel R, Bray, Nicholas J, Sestan, Nenad, Geschwind, Daniel H, Roeder, Kathryn, Gusev, Alexander, Pasaniuc, Bogdan, Stein, Jason L, Love, Michael I, Pollard, Katherine S, Liu, Chunyu, Gandal, Michael J, Akbarian, Schahram, Abyzov, Alexej, Ahituv, Nadav, Arasappan, Dhivya, Almagro Armenteros, Jose Juan, Beliveau, Brian J, Bendl, Jaroslav, Berretta, Sabina, Bharadwaj, Rahul A, Bicks, Lucy, Brennand, Kristen, Capauto, Davide, Champagne, Frances A, Chatterjee, Tanima, Chatzinakos, Chris, Chen, Yuhang, Chen, H Isaac, Cheng, Yuyan, Cheng, Lijun, Chess, Andrew, Chien, Jo-fan, Chu, Zhiyuan, Clement, Ashley, Collado-Torres, Leonardo, Cooper, Gregory M, Crawford, Gregory E, Davila-Velderrain, Jose, Deep-Soboslay, Amy, Deng, Chengyu, DiPietro, Christopher P, Dracheva, Stella, Drusinsky, Shiron, Duan, Ziheng, Duong, Duc, Dursun, Cagatay, Eagles, Nicholas J, Edelstein, Jonathan, Emani, Prashant S, Fullard, John F, Galani, Kiki, Galeev, Timur, Gaynor, Sophia, Girdhar, Kiran, Goes, Fernando S, Greenleaf, William, Grundman, Jennifer, Guo, Hanmin, Guo, Qiuyu, Gupta, Chirag, Hadas, Yoav, Hallmayer, Joachim, Han, Xikun, Haroutunian, Vahram, Hawken, Natalie, He, Chuan, Henry, Ella, Hicks, Stephanie C, Ho, Marcus, Ho, Li-Lun, Hoffman, Gabriel E, Huang, Yiling, Huuki-Myers, Louise A, and Hwang, Ahyeon

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biological Psychology, Psychology, Mental Illness, Mental Health, Human Genome, Neurosciences, Brain Disorders, Mental health, Humans, Alternative Splicing, Atlases as Topic, Autism Spectrum Disorder, Brain, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Genome-Wide Association Study, Protein Isoforms, Quantitative Trait Loci, Schizophrenia, Transcriptome, Mental Disorders, PsychENCODE Consortium†, PsychENCODE Consortium, General Science & Technology
Abstract

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

Published
2024

3. Massively parallel characterization of regulatory elements in the developing human cortex

Author

Deng, Chengyu, Whalen, Sean, Steyert, Marilyn, Ziffra, Ryan, Przytycki, Pawel F, Inoue, Fumitaka, Pereira, Daniela A, Capauto, Davide, Norton, Scott, Vaccarino, Flora M, Pollen, Alex A, Nowakowski, Tomasz J, Ahituv, Nadav, Pollard, Katherine S, Akbarian, Schahram, Abyzov, Alexej, Arasappan, Dhivya, Almagro Armenteros, Jose Juan, Beliveau, Brian J, Bendl, Jaroslav, Berretta, Sabina, Bharadwaj, Rahul A, Bhattacharya, Arjun, Bicks, Lucy, Brennand, Kristen, Champagne, Frances A, Chatterjee, Tanima, Chatzinakos, Chris, Chen, Yuhang, Chen, H Isaac, Cheng, Yuyan, Cheng, Lijun, Chess, Andrew, Chien, Jo-fan, Chu, Zhiyuan, Clarke, Declan, Clement, Ashley, Collado-Torres, Leonardo, Cooper, Gregory M, Crawford, Gregory E, Dai, Rujia, Daskalakis, Nikolaos P, Davila-Velderrain, Jose, Deep-Soboslay, Amy, DiPietro, Christopher P, Dracheva, Stella, Drusinsky, Shiron, Duan, Ziheng, Duong, Duc, Dursun, Cagatay, Eagles, Nicholas J, Edelstein, Jonathan, Emani, Prashant S, Fullard, John F, Galani, Kiki, Galeev, Timur, Gandal, Michael J, Gaynor, Sophia, Gerstein, Mark, Geschwind, Daniel H, Girdhar, Kiran, Goes, Fernando S, Greenleaf, William, Grundman, Jennifer, Guo, Hanmin, Guo, Qiuyu, Gupta, Chirag, Hadas, Yoav, Hallmayer, Joachim, Han, Xikun, Haroutunian, Vahram, Hawken, Natalie, He, Chuan, Henry, Ella, Hicks, Stephanie C, Ho, Marcus, Ho, Li-Lun, Hoffman, Gabriel E, Huang, Yiling, Huuki-Myers, Louise A, Hwang, Ahyeon, Hyde, Thomas M, Iatrou, Artemis, Jajoo, Aarti, Jensen, Matthew, Jiang, Lihua, Jin, Peng, Jin, Ting, Jops, Connor, Jourdon, Alexandre, Kawaguchi, Riki, Kellis, Manolis, Khullar, Saniya, Kleinman, Joel E, Kleopoulos, Steven P, and Kozlenkov, Alex

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Stem Cell Research - Embryonic - Human, Stem Cell Research, Human Genome, Genetics, Neurosciences, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological, Humans, Cerebral Cortex, Chromatin, Deep Learning, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, Neurogenesis, Neurons, Organoids, Regulatory Sequences, Nucleic Acid, Promoter Regions, Genetic, Regulatory Elements, Transcriptional, PsychENCODE Consortium‡, PsychENCODE Consortium, General Science & Technology
Abstract

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 open chromatin regions, including thousands of sequences with cell type-specific accessibility and variants associated with brain gene regulation. In primary cells, we identified 46,802 active enhancer sequences and 164 variants that alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.

