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1. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Author

Fu, Jack M, Satterstrom, F Kyle, Peng, Minshi, Brand, Harrison, Collins, Ryan L, Dong, Shan, Wamsley, Brie, Klei, Lambertus, Wang, Lily, Hao, Stephanie P, Stevens, Christine R, Cusick, Caroline, Babadi, Mehrtash, Banks, Eric, Collins, Brett, Dodge, Sheila, Gabriel, Stacey B, Gauthier, Laura, Lee, Samuel K, Liang, Lindsay, Ljungdahl, Alicia, Mahjani, Behrang, Sloofman, Laura, Smirnov, Andrey N, Barbosa, Mafalda, Betancur, Catalina, Brusco, Alfredo, Chung, Brian HY, Cook, Edwin H, Cuccaro, Michael L, Domenici, Enrico, Ferrero, Giovanni Battista, Gargus, J Jay, Herman, Gail E, Hertz-Picciotto, Irva, Maciel, Patricia, Manoach, Dara S, Passos-Bueno, Maria Rita, Persico, Antonio M, Renieri, Alessandra, Sutcliffe, James S, Tassone, Flora, Trabetti, Elisabetta, Campos, Gabriele, Cardaropoli, Simona, Carli, Diana, Chan, Marcus CY, Fallerini, Chiara, Giorgio, Elisa, Girardi, Ana Cristina, Hansen-Kiss, Emily, Lee, So Lun, Lintas, Carla, Ludena, Yunin, Nguyen, Rachel, Pavinato, Lisa, Pericak-Vance, Margaret, Pessah, Isaac N, Schmidt, Rebecca J, Smith, Moyra, Costa, Claudia IS, Trajkova, Slavica, Wang, Jaqueline YT, Yu, Mullin HC, Cutler, David J, De Rubeis, Silvia, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, Sanders, Stephan J, and Talkowski, Michael E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Stem Cell Research, Intellectual and Developmental Disabilities (IDD), Clinical Research, Mental Health, Human Genome, Mental Illness, Neurosciences, Autism, Schizophrenia, Pediatric, 2.1 Biological and endogenous factors, Mental health, Autism Spectrum Disorder, Autistic Disorder, DNA Copy Number Variations, Genetic Predisposition to Disease, Humans, Mutation, Autism Sequencing Consortium, Broad Institute Center for Common Disease Genomics, iPSYCH-BROAD Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

Published
2022

2. Rare coding variants in ten genes confer substantial risk for schizophrenia.

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D, Bass, Nicholas, Bigdeli, Tim B, Breen, Gerome, Bromet, Evelyn J, Buckley, Peter F, Bunney, William E, Bybjerg-Grauholm, Jonas, Byerley, William F, Chapman, Sinéad B, Chen, Wei J, Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M, DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A, Eskelinen, Saana, Fanous, Ayman H, Faraone, Stephen V, Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B, Gage, Diane, Gagliano Taliun, Sarah A, Ganna, Andrea, Genovese, Giulio, Glahn, David C, Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O, Holi, Matti, Hougaard, David M, Howrigan, Daniel P, Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S, Kang, Hyun Min, Karczewski, Konrad J, Kirov, George, Knowles, James A, Lee, Francis S, Lehrer, Douglas S, Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R, McCarroll, Steven A, McIntosh, Andrew M, Medeiros, Helena, Milani, Lili, Morley, Christopher P, Morris, Derek W, Mortensen, Preben Bo, Myers, Richard M, Nordentoft, Merete, O'Brien, Niamh L, Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H, Palmer, Duncan S, Paunio, Tiina, Quested, Digby, Rapaport, Mark H, Rees, Elliott, Rollins, Brandi, Satterstrom, F Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J, Sharp, Sally I, Sklar, Pamela, Smoller, Jordan W, Sobell, Janet L, Solomonson, Matthew, Stahl, Eli A, Stevens, Christine R, Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J, Watts, Nicholas A, Blackwood, Douglas H, Børglum, Anders D, Cohen, Bruce M, Corvin, Aiden P, Esko, Tõnu, Freimer, Nelson B, Glatt, Stephen J, Hultman, Christina M, McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N, Pato, Michele T, Pulver, Ann E, and St Clair, David

