92 results on '"A. P. Sullivan"'
Search Results
2. Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions
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Purdue, Mark P., Dutta, Diptavo, Machiela, Mitchell J., Gorman, Bryan R., Winter, Timothy, Okuhara, Dayne, Cleland, Sara, Ferreiro-Iglesias, Aida, Scheet, Paul, Liu, Aoxing, Wu, Chao, Antwi, Samuel O., Larkin, James, Zequi, Stênio C., Sun, Maxine, Hikino, Keiko, Hajiran, Ali, Lawson, Keith A., Cárcano, Flavio, Blanchet, Odile, Shuch, Brian, Nepple, Kenneth G., Margue, Gaëlle, Sundi, Debasish, Diver, W. Ryan, Folgueira, Maria A. A. K., van Bokhoven, Adrie, Neffa, Florencia, Brown, Kevin M., Hofmann, Jonathan N., Rhee, Jongeun, Yeager, Meredith, Cole, Nathan R., Hicks, Belynda D., Manning, Michelle R., Hutchinson, Amy A., Rothman, Nathaniel, Huang, Wen-Yi, Linehan, W. Marston, Lori, Adriana, Ferragu, Matthieu, Zidane-Marinnes, Merzouka, Serrano, Sérgio V., Magnabosco, Wesley J., Vilas, Ana, Decia, Ricardo, Carusso, Florencia, Graham, Laura S., Anderson, Kyra, Bilen, Mehmet A., Arciero, Cletus, Pellegrin, Isabelle, Ricard, Solène, Scelo, Ghislaine, Banks, Rosamonde E., Vasudev, Naveen S., Soomro, Naeem, Stewart, Grant D., Adeyoju, Adebanji, Bromage, Stephen, Hrouda, David, Gibbons, Norma, Patel, Poulam, Sullivan, Mark, Protheroe, Andrew, Nugent, Francesca I., Fournier, Michelle J., Zhang, Xiaoyu, Martin, Lisa J., Komisarenko, Maria, Eisen, Timothy, Cunningham, Sonia A., Connolly, Denise C., Uzzo, Robert G., Zaridze, David, Mukeria, Anush, Holcatova, Ivana, Hornakova, Anna, Foretova, Lenka, Janout, Vladimir, Mates, Dana, Jinga, Viorel, Rascu, Stefan, Mijuskovic, Mirjana, Savic, Slavisa, Milosavljevic, Sasa, Gaborieau, Valérie, Abedi-Ardekani, Behnoush, McKay, James, Johansson, Mattias, Phouthavongsy, Larry, Hayman, Lindsay, Li, Jason, Lungu, Ilinca, Bezerra, Stephania M., Souza, Aline G., Sares, Claudia T. G., Reis, Rodolfo B., Gallucci, Fabio P., Cordeiro, Mauricio D., Pomerantz, Mark, Lee, Gwo-Shu M., Freedman, Matthew L., Jeong, Anhyo, Greenberg, Samantha E., Sanchez, Alejandro, Thompson, R. Houston, Sharma, Vidit, Thiel, David D., Ball, Colleen T., Abreu, Diego, Lam, Elaine T., Nahas, William C., Master, Viraj A., Patel, Alpa V., Bernhard, Jean-Christophe, Freedman, Neal D., Bigot, Pierre, Reis, Rui M., Colli, Leandro M., Finelli, Antonio, Manley, Brandon J., Terao, Chikashi, Choueiri, Toni K., Carraro, Dirce M., Houlston, Richard, Eckel-Passow, Jeanette E., Abbosh, Philip H., Ganna, Andrea, Brennan, Paul, Gu, Jian, and Chanock, Stephen J.
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- 2024
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3. Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model
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Waugh, Katherine A., Minter, Ross, Baxter, Jessica, Chi, Congwu, Galbraith, Matthew D., Tuttle, Kathryn D., Eduthan, Neetha P., Kinning, Kohl T., Andrysik, Zdenek, Araya, Paula, Dougherty, Hannah, Dunn, Lauren N., Ludwig, Michael, Schade, Kyndal A., Tracy, Dayna, Smith, Keith P., Granrath, Ross E., Busquet, Nicolas, Khanal, Santosh, Anderson, Ryan D., Cox, Liza L., Estrada, Belinda Enriquez, Rachubinski, Angela L., Lyford, Hannah R., Britton, Eleanor C., Fantauzzo, Katherine A., Orlicky, David J., Matsuda, Jennifer L., Song, Kunhua, Cox, Timothy C., Sullivan, Kelly D., and Espinosa, Joaquin M.