Published
2024

4. A multi-region single nucleus transcriptomic atlas of Parkinson’s disease

Author

N. M., Prashant, Fullard, John F., Clarence, Tereza, Mathur, Deepika, Casey, Clara, Hennigan, Evelyn, Alvia, Marcela, Krause-Massaguer, Joana, Barreda, Ayled, Davis, David A., Vontell, Regina T., Garamszegi, Susanna P., Vance, Jeffery M., Sang, Lorelle, Chatigny, Michael, Vismer, David, Landin, Barry, Burstein, David, Lee, Donghoon, Voloudakis, Georgios, Berretta, Sabina, Haroutunian, Vahram, Scott, William K., Bendl, Jaroslav, and Roussos, Panos

Published
2024
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7. Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses.

Author

Als, Thomas, Kurki, Mitja, Grove, Jakob, Voloudakis, Georgios, Therrien, Karen, Tasanko, Elisa, Nielsen, Trine, Naamanka, Joonas, Veerapen, Kumar, Levey, Daniel, Bendl, Jaroslav, Bybjerg-Grauholm, Jonas, Zeng, Biao, Demontis, Ditte, Rosengren, Anders, Athanasiadis, Georgios, Bækved-Hansen, Marie, Qvist, Per, Bragi Walters, G, Thorgeirsson, Thorgeir, Stefánsson, Hreinn, Musliner, Katherine, Rajagopal, Veera, Farajzadeh, Leila, Thirstrup, Janne, Vilhjálmsson, Bjarni, McGrath, John, Mattheisen, Manuel, Meier, Sandra, Agerbo, Esben, Stefánsson, Kári, Nordentoft, Merete, Werge, Thomas, Hougaard, David, Mortensen, Preben, Stein, Murray, Gelernter, Joel, Hovatta, Iiris, Roussos, Panos, Daly, Mark, Mors, Ole, Palotie, Aarno, and Børglum, Anders

Subjects
Male, Female, Humans, Genome-Wide Association Study, Depression, Bipolar Disorder, Schizophrenia, Attention Deficit Disorder with Hyperactivity, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease
Abstract

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

Published
2023

8. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Author

Demontis, Ditte, Walters, G, Athanasiadis, Georgios, Walters, Raymond, Therrien, Karen, Nielsen, Trine, Farajzadeh, Leila, Voloudakis, Georgios, Bendl, Jaroslav, Zeng, Biau, Zhang, Wen, Grove, Jakob, Als, Thomas, Duan, Jinjie, Satterstrom, F, Bybjerg-Grauholm, Jonas, Bækved-Hansen, Marie, Gudmundsson, Olafur, Magnusson, Sigurdur, Baldursson, Gisli, Davidsdottir, Katrin, Haraldsdottir, Gyda, Agerbo, Esben, Hoffman, Gabriel, Dalsgaard, Søren, Martin, Joanna, Ribasés, Marta, Boomsma, Dorret, Soler Artigas, Maria, Roth Mota, Nina, Howrigan, Daniel, Medland, Sarah, Zayats, Tetyana, Rajagopal, Veera, Nordentoft, Merete, Mors, Ole, Hougaard, David, Mortensen, Preben, Daly, Mark, Faraone, Stephen, Stefansson, Hreinn, Roussos, Panos, Franke, Barbara, Werge, Thomas, Neale, Benjamin, Stefansson, Kari, and Børglum, Anders

Subjects
Humans, Genome-Wide Association Study, Attention Deficit Disorder with Hyperactivity, Brain, Cognition, Genetic Predisposition to Disease
Abstract

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

Published
2023

9. Detection and analysis of complex structural variation in human genomes across populations and in brains of donors with psychiatric disorders

Author

Zhou, Bo, Arthur, Joseph G., Guo, Hanmin, Kim, Taeyoung, Huang, Yiling, Pattni, Reenal, Wang, Tao, Kundu, Soumya, Luo, Jay X.J., Lee, HoJoon, Nachun, Daniel C., Purmann, Carolin, Monte, Emma M., Weimer, Annika K., Qu, Ping-Ping, Shi, Minyi, Jiang, Lixia, Yang, Xinqiong, Fullard, John F., Bendl, Jaroslav, Girdhar, Kiran, Kim, Minsu, Chen, Xi, Greenleaf, William J., Duncan, Laramie, Ji, Hanlee P., Zhu, Xiang, Song, Giltae, Montgomery, Stephen B., Palejev, Dean, zu Dohna, Heinrich, Roussos, Panos, Kundaje, Anshul, Hallmayer, Joachim F., Snyder, Michael P., Wong, Wing H., and Urban, Alexander E.