Subjects
Humans, Genetic Predisposition to Disease, Receptors, N-Methyl-D-Aspartate, Case-Control Studies, Schizophrenia, Mutation, Exome, Neurodevelopmental Disorders, Human Genome, Biotechnology, Mental Health, Neurosciences, Brain Disorders, Genetics, Serious Mental Illness, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P

Published
2022

4. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

Sazonovs, Aleksejs, Stevens, Christine R., Venkataraman, Guhan R., Yuan, Kai, Avila, Brandon, Abreu, Maria T., Ahmad, Tariq, Allez, Matthieu, Ananthakrishnan, Ashwin N., Atzmon, Gil, Baras, Aris, Barrett, Jeffrey C., Barzilai, Nir, Beaugerie, Laurent, Beecham, Ashley, Bernstein, Charles N., Bitton, Alain, Bokemeyer, Bernd, Chan, Andrew, Chung, Daniel, Cleynen, Isabelle, Cosnes, Jacques, Cutler, David J., Daly, Allan, Damas, Oriana M., Datta, Lisa W., Dawany, Noor, Devoto, Marcella, Dodge, Sheila, Ellinghaus, Eva, Fachal, Laura, Farkkila, Martti, Faubion, William, Ferreira, Manuel, Franchimont, Denis, Gabriel, Stacey B., Ge, Tian, Georges, Michel, Gettler, Kyle, Giri, Mamta, Glaser, Benjamin, Goerg, Siegfried, Goyette, Philippe, Graham, Daniel, Hämäläinen, Eija, Haritunians, Talin, Heap, Graham A., Hiltunen, Mikko, Hoeppner, Marc, Horowitz, Julie E., Irving, Peter, Iyer, Vivek, Jalas, Chaim, Kelsen, Judith, Khalili, Hamed, Kirschner, Barbara S., Kontula, Kimmo, Koskela, Jukka T., Kugathasan, Subra, Kupcinskas, Juozas, Lamb, Christopher A., Laudes, Matthias, Lévesque, Chloé, Levine, Adam P., Lewis, James D., Liefferinckx, Claire, Loescher, Britt-Sabina, Louis, Edouard, Mansfield, John, May, Sandra, McCauley, Jacob L., Mengesha, Emebet, Mni, Myriam, Moayyedi, Paul, Moran, Christopher J., Newberry, Rodney D., O’Charoen, Sirimon, Okou, David T., Oldenburg, Bas, Ostrer, Harry, Palotie, Aarno, Paquette, Jean, Pekow, Joel, Peter, Inga, Pierik, Marieke J., Ponsioen, Cyriel Y., Pontikos, Nikolas, Prescott, Natalie, Pulver, Ann E., Rahmouni, Souad, Rice, Daniel L., Saavalainen, Päivi, Sands, Bruce, Sartor, R. Balfour, Schiff, Elena R., Schreiber, Stefan, Schumm, L. Philip, Segal, Anthony W., Seksik, Philippe, Shawky, Rasha, Sheikh, Shehzad Z., Silverberg, Mark S., Simmons, Alison, Skeiceviciene, Jurgita, Sokol, Harry, Solomonson, Matthew, Somineni, Hari, Sun, Dylan, Targan, Stephan, Turner, Dan, Uhlig, Holm H., van der Meulen, Andrea E., Vermeire, Séverine, Verstockt, Sare, Voskuil, Michiel D., Winter, Harland S., Young, Justine, Duerr, Richard H., Franke, Andre, Brant, Steven R., Cho, Judy, Weersma, Rinse K., Parkes, Miles, Xavier, Ramnik J., Rivas, Manuel A., Rioux, John D., McGovern, Dermot P. B., Huang, Hailiang, Anderson, Carl A., and Daly, Mark J.