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- 2023
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4. Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations
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Liu, Dongjing, Meyer, Dara, Fennessy, Brian, Feng, Claudia, Cheng, Esther, Johnson, Jessica S., Park, You Jeong, Rieder, Marysia-Kolbe, Ascolillo, Steven, de Pins, Agathe, Dobbyn, Amanda, Lebovitch, Dannielle, Moya, Emily, Nguyen, Tan-Hoang, Wilkins, Lillian, Hassan, Arsalan, Burdick, Katherine E., Buxbaum, Joseph D., Domenici, Enrico, Frangou, Sophia, Hartmann, Annette M., Laurent-Levinson, Claudine, Malhotra, Dheeraj, Pato, Carlos N., Pato, Michele T., Ressler, Kerry, Roussos, Panos, Rujescu, Dan, Arango, Celso, Bertolino, Alessandro, Blasi, Giuseppe, Bocchio-Chiavetto, Luisella, Campion, Dominique, Carr, Vaughan, Fullerton, Janice M., Gennarelli, Massimo, González-Peñas, Javier, Levinson, Douglas F., Mowry, Bryan, Nimgaokar, Vishwajit L., Pergola, Giulio, Rampino, Antonio, Cervilla, Jorge A., Rivera, Margarita, Schwab, Sibylle G., Wildenauer, Dieter B., Daly, Mark, Neale, Benjamin, Singh, Tarjinder, O’Donovan, Michael C., Owen, Michael J., Walters, James T., Ayub, Muhammad, Malhotra, Anil K., Lencz, Todd, Sullivan, Patrick F., Sklar, Pamela, Stahl, Eli A., Huckins, Laura M., and Charney, Alexander W.
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- 2023
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5. Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
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Bryois, Julien, Skene, Nathan G, Hansen, Thomas Folkmann, Kogelman, Lisette JA, Watson, Hunna J, Liu, Zijing, Brueggeman, Leo, Breen, Gerome, Bulik, Cynthia M, Arenas, Ernest, Hjerling-Leffler, Jens, and Sullivan, Patrick F
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Human Genome ,Genetics ,Aging ,Parkinson's Disease ,Brain Disorders ,Neurodegenerative ,Neurosciences ,2.1 Biological and endogenous factors ,Underpinning research ,1.1 Normal biological development and functioning ,Aetiology ,Neurological ,Animals ,Brain ,Genome-Wide Association Study ,Humans ,Mice ,Neurons ,Parkinson Disease ,Transcriptome ,Eating Disorders Working Group of the Psychiatric Genomics Consortium ,International Headache Genetics Consortium ,23andMe Research Team ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease.
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- 2020
6. Comparative genetic architectures of schizophrenia in East Asian and European populations
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Lam, Max, Chen, Chia-Yen, Li, Zhiqiang, Martin, Alicia R, Bryois, Julien, Ma, Xixian, Gaspar, Helena, Ikeda, Masashi, Benyamin, Beben, Brown, Brielin C, Liu, Ruize, Zhou, Wei, Guan, Lili, Kamatani, Yoichiro, Kim, Sung-Wan, Kubo, Michiaki, Kusumawardhani, Agung AAA, Liu, Chih-Min, Ma, Hong, Periyasamy, Sathish, Takahashi, Atsushi, Xu, Zhida, Yu, Hao, Zhu, Feng, Chen, Wei J, Faraone, Stephen, Glatt, Stephen J, He, Lin, Hyman, Steven E, Hwu, Hai-Gwo, McCarroll, Steven A, Neale, Benjamin M, Sklar, Pamela, Wildenauer, Dieter B, Yu, Xin, Zhang, Dai, Mowry, Bryan J, Lee, Jimmy, Holmans, Peter, Xu, Shuhua, Sullivan, Patrick F, Ripke, Stephan, O’Donovan, Michael C, Daly, Mark J, Qin, Shengying, Sham, Pak, Iwata, Nakao, Hong, Kyung S, Schwab, Sibylle G, Yue, Weihua, Tsuang, Ming, Liu, Jianjun, Ma, Xiancang, Kahn, René S, Shi, Yongyong, and Huang, Hailiang
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Genetics ,Human Genome ,Serious Mental Illness ,Schizophrenia ,Brain Disorders ,Mental Health ,Prevention ,Aetiology ,2.1 Biological and endogenous factors ,Mental health ,Good Health and Well Being ,Asian People ,Case-Control Studies ,Asia ,Eastern ,Genetics ,Population ,Genome-Wide Association Study ,Humans ,Polymorphism ,Single Nucleotide ,White People ,Schizophrenia Working Group of the Psychiatric Genomics Consortium ,Indonesia Schizophrenia Consortium ,Genetic REsearch on schizophreniA neTwork-China and the Netherlands ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
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- 2019
7. Publisher Correction: Gene expression imputation across multiple brain regions provides insights into schizophrenia risk
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Huckins, Laura M, Dobbyn, Amanda, Ruderfer, Douglas M, Hoffman, Gabriel, Wang, Weiqing, Pardiñas, Antonio F, Rajagopal, Veera M, Als, Thomas D, T. Nguyen, Hoang, Girdhar, Kiran, Boocock, James, Roussos, Panos, Fromer, Menachem, Kramer, Robin, Domenici, Enrico, Gamazon, Eric R, Purcell, Shaun, Demontis, Ditte, Børglum, Anders D, Walters, James TR, O’Donovan, Michael C, Sullivan, Patrick, Owen, Michael J, Devlin, Bernie, Sieberts, Solveig K, Cox, Nancy J, Im, Hae Kyung, Sklar, Pamela, and Stahl, Eli A
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Genetics ,Neurosciences ,Human Genome ,Serious Mental Illness ,Schizophrenia ,Brain Disorders ,Mental Health ,Biotechnology ,Mental health ,CommonMind Consortium ,Schizophrenia Working Group of the Psychiatric Genomics Consortium ,iPSYCH-GEMS Schizophrenia Working Group ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
In the HTML version of the article originally published, the author group 'The Schizophrenia Working Group of the Psychiatric Genomics Consortium' was displayed incorrectly. The error has been corrected in the HTML version of the article.