Published
2024
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14. Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes

Author

Novikova, Gloriia, Kapoor, Manav, TCW, Julia, Abud, Edsel M, Efthymiou, Anastasia G, Chen, Steven X, Cheng, Haoxiang, Fullard, John F, Bendl, Jaroslav, Liu, Yiyuan, Roussos, Panos, Björkegren, Johan LM, Liu, Yunlong, Poon, Wayne W, Hao, Ke, Marcora, Edoardo, and Goate, Alison M

Subjects
Biological Sciences, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Neurodegenerative, Dementia, Alzheimer's Disease, Aging, Stem Cell Research, Human Genome, Biotechnology, Prevention, Brain Disorders, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alleles, Alzheimer Disease, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Induced Pluripotent Stem Cells, Macrophages, Microglia, Myeloid Cells, Regulatory Sequences, Nucleic Acid, Transcriptome
Abstract

Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.

Published
2021

16. Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups

Author

Mattheisen, Manuel, Grove, Jakob, Als, Thomas D., Martin, Joanna, Voloudakis, Georgios, Meier, Sandra, Demontis, Ditte, Bendl, Jaroslav, Walters, Raymond, Carey, Caitlin E., Rosengren, Anders, Strom, Nora I., Hauberg, Mads Engel, Zeng, Biao, Hoffman, Gabriel, Zhang, Wen, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Agerbo, Esben, Cormand, Bru, Nordentoft, Merete, Werge, Thomas, Mors, Ole, Hougaard, David M., Buxbaum, Joseph D., Faraone, Stephen V., Franke, Barbara, Dalsgaard, Søren, Mortensen, Preben B., Robinson, Elise B., Roussos, Panos, Neale, Benjamin M., Daly, Mark J., and Børglum, Anders D.

Published
2022
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18. The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease

Author

Bendl, Jaroslav, Hauberg, Mads E., Girdhar, Kiran, Im, Eunju, Vicari, James M., Rahman, Samir, Fernando, Michael B., Townsley, Kayla G., Dong, Pengfei, Misir, Ruth, Kleopoulos, Steven P., Reach, Sarah M., Apontes, Pasha, Zeng, Biao, Zhang, Wen, Voloudakis, Georgios, Brennand, Kristen J., Nixon, Ralph A., Haroutunian, Vahram, Hoffman, Gabriel E., Fullard, John F., and Roussos, Panos

Published
2022
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19. Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development

Author

Liu, Dongxin, Zinski, Amy, Mishra, Akanksha, Noh, Haneul, Park, Gun-Hoo, Qin, Yiren, Olorife, Oshoname, Park, James M., Abani, Chiderah P., Park, Joy S., Fung, Janice, Sawaqed, Farah, Coyle, Joseph T., Stahl, Eli, Bendl, Jaroslav, Fullard, John F., Roussos, Panos, Zhang, Xiaolei, Stanton, Patric K., Yin, Changhong, Huang, Weihua, Kim, Hae-Young, Won, Hyejung, Cho, Jun-Hyeong, and Chung, Sangmi

Published
2022
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21. Transcriptome and epigenome landscape of human cortical development modeled in organoids

Author

Amiri, Anahita, Coppola, Gianfilippo, Scuderi, Soraya, Wu, Feinan, Roychowdhury, Tanmoy, Liu, Fuchen, Pochareddy, Sirisha, Shin, Yurae, Safi, Alexias, Song, Lingyun, Zhu, Ying, Sousa, André MM, Gerstein, Mark, Crawford, Gregory E, Sestan, Nenad, Abyzov, Alexej, Vaccarino, Flora M, Akbarian, Schahram, An, Joon-Yong, Armoskus, Christoper, Ashley-Koch, Allison E, Beach, Thomas G, Belmont, Judson, Bendl, Jaroslav, Borrman, Tyler, Brown, Leanne, Brown, Miguel, Brown, Mimi, Brunetti, Tonya, Bryois, Julien, Burke, Emily E, Camarena, Adrian, Carlyle, Becky C, Chae, Yooree, Charney, Alexander W, Chen, Chao, Cheng, Lijun, Cherskov, Adriana, Choi, Jinmyung, Clarke, Declan, Collado-Torres, Leonardo, Dai, Rujia, De La Torre Ubieta, Luis, DelValle, Diane, Devillers, Olivia, Dracheva, Stella, Emani, Prashant S, Evgrafov, Oleg V, Farnham, Peggy J, Fitzgerald, Dominic, Flatow, Elie, Francoeur, Nancy, Fullard, John F, Gandal, Michael J, Gao, Tianliuyun, Garrett, Melanie E, Geschwind, Daniel H, Giase, Gina, Girdhar, Kiran, Giusti-Rodriguez, Paola, Goes, Fernando S, Goodman, Thomas, Grennan, Kay S, Gu, Mengting, Gürsoy, Gamze, Hadjimichael, Evi, Hahn, Chang-Gyu, Haroutunian, Vahram, Hauberg, Mads E, Hoffman, Gabriel E, Huey, Jack, Hyde, Thomas M, Ivanov, Nikolay A, Jacobov, Rivka, Jaffe, Andrew E, Jiang, Yan, Jiang, Yi, Johnson, Graham D, Kassim, Bibi S, Kefi, Amira, Kim, Yunjung, Kitchen, Robert R, Kleiman, Joel E, Knowles, James A, Kozlenkov, Alexey, Li, Mingfeng, Li, Zhen, Lipska, Barbara K, Liu, Chunyu, Liu, Shuang, Mangravite, Lara M, Mariani, Jessica, Mattei, Eugenio, Miller, Daniel J, Moore, Jill, Nairn, Angus C, Navarro, Fabio CP, Park, Royce B, Peters, Mette A, and Pinto, Dalila

Subjects
Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Embryonic - Human, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell, Human Genome, Intellectual and Developmental Disabilities (IDD), Autism, Brain Disorders, Biotechnology, Clinical Research, Mental Health, Pediatric, Neurosciences, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Neurological, Cerebral Cortex, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Humans, Induced Pluripotent Stem Cells, Models, Neurological, Neurogenesis, Organoids, Transcriptome, PsychENCODE Consortium, General Science & Technology
Abstract

Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.