Published
2022
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5. Identification of common genetic risk variants for autism spectrum disorder

Author

Grove, Jakob, Ripke, Stephan, Als, Thomas D, Mattheisen, Manuel, Walters, Raymond K, Won, Hyejung, Pallesen, Jonatan, Agerbo, Esben, Andreassen, Ole A, Anney, Richard, Awashti, Swapnil, Belliveau, Rich, Bettella, Francesco, Buxbaum, Joseph D, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Christensen, Jane H, Churchhouse, Claire, Dellenvall, Karin, Demontis, Ditte, De Rubeis, Silvia, Devlin, Bernie, Djurovic, Srdjan, Dumont, Ashley L, Goldstein, Jacqueline I, Hansen, Christine S, Hauberg, Mads Engel, Hollegaard, Mads V, Hope, Sigrun, Howrigan, Daniel P, Huang, Hailiang, Hultman, Christina M, Klei, Lambertus, Maller, Julian, Martin, Joanna, Martin, Alicia R, Moran, Jennifer L, Nyegaard, Mette, Nærland, Terje, Palmer, Duncan S, Palotie, Aarno, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, dPoterba, Timothy, Poulsen, Jesper Buchhave, Pourcain, Beate St, Qvist, Per, Rehnström, Karola, Reichenberg, Abraham, Reichert, Jennifer, Robinson, Elise B, Roeder, Kathryn, Roussos, Panos, Saemundsen, Evald, Sandin, Sven, Satterstrom, F Kyle, Davey Smith, George, Stefansson, Hreinn, Steinberg, Stacy, Stevens, Christine R, Sullivan, Patrick F, Turley, Patrick, Walters, G Bragi, Xu, Xinyi, Stefansson, Kari, Geschwind, Daniel H, Nordentoft, Merete, Hougaard, David M, Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Neale, Benjamin M, Daly, Mark J, and Børglum, Anders D

Subjects
Intellectual and Developmental Disabilities (IDD), Human Genome, Pediatric, Brain Disorders, Autism, Biotechnology, Genetics, Mental Health, Prevention, 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, Denmark, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Published
2019

6. Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Author

Yu, Timothy W, Chahrour, Maria H, Coulter, Michael E, Jiralerspong, Sarn, Okamura-Ikeda, Kazuko, Ataman, Bulent, Schmitz-Abe, Klaus, Harmin, David A, Adli, Mazhar, Malik, Athar N, D’Gama, Alissa M, Lim, Elaine T, Sanders, Stephan J, Mochida, Ganesh H, Partlow, Jennifer N, Sunu, Christine M, Felie, Jillian M, Rodriguez, Jacqueline, Nasir, Ramzi H, Ware, Janice, Joseph, Robert M, Hill, R Sean, Kwan, Benjamin Y, Al-Saffar, Muna, Mukaddes, Nahit M, Hashmi, Asif, Balkhy, Soher, Gascon, Generoso G, Hisama, Fuki M, LeClair, Elaine, Poduri, Annapurna, Oner, Ozgur, Al-Saad, Samira, Al-Awadi, Sadika A, Bastaki, Laila, Ben-Omran, Tawfeg, Teebi, Ahmad S, Al-Gazali, Lihadh, Eapen, Valsamma, Stevens, Christine R, Rappaport, Leonard, Gabriel, Stacey B, Markianos, Kyriacos, State, Matthew W, Greenberg, Michael E, Taniguchi, Hisaaki, Braverman, Nancy E, Morrow, Eric M, and Walsh, Christopher A

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Human Genome, Brain Disorders, Genetic Testing, Genetics, Clinical Research, Intellectual and Developmental Disabilities (IDD), Mental Health, Autism, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Animals, Autistic Disorder, Cells, Cultured, Child, Child, Preschool, Cohort Studies, Exome, Female, Genome-Wide Association Study, Humans, Male, Pedigree, Rats, Sequence Analysis, DNA, Young Adult, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

Published
2013

7. CHARR efficiently estimates contamination from DNA sequencing data

Author

Lu, Wenhan, primary, Gauthier, Laura D., additional, Poterba, Timothy, additional, Giacopuzzi, Edoardo, additional, Goodrich, Julia K., additional, Stevens, Christine R., additional, King, Daniel, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, and Karczewski, Konrad J., additional