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- 2019
8. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk
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Huckins, Laura M, Dobbyn, Amanda, Ruderfer, Douglas M, Hoffman, Gabriel, Wang, Weiqing, Pardiñas, Antonio F, Rajagopal, Veera M, Als, Thomas D, T. Nguyen, Hoang, Girdhar, Kiran, Boocock, James, Roussos, Panos, Fromer, Menachem, Kramer, Robin, Domenici, Enrico, Gamazon, Eric R, Purcell, Shaun, Demontis, Ditte, Børglum, Anders D, Walters, James TR, O’Donovan, Michael C, Sullivan, Patrick, Owen, Michael J, Devlin, Bernie, Sieberts, Solveig K, Cox, Nancy J, Im, Hae Kyung, Sklar, Pamela, and Stahl, Eli A
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Biological Sciences ,Genetics ,Mental Health ,Brain Disorders ,Human Genome ,Schizophrenia ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Brain ,Case-Control Studies ,Gene Expression ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Risk ,Transcriptome ,CommonMind Consortium ,Schizophrenia Working Group of the Psychiatric Genomics Consortium ,iPSYCH-GEMS Schizophrenia Working Group ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.
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- 2019
9. Identification of common genetic risk variants for autism spectrum disorder
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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
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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.
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- 2019
10. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
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Demontis, Ditte, Walters, Raymond K, Martin, Joanna, Mattheisen, Manuel, Als, Thomas D, Agerbo, Esben, Baldursson, Gísli, Belliveau, Rich, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dumont, Ashley, Eriksson, Nicholas, Gandal, Michael, Goldstein, Jacqueline I, Grasby, Katrina L, Grove, Jakob, Gudmundsson, Olafur O, Hansen, Christine S, Hauberg, Mads Engel, Hollegaard, Mads V, Howrigan, Daniel P, Huang, Hailiang, Maller, Julian B, Martin, Alicia R, Martin, Nicholas G, Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Poterba, Timothy, Poulsen, Jesper Buchhave, Ripke, Stephan, Robinson, Elise B, Satterstrom, F Kyle, Stefansson, Hreinn, Stevens, Christine, Turley, Patrick, Walters, G Bragi, Won, Hyejung, Wright, Margaret J, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Andreassen, Ole A, Asherson, Philip, Burton, Christie L, Boomsma, Dorret I, Cormand, Bru, Dalsgaard, Søren, Franke, Barbara, Gelernter, Joel, Geschwind, Daniel, Hakonarson, Hakon, Haavik, Jan, Kranzler, Henry R, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Middeldorp, Christel, Reif, Andreas, Rohde, Luis Augusto, Roussos, Panos, Schachar, Russell, Sklar, Pamela, Sonuga-Barke, Edmund JS, Sullivan, Patrick F, Thapar, Anita, Tung, Joyce Y, Waldman, Irwin D, Medland, Sarah E, Stefansson, Kari, Nordentoft, Merete, Hougaard, David M, Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Daly, Mark J, Faraone, Stephen V, Børglum, Anders D, and Neale, Benjamin M
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ADHD Working Group of the Psychiatric Genomics Consortium ,Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium ,23andMe Research Team ,Brain ,Humans ,Genetic Predisposition to Disease ,Risk ,Cohort Studies ,Attention Deficit Disorder with Hyperactivity ,Gene Expression Regulation ,Polymorphism ,Single Nucleotide ,Adolescent ,Child ,Child ,Preschool ,Female ,Male ,Genome-Wide Association Study ,Genetic Loci ,Clinical Research ,Mental Health ,Human Genome ,Pediatric ,Prevention ,Genetics ,Brain Disorders ,Attention Deficit Hyperactivity Disorder (ADHD) ,Behavioral and Social Science ,Aetiology ,2.1 Biological and endogenous factors ,Mental health ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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- 2019
11. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.