Published
2018

22. Comprehensive functional genomic resource and integrative model for the human brain

Author

Wang, Daifeng, Liu, Shuang, Warrell, Jonathan, Won, Hyejung, Shi, Xu, Navarro, Fabio CP, Clarke, Declan, Gu, Mengting, Emani, Prashant, Yang, Yucheng T, Xu, Min, Gandal, Michael J, Lou, Shaoke, Zhang, Jing, Park, Jonathan J, Yan, Chengfei, Rhie, Suhn Kyong, Manakongtreecheep, Kasidet, Zhou, Holly, Nathan, Aparna, Peters, Mette, Mattei, Eugenio, Fitzgerald, Dominic, Brunetti, Tonya, Moore, Jill, Jiang, Yan, Girdhar, Kiran, Hoffman, Gabriel E, Kalayci, Selim, Gümüş, Zeynep H, Crawford, Gregory E, Roussos, Panos, Akbarian, Schahram, Jaffe, Andrew E, White, Kevin P, Weng, Zhiping, Sestan, Nenad, Geschwind, Daniel H, Knowles, James A, Gerstein, Mark B, Ashley-Koch, Allison E, Garrett, Melanie E, Song, Lingyun, Safi, Alexias, Johnson, Graham D, Wray, Gregory A, Reddy, Timothy E, Goes, Fernando S, Zandi, Peter, Bryois, Julien, Price, Amanda J, Ivanov, Nikolay A, Collado-Torres, Leonardo, Hyde, Thomas M, Burke, Emily E, Kleiman, Joel E, Tao, Ran, Shin, Joo Heon, Kundakovic, Marija, Brown, Leanne, Kassim, Bibi S, Park, Royce B, Wiseman, Jennifer R, Zharovsky, Elizabeth, Jacobov, Rivka, Devillers, Olivia, Flatow, Elie, Lipska, Barbara K, Lewis, David A, Haroutunian, Vahram, Hahn, Chang-Gyu, Charney, Alexander W, Dracheva, Stella, Kozlenkov, Alexey, Belmont, Judson, DelValle, Diane, Francoeur, Nancy, Hadjimichael, Evi, Pinto, Dalila, van Bakel, Harm, Fullard, John F, Bendl, Jaroslav, Hauberg, Mads E, Mangravite, Lara M, Peters, Mette A, Chae, Yooree, Peng, Junmin, Niu, Mingming, Wang, Xusheng, Webster, Maree J, Beach, Thomas G, Chen, Chao, and Jiang, Yi

Subjects
Human Genome, Biotechnology, Schizophrenia, Mental Health, Brain Disorders, Genetics, Neurosciences, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Mental health, Brain, Datasets as Topic, Deep Learning, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Gene Expression Regulation, Gene Regulatory Networks, Genome-Wide Association Study, Humans, Mental Disorders, Quantitative Trait Loci, Single-Cell Analysis, Transcriptome, PsychENCODE Consortium, General Science & Technology
Abstract

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.

Published
2018

23. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

Author

Gandal, Michael J, Zhang, Pan, Hadjimichael, Evi, Walker, Rebecca L, Chen, Chao, Liu, Shuang, Won, Hyejung, van Bakel, Harm, Varghese, Merina, Wang, Yongjun, Shieh, Annie W, Haney, Jillian, Parhami, Sepideh, Belmont, Judson, Kim, Minsoo, Moran Losada, Patricia, Khan, Zenab, Mleczko, Justyna, Xia, Yan, Dai, Rujia, Wang, Daifeng, Yang, Yucheng T, Xu, Min, Fish, Kenneth, Hof, Patrick R, Warrell, Jonathan, Fitzgerald, Dominic, White, Kevin, Jaffe, Andrew E, Peters, Mette A, Gerstein, Mark, Liu, Chunyu, Iakoucheva, Lilia M, Pinto, Dalila, Geschwind, Daniel H, Ashley-Koch, Allison E, Crawford, Gregory E, Garrett, Melanie E, Song, Lingyun, Safi, Alexias, Johnson, Graham D, Wray, Gregory A, Reddy, Timothy E, Goes, Fernando S, Zandi, Peter, Bryois, Julien, Price, Amanda J, Ivanov, Nikolay A, Collado-Torres, Leonardo, Hyde, Thomas M, Burke, Emily E, Kleiman, Joel E, Tao, Ran, Shin, Joo Heon, Akbarian, Schahram, Girdhar, Kiran, Jiang, Yan, Kundakovic, Marija, Brown, Leanne, Kassim, Bibi S, Park, Royce B, Wiseman, Jennifer R, Zharovsky, Elizabeth, Jacobov, Rivka, Devillers, Olivia, Flatow, Elie, Hoffman, Gabriel E, Lipska, Barbara K, Lewis, David A, Haroutunian, Vahram, Hahn, Chang-Gyu, Charney, Alexander W, Dracheva, Stella, Kozlenkov, Alexey, DelValle, Diane, Francoeur, Nancy, Roussos, Panos, Fullard, John F, Bendl, Jaroslav, Hauberg, Mads E, Mangravite, Lara M, Chae, Yooree, Peng, Junmin, Niu, Mingming, Wang, Xusheng, Webster, Maree J, Beach, Thomas G, Jiang, Yi, and Grennan, Kay S