Published
2023
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9. Evolution of Osteocrin as an activity-regulated factor in the primate brain

Author

Ataman, Bulent, Boulting, Gabriella L., Harmin, David A., Yang, Marty G., Baker-Salisbury, Mollie, Yap, Ee-Lynn, Malik, Athar N., Mei, Kevin, Rubin, Alex A., Spiegel, Ivo, Durresi, Ershela, Sharma, Nikhil, Hu, Linda S., Pletikos, Mihovil, Griffith, Eric C., Partlow, Jennifer N., Stevens, Christine R., Adli, Mazhar, Chahrour, Maria, Sestan, Nenad, Walsh, Christopher A., Berezovskii, Vladimir K., Livingstone, Margaret S., and Greenberg, Michael E.

Subjects
Physiological aspects, Research, Methods, Primates -- Physiological aspects, Fetal brain -- Research, Transcription (Genetics) -- Methods, Brain research
Abstract

Author(s): Bulent Ataman [1]; Gabriella L. Boulting [1]; David A. Harmin [1]; Marty G. Yang [1]; Mollie Baker-Salisbury [1]; Ee-Lynn Yap [1]; Athar N. Malik [1]; Kevin Mei [1]; Alex [...], Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates.

Published
2016
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10. Rare coding variants in 10 genes confer substantial risk for schizophrenia

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D., Bass, Nicholas, Bigdeli, Tim B., Breen, Gerome, Bromet, Evelyn J., Buckley, Peter F., Bunney, William E., Bybjerg-Grauholm, Jonas, Byerley, William F., Chapman, Sinéad B., Chen, Wei J., Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M., DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A., Eskelinen, Saana, Fanous, Ayman H., Faraone, Stephen V., Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B., Gage, Diane, Taliun, Sarah A. Gagliano, Ganna, Andrea, Genovese, Giulio, Glahn, David C., Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O., Holi, Matti, Hougaard, David M., Howrigan, Daniel P., Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S., Kang, Hyun Min, Karczewski, Konrad J., Kirov, George, Knowles, James A., Lee, Francis S., Lehrer, Douglas S., Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R., McCarroll, Steven A., McIntosh, Andrew M., Medeiros, Helena, Milani, Lili, Morley, Christopher P., Morris, Derek W., Bo Mortensen, Preben, Myers, Richard M., Nordentoft, Merete, O’Brien, Niamh L., Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H., Palmer, Duncan S., Paunio, Tiina, Quested, Digby, Rapaport, Mark H., Rees, Elliott, Rollins, Brandi, Satterstrom, F. Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J., Sharp, Sally I., Sklar, Pamela, Smoller, Jordan W., Sobell, Janet l., Solomonson, Matthew, Stevens, Christine R., Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J., Watts, Nicholas A., Blackwood, Douglas H., Børglum, Anders D., Cohen, Bruce M., Corvin, Aiden P., Esko, Tõnu, Freimer, Nelson B., Glatt, Stephen J., Hultman, Christina M., McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N., Pato, Michele T., Pulver, Ann E., St. Clair, David, Tsuang, Ming T., Vawter, Marquis P., Walters, James T., Werge, Thomas M., Ophoff, Roel A., Sullivan, Patrick F., Owen, Michael J., Boehnke, Michael, O’Donovan, Michael C., Neale, Benjamin M., and Daly, Mark J.

Subjects
Article
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 – 50, P < 2.14 × 10(−6)), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)(1), epilepsy and severe neurodevelopmental disorders (DD/ID)(2), though in some shared genes different mutation types are implicated. Most genes described here however are not implicated in neurodevelopment and we demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk(3), suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more risk genes await discovery using this approach.