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Gusev, Alexander, Mancuso, Nicholas, Won, Hyejung, Kousi, Maria, Finucane, Hilary K, Reshef, Yakir, Song, Lingyun, Safi, Alexias, Schizophrenia Working Group of the Psychiatric Genomics Consortium, McCarroll, Steven, Neale, Benjamin M, Ophoff, Roel A, O'Donovan, Michael C, Crawford, Gregory E, Geschwind, Daniel H, Katsanis, Nicholas, Sullivan, Patrick F, Pasaniuc, Bogdan, and Price, Alkes L
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Schizophrenia Working Group of the Psychiatric Genomics Consortium ,Brain ,Chromatin ,Animals ,Zebrafish ,Humans ,Genetic Predisposition to Disease ,Mitogen-Activated Protein Kinase 3 ,Microtubule-Associated Proteins ,Zebrafish Proteins ,Gene Expression Profiling ,Schizophrenia ,Gene Dosage ,Multifactorial Inheritance ,Quantitative Trait Loci ,Protein Phosphatase 2 ,Genome-Wide Association Study ,Human Genome ,Genetics ,Mental Health ,Neurosciences ,Brain Disorders ,Serious Mental Illness ,2.1 Biological and endogenous factors ,Mental health ,Developmental Biology ,Biological Sciences ,Medical and Health Sciences - Abstract
Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.
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- 2018
12. Widespread adenine N6-methylation of active genes in fungi
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Mondo, Stephen J, Dannebaum, Richard O, Kuo, Rita C, Louie, Katherine B, Bewick, Adam J, LaButti, Kurt, Haridas, Sajeet, Kuo, Alan, Salamov, Asaf, Ahrendt, Steven R, Lau, Rebecca, Bowen, Benjamin P, Lipzen, Anna, Sullivan, William, Andreopoulos, Bill B, Clum, Alicia, Lindquist, Erika, Daum, Christopher, Northen, Trent R, Kunde-Ramamoorthy, Govindarajan, Schmitz, Robert J, Gryganskyi, Andrii, Culley, David, Magnuson, Jon, James, Timothy Y, O'Malley, Michelle A, Stajich, Jason E, Spatafora, Joseph W, Visel, Axel, and Grigoriev, Igor V
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Microbiology ,Biological Sciences ,Genetics ,5-Methylcytosine ,Adenine ,DNA Methylation ,Epigenesis ,Genetic ,Fungi ,Gene Expression Regulation ,Fungal ,Genome ,Fungal ,Phylogeny ,Transcription Initiation Site ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
N6-methyldeoxyadenine (6mA) is a noncanonical DNA base modification present at low levels in plant and animal genomes, but its prevalence and association with genome function in other eukaryotic lineages remains poorly understood. Here we report that abundant 6mA is associated with transcriptionally active genes in early-diverging fungal lineages. Using single-molecule long-read sequencing of 16 diverse fungal genomes, we observed that up to 2.8% of all adenines were methylated in early-diverging fungi, far exceeding levels observed in other eukaryotes and more derived fungi. 6mA occurred symmetrically at ApT dinucleotides and was concentrated in dense methylated adenine clusters surrounding the transcriptional start sites of expressed genes; its distribution was inversely correlated with that of 5-methylcytosine. Our results show a striking contrast in the genomic distributions of 6mA and 5-methylcytosine and reinforce a distinct role for 6mA as a gene-expression-associated epigenomic mark in eukaryotes.
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- 2017
13. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects
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Marshall, Christian R, Howrigan, Daniel P, Merico, Daniele, Thiruvahindrapuram, Bhooma, Wu, Wenting, Greer, Douglas S, Antaki, Danny, Shetty, Aniket, Holmans, Peter A, Pinto, Dalila, Gujral, Madhusudan, Brandler, William M, Malhotra, Dheeraj, Wang, Zhouzhi, Fajarado, Karin V Fuentes, Maile, Michelle S, Ripke, Stephan, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Atkins, Joshua, Bacanu, Silviu A, Belliveau, Richard A, Bergen, Sarah E, Bertalan, Marcelo, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Cheng, Wei, Cloninger, C Robert, Cohen, David, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedman, Joseph I, Forstner, Andreas J, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Gratten, Jacob, de Haan, Lieuwe, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Huang, Hailiang, Ikeda, Masashi, Joa, Inge, and Kähler, Anna K
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Serious Mental Illness ,Human Genome ,Schizophrenia ,Genetics ,Biotechnology ,Prevention ,Mental Health ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Case-Control Studies ,DNA Copy Number Variations ,Female ,Genetic Loci ,Genetic Markers ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Male ,Risk Factors ,Psychosis Endophenotypes International Consortium ,CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
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- 2017
14. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
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Mullins, Niamh, Forstner, Andreas J., O’Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R. I., Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Børte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Magnusson, Sigurdur H., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O’Brien, Niamh, O’Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Smith, Daniel J., Sobell, Janet L., Søholm Hansen, Christine, Soler Artigas, Maria, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Børglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tõnu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Jones, Ian, Jones, Lisa A., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., and Andreassen, Ole A.