Subjects
Pharmacology and Pharmaceutical Sciences, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurosciences, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Illness, Bipolar Disorder, Mental Health, Schizophrenia, Biotechnology, Serious Mental Illness, Autism, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Autism Spectrum Disorder, Brain, Genetic Predisposition to Disease, Humans, Protein Isoforms, RNA Splicing, Sequence Analysis, RNA, Transcriptome, PsychENCODE Consortium, General Science & Technology
Abstract

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Published
2018

25. Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains

Author

Girdhar, Kiran, Hoffman, Gabriel E., Bendl, Jaroslav, Rahman, Samir, Dong, Pengfei, Liao, Will, Hauberg, Mads E., Sloofman, Laura, Brown, Leanne, Devillers, Olivia, Kassim, Bibi S., Wiseman, Jennifer R., Park, Royce, Zharovsky, Elizabeth, Jacobov, Rivky, Flatow, Elie, Kozlenkov, Alexey, Gilgenast, Thomas, Johnson, Jessica S., Couto, Lizette, Peters, Mette A., Phillips-Cremins, Jennifer E., Hahn, Chang-Gyu, Gur, Raquel E., Tamminga, Carol A., Lewis, David A., Haroutunian, Vahram, Dracheva, Stella, Lipska, Barbara K., Marenco, Stefano, Kundakovic, Marija, Fullard, John F., Jiang, Yan, Roussos, Panos, and Akbarian, Schahram

Published
2022
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26. Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome

Author

Fulton, Sasha L., Wenderski, Wendy, Lepack, Ashley E., Eagle, Andrew L., Fanutza, Tomas, Bastle, Ryan M., Ramakrishnan, Aarthi, Hays, Emma C., Neal, Arianna, Bendl, Jaroslav, Farrelly, Lorna A., Al-Kachak, Amni, Lyu, Yang, Cetin, Bulent, Chan, Jennifer C., Tran, Tina N., Neve, Rachael L., Roper, Randall J., Brennand, Kristen J., Roussos, Panos, Schimenti, John C., Friedman, Allyson K., Shen, Li, Blitzer, Robert D., Robison, Alfred J., Crabtree, Gerald R., and Maze, Ian

Published
2022
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28. Genetic regulation of cell type–specific chromatin accessibility shapes brain disease etiology

Author

Zeng, Biao, primary, Bendl, Jaroslav, additional, Deng, Chengyu, additional, Lee, Donghoon, additional, Misir, Ruth, additional, Reach, Sarah M., additional, Kleopoulos, Steven P., additional, Auluck, Pavan, additional, Marenco, Stefano, additional, Lewis, David A., additional, Haroutunian, Vahram, additional, Ahituv, Nadav, additional, Fullard, John F., additional, Hoffman, Gabriel E., additional, and Roussos, Panos, additional

Published
2024
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29. 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
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30. Author Correction: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Author

Demontis, Ditte, Walters, G. Bragi, Athanasiadis, Georgios, Walters, Raymond, Therrien, Karen, Nielsen, Trine Tollerup, Farajzadeh, Leila, Voloudakis, Georgios, Bendl, Jaroslav, Zeng, Biau, Zhang, Wen, Grove, Jakob, Als, Thomas D., Duan, Jinjie, Satterstrom, F. Kyle, Bybjerg-Grauholm, Jonas, Bækved-Hansen, Marie, Gudmundsson, Olafur O., Magnusson, Sigurdur H., Baldursson, Gisli, Davidsdottir, Katrin, Haraldsdottir, Gyda S., Agerbo, Esben, Hoffman, Gabriel E., Dalsgaard, Søren, Martin, Jonna, Ribasés, Marta, Boomsma, Dorret I., Soler Artigas, Maria, Roth Mota, Nina, Howrigan, Daniel, Medland, Sarah E., Zayats, Tetyana, Rajagopal, Veera M., Nordentoft, Merete, Mors, Ole, Hougaard, David M., Mortensen, Preben Bo, Daly, Mark J., Faraone, Stephen V., Stefansson, Hreinn, Roussos, Panos, Franke, Barbara, Werge, Thomas, Neale, Benjamin M., Stefansson, Kari, and Børglum, Anders D.

Published
2023
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31. Alzheimer's disease transcriptional landscape in ex-vivo human microglia

Author

Roussos, Panos, primary, Kosoy, Roman, additional, Fullard, John, additional, Bendl, Jaroslav, additional, Kleopoulos, Steven, additional, Shao, Zhiping, additional, Argyriou, Stathis, additional, Mathur, Deepika, additional, Vicari, James, additional, Ma, Yixuan, additional, Humphrey, Jack, additional, Brophy, Erica, additional, Raj, Towfique, additional, Katsel, Pavel, additional, Voloudakis, Georgios, additional, Lee, Donghoon, additional, Bennett, David, additional, Haroutunian, Vahram, additional, and Hoffman, Gabriel, additional

Published
2024
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32. Transcriptomic profiling of prefrontal cortex reveals shared mechanisms underlying Alzheimer’s and Parkinson’s Diseases

Author

Bendl, Jaroslav, primary, Hoffman, Gabriel E, additional, Lee, Donghoon, additional, M, Prashant N, additional, Bennett, David A. A, additional, Davis, David A., additional, Scott, William K., additional, Berretta, Sabina, additional, Haroutunian, Vahram, additional, Fullard, John F, additional, and Roussos, Panos, additional