Published
2022

11. PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features

Author

Khalil, Raida, primary, Kenny, Connor, additional, Hill, R. Sean, additional, Mochida, Ganeshwaran H., additional, Nasir, Ramzi, additional, Partlow, Jennifer N., additional, Barry, Brenda J., additional, Al-Saffar, Muna, additional, Egan, Chloe, additional, Stevens, Christine R., additional, Gabriel, Stacey B., additional, Barkovich, A. James, additional, Ellison, Jay W., additional, Al-Gazali, Lihadh, additional, Walsh, Christopher A., additional, and Chahrour, Maria H., additional

Published
2018
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12. UNTANGLING THE FMLA

Author

Engbarth, Fred and Stevens, Christine R.

Subjects
Business, Human resources and labor relations
Abstract

This was a great article (March 2018). Remember, it is important to know and comply with the rules of the state you are doing business in as well as those [...]

Published
2018

13. Exome Sequencing and Functional Validation in Zebrafish Identify GTDC2 Mutations as a Cause of Walker-Warburg Syndrome

Author

Manzini, M. Chiara, Tambunan, Dimira E., Hill, R. Sean, Yu, Tim W., Maynard, Thomas M., Heinzen, Erin L., Shianna, Kevin V., Stevens, Christine R., Partlow, Jennifer N., Barry, Brenda J., Rodriguez, Jacqueline, Gupta, Vandana A., Al-Qudah, Abdel-Karim, Eyaid, Wafaa M., Friedman, Jan M., Salih, Mustafa A., Clark, Robin, Moroni, Isabella, Mora, Marina, Beggs, Alan H., Gabriel, Stacey B., and Walsh, Christopher A.

Published
2012
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14. PSMD12haploinsufficiency in a neurodevelopmental disorder with autistic features

Author

Khalil, Raida, Kenny, Connor, Hill, R. Sean, Mochida, Ganeshwaran H., Nasir, Ramzi, Partlow, Jennifer N., Barry, Brenda J., Al‐Saffar, Muna, Egan, Chloe, Stevens, Christine R., Gabriel, Stacey B., Barkovich, A. James, Ellison, Jay W., Al‐Gazali, Lihadh, Walsh, Christopher A., and Chahrour, Maria H.

Abstract

Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12(NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novononsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12encodes a non‐ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12with ID, present the first cases of inherited PSMD12mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12mutations.

Published
2018
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15. Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism

Author

Massachusetts Institute of Technology. Research Laboratory of Electronics, Schubert, Christian R., Chahrour, Maria H., Yu, Timothy W., Lim, Elaine T., Ataman, Bulent, Coulter, Michael E., Hill, R. Sean, Stevens, Christine R., Greenberg, Michael E., Gabriel, Stacey B., Walsh, Christopher A., Massachusetts Institute of Technology. Research Laboratory of Electronics, Schubert, Christian R., Chahrour, Maria H., Yu, Timothy W., Lim, Elaine T., Ataman, Bulent, Coulter, Michael E., Hill, R. Sean, Stevens, Christine R., Greenberg, Michael E., Gabriel, Stacey B., and Walsh, Christopher A.

Abstract

Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders., National Institutes of Health (U.S.) (Grant no. T32 NS007473-11), National Institutes of Health (U.S.) (Grant no. T32 NS007484-11)