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- 2021
- Full Text
- View/download PDF
15. Integrative approaches for large-scale transcriptome-wide association studies
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Gusev, Alexander, Ko, Arthur, Shi, Huwenbo, Bhatia, Gaurav, Chung, Wonil, Penninx, Brenda WJH, Jansen, Rick, de Geus, Eco JC, Boomsma, Dorret I, Wright, Fred A, Sullivan, Patrick F, Nikkola, Elina, Alvarez, Marcus, Civelek, Mete, Lusis, Aldons J, Lehtimäki, Terho, Raitoharju, Emma, Kähönen, Mika, Seppälä, Ilkka, Raitakari, Olli T, Kuusisto, Johanna, Laakso, Markku, Price, Alkes L, Pajukanta, Päivi, and Pasaniuc, Bogdan
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Biological Sciences ,Genetics ,Obesity ,Human Genome ,Cancer ,Generic health relevance ,Animals ,Gene Expression Regulation ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Mice ,Phenotype ,Quantitative Trait Loci ,Transcriptome ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance of one or multiple proteins. Here we introduce a powerful strategy that integrates gene expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated with complex traits. We leverage expression imputation from genetic data to perform a transcriptome-wide association study (TWAS) to identify significant expression-trait associations. We applied our approaches to expression data from blood and adipose tissue measured in ∼ 3,000 individuals overall. We imputed gene expression into GWAS data from over 900,000 phenotype measurements to identify 69 new genes significantly associated with obesity-related traits (BMI, lipids and height). Many of these genes are associated with relevant phenotypes in the Hybrid Mouse Diversity Panel. Our results showcase the power of integrating genotype, gene expression and phenotype to gain insights into the genetic basis of complex traits.
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- 2016
16. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.
- Author
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Day, Felix R, Ruth, Katherine S, Thompson, Deborah J, Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D, Elks, Cathy E, Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A, Franke, Lude L, Huffman, Jennifer E, Keller, Margaux F, McArdle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Smith, Jennifer A, Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V, Tanaka, Toshiko, Abecasis, Goncalo, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Arnold, Alice M, Barbieri, Caterina, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen-Dale, Anne-Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J, Chapman, J Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E, García-Closas, Montserrat, Giles, Graham G, Girotto, Giorgia G, Goldberg, Mark S, González-Neira, Anna, Goodarzi, Mark O, Grove, Megan L, Gudbjartsson, Daniel F, Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A, Hall, Per, and Hamann, Ute
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PRACTICAL consortium ,kConFab Investigators ,AOCS Investigators ,Generation Scotland ,EPIC-InterAct Consortium ,LifeLines Cohort Study ,Hypothalamus ,Humans ,Breast Neoplasms ,Genetic Predisposition to Disease ,BRCA1 Protein ,Genomics ,Age Factors ,Signal Transduction ,DNA Repair ,Aging ,Reproduction ,Menopause ,Genotype ,Phenotype ,Models ,Genetic ,Adult ,Middle Aged ,Female ,Gene Regulatory Networks ,Genetic Variation ,Genome-Wide Association Study ,Models ,Genetic ,Developmental Biology ,Medical and Health Sciences ,Biological Sciences - Abstract
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
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- 2015
17. Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance
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Crowley, James J, Zhabotynsky, Vasyl, Sun, Wei, Huang, Shunping, Pakatci, Isa Kemal, Kim, Yunjung, Wang, Jeremy R, Morgan, Andrew P, Calaway, John D, Aylor, David L, Yun, Zaining, Bell, Timothy A, Buus, Ryan J, Calaway, Mark E, Didion, John P, Gooch, Terry J, Hansen, Stephanie D, Robinson, Nashiya N, Shaw, Ginger D, Spence, Jason S, Quackenbush, Corey R, Barrick, Cordelia J, Nonneman, Randal J, Kim, Kyungsu, Xenakis, James, Xie, Yuying, Valdar, William, Lenarcic, Alan B, Wang, Wei, Welsh, Catherine E, Fu, Chen-Ping, Zhang, Zhaojun, Holt, James, Guo, Zhishan, Threadgill, David W, Tarantino, Lisa M, Miller, Darla R, Zou, Fei, McMillan, Leonard, Sullivan, Patrick F, and Pardo-Manuel de Villena, Fernando
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Biotechnology ,Human Genome ,Genetics ,Alleles ,Allelic Imbalance ,Animals ,Crosses ,Genetic ,Dosage Compensation ,Genetic ,Female ,Gene Expression ,Genetic Speciation ,Humans ,Male ,Mice ,Mice ,Knockout ,Phylogeny ,Polymorphism ,Single Nucleotide ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Because regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in further characterizing these mechanisms. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. Effects from these variants influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. We also observe two types of parent-of-origin effects, including classical imprinting and a new global allelic imbalance in expression favoring the paternal allele. We conclude that, as with humans, pervasive regulatory variation influences complex genetic traits in mice and provide a new resource toward understanding the genetic control of transcription in mammals.