Published
2023
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33. Unraveling the transcriptomic landscape of healthy aging

Author

Girdhar, Kiran, primary, Bendl, Jaroslav, additional, Hoffman, Gabriel E, additional, Lee, Donghoon, additional, M, Prashant N, additional, Bennett, David A. A, additional, Haroutunian, Vahram, additional, Fullard, John F, additional, and Roussos, Panos, additional

Published
2023
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35. List of contributors

Author

Abdolmaleky, Hamid Mostafavi, primary, Akbarian, Schahram, additional, Ambrosini, Alexander, additional, Avramopoulos, Dimitrios, additional, Bendersky, Cari J., additional, Bendl, Jaroslav, additional, Bérubé, Nathalie G., additional, Bhat, Unis Ahmad, additional, Borreggine, Kristin, additional, Braun, Patricia R., additional, Brennand, Kristen J., additional, Castro, Amanda, additional, Chakravarty, Sumana, additional, Chang, Connie, additional, Cohen, Sophie, additional, Coppedè, Fabio, additional, Dahrendorff, Jan, additional, Dunn, Jeffrey T., additional, Eberwine, James H., additional, Elia, Josephine, additional, Fang, Gang, additional, Fels, Samuel, additional, Fernando, Michael B., additional, Franklin, Tamara Brook, additional, Fries, Gabriel R., additional, Frizzola, Meg, additional, Fullard, John F., additional, Ganguly, Sebanti, additional, Gapp, Katharina, additional, Garcia, Meilin Fernandez, additional, Gatta, Eleonora, additional, Grayson, Dennis R., additional, Gropman, Andrea L., additional, Guidotti, Alessandro, additional, Gupta, Praveer, additional, Hakonarson, Hakon, additional, Hunter, Richard G., additional, Imamura, Takuya, additional, Izaki, Yumiko, additional, Jakub, Taryn, additional, Keung, Crystal, additional, Kramer, Jamie M., additional, Kumar, Arvind, additional, Kundakovic, Marija, additional, Labonté, Benoit, additional, LaMarca, Elizabeth A., additional, Lee, Richard S., additional, Lima, Camila N.C., additional, Lutz, Pierre-Eric, additional, Matt, Stephanie M., additional, Milian, Allison A., additional, Miyashiro, Kevin Y., additional, Murgatroyd, Chris, additional, Nakashima, Kinichi, additional, Paul, Bidisha, additional, Peedicayil, Jacob, additional, Pinjari, Omar F., additional, Poddar, Karuna, additional, Potash, James B., additional, Powell, Samuel K., additional, Quesnel, Katerine, additional, Rayfield, Jessica, additional, Reddy, R. Gajendra, additional, Richter, Troy A., additional, Roth, Eric D., additional, Roth, Tania L., additional, Roussos, Panos, additional, Ruzicka, W. Brad, additional, Salarda, Erika M., additional, Santhosh, Samuel, additional, Saudagar, Vikram, additional, Stoccoro, Andrea, additional, Syed, Shariful A., additional, Thiagalingam, Sam, additional, Tollefsbol, Trygve O., additional, Turecki, Gustavo, additional, Uddin, Monica, additional, Uesaka, Masahiro, additional, Walker, Deena, additional, Yamamoto, Naoki, additional, Yost, Oliver, additional, and Zannas, Anthony S., additional

Published
2021
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36. Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer’s Disease

Author

Lee, Donghoon, primary, Porras, Christian, additional, Spencer, Collin, additional, Pjanic, Milos, additional, Weiler, Philipp, additional, Kosoy, Roman, additional, Bendl, Jaroslav, additional, Prashant, N M, additional, Wang, Xinyi, additional, Zheng, Shiwei, additional, Therrien, Karen, additional, Mathur, Deepika, additional, Kleopoulos, Steven P., additional, Shao, Zhiping, additional, Argyriou, Stathis, additional, Alvia, Marcela, additional, Casey, Clara, additional, Hong, Aram, additional, Beaumont, Kristin G., additional, Sebra, Robert, additional, Kellner, Christopher P., additional, Bennett, David A., additional, Yuan, Guo-Cheng, additional, Voloudakis, George, additional, Theis, Fabian J., additional, Haroutunian, Vahram, additional, Hoffman, Gabriel E., additional, Fullard, John F., additional, and Roussos, Panos, additional

Published
2023
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37. A public resource of single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease

Author

Wang, Qi, primary, Antone, Jerry, additional, Alsop, Eric, additional, Reiman, Rebecca, additional, Funk, Cory, additional, Bendl, Jaroslav, additional, Dudley, Joel T, additional, Liang, Winnie S, additional, Karr, Timothy L, additional, Roussos, Panos, additional, Bennett, David A, additional, De Jager, Philip L, additional, Serrano, Geidy E, additional, Beach, Thomas G, additional, Keuren-Jensen, Kendall Van, additional, Mastroeni, Diego, additional, Reiman, Eric M, additional, and Readhead, Benjamin P, additional

Published
2023
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38. Multi-omic profiling of the developing human cerebral cortex at the single-cell level