Published
2012

16. Genome-wide association identifies multiple ulcerative colitis susceptibility loci (vol 42, pg 332, 2010)

Author

McGovern, Dermot P. B., Gardet, Agnes, Törkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagace, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Loerdal, Mikael, Padyukov, Leonid, Andriulli, Angelo, Colombo, Elisabetta, Latiano, Anna, Palmieri, Orazio, Bernard, Edmond-Jean, Deslandres, Colette, Hommes, Daan W., de Jong, Dirk J., Stokkers, Pieter C., Weersma, Rinse K., Sharma, Yashoda, Silverberg, Mark S., Cho, Judy H., Wu, Jing, Roeder, Kathryn, Brant, Steven R., Schumm, L. Phillip, Duerr, Richard H., Dubinsky, Marla C., Glazer, Nicole L., Haritunians, Talin, Ippoliti, Andy, Melmed, Gil Y., Siscovick, David S., Vasiliauskas, Eric A., Targan, Stephan R., Annese, Vito, Wijmenga, Cisca, Pettersson, Sven, Rotter, Jerome I., Xavier, Ramnik J., Daly, Mark J., Rioux, John D., Seielstad, Mark, McGovern, Dermot P. B., Gardet, Agnes, Törkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagace, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Loerdal, Mikael, Padyukov, Leonid, Andriulli, Angelo, Colombo, Elisabetta, Latiano, Anna, Palmieri, Orazio, Bernard, Edmond-Jean, Deslandres, Colette, Hommes, Daan W., de Jong, Dirk J., Stokkers, Pieter C., Weersma, Rinse K., Sharma, Yashoda, Silverberg, Mark S., Cho, Judy H., Wu, Jing, Roeder, Kathryn, Brant, Steven R., Schumm, L. Phillip, Duerr, Richard H., Dubinsky, Marla C., Glazer, Nicole L., Haritunians, Talin, Ippoliti, Andy, Melmed, Gil Y., Siscovick, David S., Vasiliauskas, Eric A., Targan, Stephan R., Annese, Vito, Wijmenga, Cisca, Pettersson, Sven, Rotter, Jerome I., Xavier, Ramnik J., Daly, Mark J., Rioux, John D., and Seielstad, Mark

Published
2011
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17. Genome-wide association identifies multiple ulcerative colitis susceptibility loci

Author

McGovern, Dermot P. B., Gardet, Agnes, Torkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagace, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Lordal, Mikael, Padyukov, Leonid, Andriulli, Angelo, Colombo, Elisabetta, Latiano, Anna, Palmieri, Orazio, Bernard, Edmond-Jean, Deslandres, Colette, Hommes, Daan W., de Jong, Dirk J., Stokkers, Pieter C., Weersma, Rinse K., Sharma, Yashoda, Silverberg, Mark S., Cho, Judy H., Wu, Jing, Roeder, Kathryn, Brant, Steven R., Schumm, L. Phillip, Duerr, Richard H., Dubinsky, Marla C., Glazer, Nicole L., Haritunians, Talin, Ippoliti, Andy, Melmed, Gil Y., Siscovick, David S., Vasiliauskas, Eric A., Targan, Stephan R., Annese, Vito, Wijmenga, Cisca, Pettersson, Sven, Rotter, Jerome I., Xavier, Ramnik J., Daly, Mark J., Rioux, John D., Seielstad, Mark, McGovern, Dermot P. B., Gardet, Agnes, Torkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagace, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Lordal, Mikael, Padyukov, Leonid, Andriulli, Angelo, Colombo, Elisabetta, Latiano, Anna, Palmieri, Orazio, Bernard, Edmond-Jean, Deslandres, Colette, Hommes, Daan W., de Jong, Dirk J., Stokkers, Pieter C., Weersma, Rinse K., Sharma, Yashoda, Silverberg, Mark S., Cho, Judy H., Wu, Jing, Roeder, Kathryn, Brant, Steven R., Schumm, L. Phillip, Duerr, Richard H., Dubinsky, Marla C., Glazer, Nicole L., Haritunians, Talin, Ippoliti, Andy, Melmed, Gil Y., Siscovick, David S., Vasiliauskas, Eric A., Targan, Stephan R., Annese, Vito, Wijmenga, Cisca, Pettersson, Sven, Rotter, Jerome I., Xavier, Ramnik J., Daly, Mark J., Rioux, John D., and Seielstad, Mark

Abstract

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan(1), comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

Published
2010
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21. Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism.

Author

Chahrour, Maria H., Yu, Timothy W., Lim, Elaine T., Ataman, Bulent, Coulter, Michael E., Hill, R. Sean, Stevens, Christine R., Schubert, Christian R., Greenberg, Michael E., Gabriel, Stacey B., and Walsh, Christopher A.