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- 2015
18. Efficient Bayesian mixed-model analysis increases association power in large cohorts
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Loh, Po-Ru, Tucker, George, Bulik-Sullivan, Brendan K, Vilhjálmsson, Bjarni J, Finucane, Hilary K, Salem, Rany M, Chasman, Daniel I, Ridker, Paul M, Neale, Benjamin M, Berger, Bonnie, Patterson, Nick, and Price, Alkes L
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Algorithms ,Bayes Theorem ,Female ,Genetic Association Studies ,Genome ,Human ,Genotyping Techniques ,Humans ,Linear Models ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Linear mixed models are a powerful statistical tool for identifying genetic associations and avoiding confounding. However, existing methods are computationally intractable in large cohorts and may not optimize power. All existing methods require time cost O(MN(2)) (where N is the number of samples and M is the number of SNPs) and implicitly assume an infinitesimal genetic architecture in which effect sizes are normally distributed, which can limit power. Here we present a far more efficient mixed-model association method, BOLT-LMM, which requires only a small number of O(MN) time iterations and increases power by modeling more realistic, non-infinitesimal genetic architectures via a Bayesian mixture prior on marker effect sizes. We applied BOLT-LMM to 9 quantitative traits in 23,294 samples from the Women's Genome Health Study (WGHS) and observed significant increases in power, consistent with simulations. Theory and simulations show that the boost in power increases with cohort size, making BOLT-LMM appealing for genome-wide association studies in large cohorts.
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- 2015
19. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.
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Bulik-Sullivan, Brendan K, Loh, Po-Ru, Finucane, Hilary K, Ripke, Stephan, Yang, Jian, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Patterson, Nick, Daly, Mark J, Price, Alkes L, and Neale, Benjamin M
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Schizophrenia Working Group of the Psychiatric Genomics Consortium ,Humans ,Regression Analysis ,Sample Size ,Linkage Disequilibrium ,Polymorphism ,Single Nucleotide ,Genome ,Human ,Computer Simulation ,Genome-Wide Association Study ,Polymorphism ,Single Nucleotide ,Genome ,Human ,Developmental Biology ,Medical and Health Sciences ,Biological Sciences - Abstract
Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.
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- 2015
20. Heritability and genomics of gene expression in peripheral blood
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Wright, Fred A, Sullivan, Patrick F, Brooks, Andrew I, Zou, Fei, Sun, Wei, Xia, Kai, Madar, Vered, Jansen, Rick, Chung, Wonil, Zhou, Yi-Hui, Abdellaoui, Abdel, Batista, Sandra, Butler, Casey, Chen, Guanhua, Chen, Ting-Huei, D'Ambrosio, David, Gallins, Paul, Ha, Min Jin, Hottenga, Jouke Jan, Huang, Shunping, Kattenberg, Mathijs, Kochar, Jaspreet, Middeldorp, Christel M, Qu, Ani, Shabalin, Andrey, Tischfield, Jay, Todd, Laura, Tzeng, Jung-Ying, van Grootheest, Gerard, Vink, Jacqueline M, Wang, Qi, Wang, Wei, Wang, Weibo, Willemsen, Gonneke, Smit, Johannes H, de Geus, Eco J, Yin, Zhaoyu, Penninx, Brenda WJH, and Boomsma, Dorret I
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Biotechnology ,Human Genome ,Genetics ,Blood ,Gene Expression Profiling ,Gene Expression Regulation ,Genotype ,Humans ,Inheritance Patterns ,Likelihood Functions ,Netherlands ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
We assessed gene expression profiles in 2,752 twins, using a classic twin design to quantify expression heritability and quantitative trait loci (eQTLs) in peripheral blood. The most highly heritable genes (∼777) were grouped into distinct expression clusters, enriched in gene-poor regions, associated with specific gene function or ontology classes, and strongly associated with disease designation. The design enabled a comparison of twin-based heritability to estimates based on dizygotic identity-by-descent sharing and distant genetic relatedness. Consideration of sampling variation suggests that previous heritability estimates have been upwardly biased. Genotyping of 2,494 twins enabled powerful identification of eQTLs, which we further examined in a replication set of 1,895 unrelated subjects. A large number of non-redundant local eQTLs (6,756) met replication criteria, whereas a relatively small number of distant eQTLs (165) met quality control and replication standards. Our results provide a new resource toward understanding the genetic control of transcription.