Author

Zhu, Kaiyi, primary, Bendl, Jaroslav, additional, Rahman, Samir, additional, Vicari, James M., additional, Coleman, Claire, additional, Clarence, Tereza, additional, Latouche, Ovaun, additional, Tsankova, Nadejda M., additional, Li, Aiqun, additional, Brennand, Kristen J., additional, Lee, Donghoon, additional, Yuan, Guo-Cheng, additional, Fullard, John F., additional, and Roussos, Panos, additional

Published
2023
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39. Lineage specific 3D genome structure in the adult human brain and neurodevelopmental changes in the chromatin interactome

Author

Rahman, Samir, primary, Dong, Pengfei, additional, Apontes, Pasha, additional, Fernando, Michael B, additional, Kosoy, Roman, additional, Townsley, Kayla G, additional, Girdhar, Kiran, additional, Bendl, Jaroslav, additional, Shao, Zhiping, additional, Misir, Ruth, additional, Tsankova, Nadia, additional, Kleopoulos, Steven P, additional, Brennand, Kristen J, additional, Fullard, John F, additional, and Roussos, Panos, additional

Published
2023
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40. The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development

Author

Girdhar, Kiran, primary, Bendl, Jaroslav, additional, Baumgartner, Andrew, additional, Therrien, Karen, additional, Venkatesh, Sanan, additional, Mathur, Deepika, additional, Dong, Pengfei, additional, Rahman, Samir, additional, Kleopoulos, Steven P., additional, Misir, Ruth, additional, Reach, Sarah M., additional, Auluck, Pavan K., additional, Marenco, Stefano, additional, Lewis, David A., additional, Haroutunian, Vahram, additional, Funk, Cory, additional, Voloudakis, Georgios, additional, Hoffman, Gabriel E., additional, Fullard, John F., additional, and Roussos, Panos, additional

Published
2023
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41. FUNCTIONAL CHARACTERIZATION OF GENETIC LIABILITY FOR AUTISM SPECTRUM DISORDER

Author

Voloudakis, Georgios, primary, Mathur, Deepika, additional, Venkatesh, Sanan, additional, Zeng, Biao, additional, Pjanic, Milos, additional, Coleman, Claire, additional, Hoffman, Gabriel, additional, Bendl, Jaroslav, additional, Lee, Donghoon, additional, Grove, Jakob, additional, Børglum, Anders, additional, and Roussos, Panos, additional

Published
2023
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43. A chromosomal connectome for psychiatric and metabolic risk variants in adult dopaminergic neurons

Author

Espeso-Gil, Sergio, Halene, Tobias, Bendl, Jaroslav, Kassim, Bibi, Ben Hutta, Gabriella, Iskhakova, Marina, Shokrian, Neda, Auluck, Pavan, Javidfar, Behnam, Rajarajan, Prashanth, Chandrasekaran, Sandhya, Peter, Cyril J., Cote, Alanna, Birnbaum, Rebecca, Liao, Will, Borrman, Tyler, Wiseman, Jennifer, Bell, Aaron, Bannon, Michael J., Roussos, Panagiotis, Crary, John F., Weng, Zhiping, Marenco, Stefano, Lipska, Barbara, Tsankova, Nadejda M., Huckins, Laura, Jiang, Yan, and Akbarian, Schahram

Published
2020
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44. ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex

Author

Fulton, Sasha L, primary, Bendl, Jaroslav, additional, Gameiro-Ros, Isabel, additional, Fullard, John F, additional, Al-Kachak, Amni, additional, Lepack, Ashley E, additional, Stewart, Andrew F, additional, Singh, Sumnima, additional, Poller, Wolfram C, additional, Bastle, Ryan M, additional, Hauberg, Mads E, additional, Fakira, Amanda K, additional, Chen, Min, additional, Durand-de Cuttoli, Romain, additional, Cathomas, Flurin, additional, Ramakrishnan, Aarthi, additional, Gleason, Kelly, additional, Shen, Li, additional, Tamminga, Carol A, additional, Milosevic, Ana, additional, Russo, Scott J, additional, Swirski, Filip, additional, Blitzer, Robert D, additional, Slesinger, Paul A, additional, Roussos, Panos, additional, and Maze, Ian, additional

Published
2023
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45. Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet

Author

Hoffman, Gabriel, primary, Lee, Donghoon, additional, Bendl, Jaroslav, additional, Fnu, Prashant, additional, Hong, Aram, additional, Casey, Clara, additional, Alvia, Marcela, additional, Shao, Zhiping, additional, Argyriou, Stathis, additional, Therrien, Karen, additional, Venkatesh, Sanan, additional, Voloudakis, Georgios, additional, Haroutunian, Vahram, additional, Fullard, John, additional, and Roussos, Panos, additional

Published
2023
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46. Extending Human Genome-Wide “Omics” Data With Mechanistic Studies in Rodent Models Identifies an Astrocyte-specific Mechanism of Orbitofrontal Cortex Dysfunction in Major Depressive Disorder

Author

Fulton, Sasha, primary, Bendl, Jaroslav, additional, Fullard, John, additional, Gameiro-Ros, Isabel, additional, Al-Kachak, Amni, additional, Stewart, Andrew, additional, Bastle, Ryan, additional, Lepack, Ashley, additional, Poller, Wolfram, additional, Singh, Sumnima, additional, Fakira, Amanda, additional, Chen, Min, additional, Cuttoli, Romain Durand-de, additional, Cathomas, Flurin, additional, Ramakrishnan, Aarthi, additional, Gleason, Kelly, additional, Shen, Li, additional, Tamminga, Carol A., additional, Milosevic, Ana, additional, Russo, Scott, additional, Swirski, Filip, additional, Blitzer, Robert, additional, Slesinger, Paul, additional, Roussos, Panos, additional, and Maze, Ian, additional