Subjects
AUTISM research, HOMOZYGOSITY, CYTOSKELETON, GENETIC mutation, PATHOGENIC microorganisms
Abstract

Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders. [ABSTRACT FROM AUTHOR]

Published
2012
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22. Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism

Author

Yu, Timothy W., Lim, Elaine T., Stevens, Christine R., Gabriel, Stacey B., Chahrour, Maria H., Ataman, Bulent, Coulter, Michael Edward, Hill, Robert Sean, Schubert, Christian R., Greenberg, Michael Eldon, and Walsh, Christopher A.

Subjects
biology, genetics, genomics, genome sequencing
Abstract

Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.

Published
2012
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24. Erratum: Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

Author

McGovern, Dermot P. B., Gardet, Agnès, Törkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagacé, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Lördal, Mikael, and Padyukov, Leonid

Subjects
SPELLING errors
Abstract

A correction to the article "Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy," by Hyun Hor and colleagues that was published in the 2010 issue is presented.

Published
2011
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25. Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populations.

Author

Avila MN, Jung S, Satterstrom FK, Fu JM, Levy T, Sloofman LG, Klei L, Pichardo T, Stevens CR, Cusick CM, Ames JL, Campos GS, Cerros H, Chaskel R, Costa CIS, Cuccaro ML, Del Pilar Lopez A, Fernandez M, Ferro E, Galeano L, Girardi ACDES, Griswold AJ, Hernandez LC, Lourenço N, Ludena Y, Nuñez DL, Oyama R, Peña KP, Pessah I, Schmidt R, Sweeney HM, Tolentino L, Wang JYT, Albores-Gallo L, Croen LA, Cruz-Fuentes CS, Hertz-Picciotto I, Kolevzon A, Lattig MC, Mayo L, Passos-Bueno MR, Pericak-Vance MA, Siper PM, Tassone F, Trelles MP, Talkowski ME, Daly MJ, Mahjani B, De Rubeis S, Cook EH, Roeder K, Betancur C, Devlin B, and Buxbaum JD

Abstract

The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high risk for autism spectrum disorder (ASD), intellectual disability, and other developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic risks across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries Consortium (GALA) was formed, presenting here the largest sequencing study of ASD in Latin American individuals (n>15,000). We identified 35 genome-wide significant (FDR < 0.05) ASD risk genes, with substantial overlap with findings from European cohorts, and highly constrained genes showing consistent signal across populations. The results provide support for emerging (e.g., MARK2 , YWHAG , PACS1 , RERE, SPEN, GSE1, GLS, TNPO3, ANKRD17 ) and established ASD genes, and for the utility of genetic testing approaches for deleterious variants in diverse populations, while also demonstrating the ongoing need for more inclusive genetic research and testing. We conclude that the biology of ASD is universal and not impacted to any detectable degree by ancestry., Competing Interests: Competing interests Lilia Albores declares to be the main author of the CRIDI-ASD interview, she is a professor of the training course for the mentioned instrument, and receives payment for the training.

Published
2025
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26. CHARR efficiently estimates contamination from DNA sequencing data.

Author

Lu W, Gauthier LD, Poterba T, Giacopuzzi E, Goodrich JK, Stevens CR, King D, Daly MJ, Neale BM, and Karczewski KJ

Abstract

DNA sample contamination is a major issue in clinical and research applications of whole genome and exome sequencing. Even modest levels of contamination can substantially affect the overall quality of variant calls and lead to widespread genotyping errors. Currently, popular tools for estimating the contamination level use short-read data (BAM/CRAM files), which are expensive to store and manipulate and often not retained or shared widely. We propose a new metric to estimate DNA sample contamination from variant-level whole genome and exome sequence data, CHARR, Contamination from Homozygous Alternate Reference Reads, which leverages the infiltration of reference reads within homozygous alternate variant calls. CHARR uses a small proportion of variant-level genotype information and thus can be computed from single-sample gVCFs or callsets in VCF or BCF formats, as well as efficiently stored variant calls in Hail VDS format. Our results demonstrate that CHARR accurately recapitulates results from existing tools with substantially reduced costs, improving the accuracy and efficiency of downstream analyses of ultra-large whole genome and exome sequencing datasets.

Published
2023
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