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- 2014
21. Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
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Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Kähler, Anna K, Akterin, Susanne, Bergen, Sarah E, Collins, Ann L, Crowley, James J, Fromer, Menachem, Kim, Yunjung, Lee, Sang Hong, Magnusson, Patrik KE, Sanchez, Nick, Stahl, Eli A, Williams, Stephanie, Wray, Naomi R, Xia, Kai, Bettella, Francesco, Borglum, Anders D, Bulik-Sullivan, Brendan K, Cormican, Paul, Craddock, Nick, de Leeuw, Christiaan, Durmishi, Naser, Gill, Michael, Golimbet, Vera, Hamshere, Marian L, Holmans, Peter, Hougaard, David M, Kendler, Kenneth S, Lin, Kuang, Morris, Derek W, Mors, Ole, Mortensen, Preben B, Neale, Benjamin M, O'Neill, Francis A, Owen, Michael J, Milovancevic, Milica Pejovic, Posthuma, Danielle, Powell, John, Richards, Alexander L, Riley, Brien P, Ruderfer, Douglas, Rujescu, Dan, Sigurdsson, Engilbert, Silagadze, Teimuraz, Smit, August B, Stefansson, Hreinn, Steinberg, Stacy, Suvisaari, Jaana, Tosato, Sarah, Verhage, Matthijs, Walters, James T, Multicenter Genetic Studies of Schizophrenia Consortium, Levinson, Douglas F, Gejman, Pablo V, Laurent, Claudine, Mowry, Bryan J, O'Donovan, Michael C, Pulver, Ann E, Schwab, Sibylle G, Wildenauer, Dieter B, Dudbridge, Frank, Shi, Jianxin, Albus, Margot, Alexander, Madeline, Campion, Dominique, Cohen, David, Dikeos, Dimitris, Duan, Jubao, Eichhammer, Peter, Godard, Stephanie, Hansen, Mark, Lerer, F Bernard, Liang, Kung-Yee, Maier, Wolfgang, Mallet, Jacques, Nertney, Deborah A, Nestadt, Gerald, Norton, Nadine, Papadimitriou, George N, Ribble, Robert, Sanders, Alan R, Silverman, Jeremy M, Walsh, Dermot, Williams, Nigel M, Wormley, Brandon, Psychosis Endophenotypes International Consortium, Arranz, Maria J, Bakker, Steven, Bender, Stephan, Bramon, Elvira, and Collier, David
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Multicenter Genetic Studies of Schizophrenia Consortium ,Psychosis Endophenotypes International Consortium ,Wellcome Trust Case Control Consortium 2 ,Humans ,Genetic Predisposition to Disease ,Case-Control Studies ,Schizophrenia ,Polymorphism ,Single Nucleotide ,Sweden ,Female ,Male ,Genome-Wide Association Study ,Polymorphism ,Single Nucleotide ,Developmental Biology ,Biological Sciences ,Medical and Health Sciences - Abstract
Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
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- 2013
22. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
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Watson, Hunna J., Yilmaz, Zeynep, Thornton, Laura M., Hübel, Christopher, Coleman, Jonathan R. I., Gaspar, Héléna A., Bryois, Julien, Hinney, Anke, Leppä, Virpi M., Mattheisen, Manuel, Medland, Sarah E., Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Anorexia Nervosa Genetics Initiative, Hanscombe, Ken B., Purves, Kirstin L., Eating Disorders Working Group of the Psychiatric Genomics Consortium, Adan, Roger A. H., Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A., Baker, Jessica H., Berrettini, Wade H., Boehm, Ilka, Boni, Claudette, Perica, Vesna Boraska, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D., Courtet, Philippe, Crow, Scott, Crowley, James J., Danner, Unna N., Davis, Oliver S. P., de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E., Dick, Danielle M., Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E., Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M., Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J., Forzan, Monica, Franklin, Christopher S., Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Mayora, Monica Gratacos, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G., Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M., Hudson, James I., Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J. H., Kennedy, James L., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klareskog, Lars, Klump, Kelly L., Knudsen, Gun Peggy S., La Via, Maria C., Le Hellard, Stephanie, Levitan, Robert D., Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J., Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R., Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Munn-Chernoff, Melissa A., Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O’Toole, Julie K., Ophoff, Roel A., Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Schork, Nicholas J., Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P. Eline, Slof-Op ‘t Landt, Margarita C. T., Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P., Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W., Boden, Joseph M., Brandt, Harry, Crawford, Steven, Halmi, Katherine A., Horwood, L. John, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Mitchell, James E., Olsen, Catherine M., Pearson, John F., Pedersen, Nancy L., Strober, Michael, Werge, Thomas, Whiteman, David C., Woodside, D. Blake, Stuber, Garret D., Gordon, Scott, Grove, Jakob, Henders, Anjali K., Juréus, Anders, Kirk, Katherine M., Larsen, Janne T., Parker, Richard, Petersen, Liselotte, Jordan, Jennifer, Kennedy, Martin, Montgomery, Grant W., Wade, Tracey D., Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Martin, Nicholas G., Mortensen, Preben Bo, Sullivan, Patrick F., Breen, Gerome, and Bulik, Cynthia M.