Published
2023
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47. A study of gene expression in the living human brain

Author

Liharska, Lora E, primary, Park, You Jeong, additional, Ziafat, Kimia, additional, Wilkins, Lillian, additional, Silk, Hannah, additional, Linares, Lisa M, additional, Vornholt, Eric, additional, Sullivan, Brendan, additional, Cohen, Vanessa, additional, Kota, Prashant, additional, Feng, Claudia, additional, Cheng, Esther, additional, Moya, Emily, additional, Thompson, Ryan C, additional, Johnson, Jessica S, additional, Rieder, Marysia-Kolbe, additional, Huang, Jia, additional, Scarpa, Joseph, additional, Hashemi, Alice, additional, Polanco, Jairo, additional, Bendl, Jaroslav, additional, Hoffman, Gabriel E, additional, Roussos, Panos, additional, Levin, Matthew A, additional, Nadkarni, Girish N, additional, Sebra, Robert, additional, Crary, John, additional, Sklar, Pamela, additional, Schadt, Eric E, additional, Beckmann, Noam D, additional, Kopell, Brian H, additional, and Charney, Alexander W, additional

Published
2023
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48. Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet

Author

Hoffman, Gabriel E., primary, Lee, Donghoon, additional, Bendl, Jaroslav, additional, Fnu, Prashant, additional, Hong, Aram, additional, Casey, Clara, additional, Alvia, Marcela, additional, Shao, Zhiping, additional, Argyriou, Stathis, additional, Therrien, Karen, additional, Venkatesh, Sanan, additional, Voloudakis, Georgios, additional, Haroutunian, Vahram, additional, Fullard, John F., additional, and Roussos, Panos, additional

Published
2023
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49. Genetic regulation of cell-type specific chromatin accessibility shapes the etiology of brain diseases

Author

Zeng, Biao, primary, Bendl, Jaroslav, additional, Deng, Chengyu, additional, Lee, Donghoon, additional, Misir, Ruth, additional, Reach, Sarah M., additional, Kleopoulos, Steven P., additional, Auluck, Pavan, additional, Marenco, Stefano, additional, Lewis, David A., additional, Haroutunian, Vahram, additional, Ahituv, Nadav, additional, Fullard, John F., additional, Hoffman, Gabriel E., additional, and Roussos, Panos, additional

Published
2023
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50. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains:[Inkl. Correction]

Author

Demontis, Ditte, Walters, G. Bragi, Athanasiadis, Georgios, Walters, Raymond, Therrien, Karen, Nielsen, Trine Tollerup, Farajzadeh, Leila, Voloudakis, Georgios, Bendl, Jaroslav, Zeng, Biau, Zhang, Wen, Grove, Jakob, Als, Thomas D., Duan, Jinjie, Satterstrom, F. Kyle, Bybjerg-Grauholm, Jonas, Bækved-Hansen, Marie, Gudmundsson, Olafur O., Magnusson, Sigurdur H., Baldursson, Gisli, Davidsdottir, Katrin, Haraldsdottir, Gyda S., Agerbo, Esben, Hoffman, Gabriel E., Dalsgaard, Søren, Martin, Joanna, Ribasés, Marta, Boomsma, Dorret I., Soler Artigas, Maria, Roth Mota, Nina, Howrigan, Daniel, Medland, Sarah E., Zayats, Tetyana, Rajagopal, Veera M., Havdahl, Alexandra, Doyle, Alysa, Reif, Andreas, Thapar, Anita, Cormand, Bru, Liao, Calwing, Burton, Christie, Bau, Claiton H.D., Rovaris, Diego Luiz, Sonuga-Barke, Edmund, Corfield, Elizabeth, Grevet, Eugenio Horacio, Larsson, Henrik, Gizer, Ian R., Nordentoft, Merete, Werge, Thomas, Demontis, Ditte, Walters, G. Bragi, Athanasiadis, Georgios, Walters, Raymond, Therrien, Karen, Nielsen, Trine Tollerup, Farajzadeh, Leila, Voloudakis, Georgios, Bendl, Jaroslav, Zeng, Biau, Zhang, Wen, Grove, Jakob, Als, Thomas D., Duan, Jinjie, Satterstrom, F. Kyle, Bybjerg-Grauholm, Jonas, Bækved-Hansen, Marie, Gudmundsson, Olafur O., Magnusson, Sigurdur H., Baldursson, Gisli, Davidsdottir, Katrin, Haraldsdottir, Gyda S., Agerbo, Esben, Hoffman, Gabriel E., Dalsgaard, Søren, Martin, Joanna, Ribasés, Marta, Boomsma, Dorret I., Soler Artigas, Maria, Roth Mota, Nina, Howrigan, Daniel, Medland, Sarah E., Zayats, Tetyana, Rajagopal, Veera M., Havdahl, Alexandra, Doyle, Alysa, Reif, Andreas, Thapar, Anita, Cormand, Bru, Liao, Calwing, Burton, Christie, Bau, Claiton H.D., Rovaris, Diego Luiz, Sonuga-Barke, Edmund, Corfield, Elizabeth, Grevet, Eugenio Horacio, Larsson, Henrik, Gizer, Ian R., Nordentoft, Merete, and Werge, Thomas

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84–98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

Published
2023

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