- Published
- 2019
- Full Text
- View/download PDF
23. Roadmap for a precision-medicine initiative in the Nordic region
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Njølstad, Pål Rasmus, Andreassen, Ole Andreas, Brunak, Søren, Børglum, Anders D., Dillner, Joakim, Esko, Tõnu, Franks, Paul W., Freimer, Nelson, Groop, Leif, Heimer, Hakon, Hougaard, David M., Hovig, Eivind, Hveem, Kristian, Jalanko, Anu, Kaprio, Jaakko, Knudsen, Gun Peggy, Melbye, Mads, Metspalu, Andres, Mortensen, Preben Bo, Palmgren, Juni, Palotie, Aarno, Reed, Wenche, Stefánsson, Hreinn, Stitziel, Nathan O., Sullivan, Patrick F., Thorsteinsdóttir, Unnur, Vaudel, Marc, Vuorio, Eero, Werge, Thomas, Stoltenberg, Camilla, and Stefánsson, Kári
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- 2019
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24. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia
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Cortese, Andrea, Simone, Roberto, Sullivan, Roisin, Vandrovcova, Jana, Tariq, Huma, Yau, Wai Yan, Humphrey, Jack, Jaunmuktane, Zane, Sivakumar, Prasanth, Polke, James, Ilyas, Muhammad, Tribollet, Eloise, Tomaselli, Pedro J., Devigili, Grazia, Callegari, Ilaria, Versino, Maurizio, Salpietro, Vincenzo, Efthymiou, Stephanie, Kaski, Diego, Wood, Nick W., Andrade, Nadja S., Buglo, Elena, Rebelo, Adriana, Rossor, Alexander M., Bronstein, Adolfo, Fratta, Pietro, Marques, Wilson J., Züchner, Stephan, Reilly, Mary M., and Houlden, Henry
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- 2019
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25. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
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Jansen, Iris E., Savage, Jeanne E., Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M., Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K., Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S., Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S., Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J., Jonsson, Palmi V., Kiddle, Steven J., Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B., Selbæk, Geir, Shoai, Maryam, Skene, Nathan G., Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D., Wang, Yunpeng, White, Linda R., Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F., van der Flier, Wiesje M., Dobson, Richard, Davis, Lea K., Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L., Ripke, Stephan, Andreassen, Ole A., and Posthuma, Danielle
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- 2019
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26. Microduplications of 16p11.2 are associated with schizophrenia
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McCarthy, Shane E, Makarov, Vladimir, Kirov, George, Addington, Anjene M, McClellan, Jon, Yoon, Seungtai, Perkins, Diana O, Dickel, Diane E, Kusenda, Mary, Krastoshevsky, Olga, Krause, Verena, Kumar, Ravinesh A, Grozeva, Detelina, Malhotra, Dheeraj, Walsh, Tom, Zackai, Elaine H, Kaplan, Paige, Ganesh, Jaya, Krantz, Ian D, Spinner, Nancy B, Roccanova, Patricia, Bhandari, Abhishek, Pavon, Kevin, Lakshmi, B, Leotta, Anthony, Kendall, Jude, Lee, Yoon-ha, Vacic, Vladimir, Gary, Sydney, Iakoucheva, Lilia M, Crow, Timothy J, Christian, Susan L, Lieberman, Jeffrey A, Stroup, T Scott, Lehtimäki, Terho, Puura, Kaija, Haldeman-Englert, Chad, Pearl, Justin, Goodell, Meredith, Willour, Virginia L, DeRosse, Pamela, Steele, Jo, Kassem, Layla, Wolff, Jessica, Chitkara, Nisha, McMahon, Francis J, Malhotra, Anil K, Potash, James B, Schulze, Thomas G, Nöthen, Markus M, Cichon, Sven, Rietschel, Marcella, Leibenluft, Ellen, Kustanovich, Vlad, Lajonchere, Clara M, Sutcliffe, James S, Skuse, David, Gill, Michael, Gallagher, Louise, Mendell, Nancy R, Craddock, Nick, Owen, Michael J, O'Donovan, Michael C, Shaikh, Tamim H, Susser, Ezra, DeLisi, Lynn E, Sullivan, Patrick F, Deutsch, Curtis K, Rapoport, Judith, Levy, Deborah L, King, Mary-Claire, and Sebat, Jonathan
- Subjects
Mental health ,Chromosomes ,Human ,Pair 16 ,Gene Duplication ,Genetic Predisposition to Disease ,Humans ,Risk Factors ,Schizophrenia ,Wellcome Trust Case Control Consortium ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
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- 2009
27. Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways
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Nagel, Mats, Jansen, Philip R., Stringer, Sven, Watanabe, Kyoko, de Leeuw, Christiaan A., Bryois, Julien, Savage, Jeanne E., Hammerschlag, Anke R., Skene, Nathan G., Muñoz-Manchado, Ana B., 23andMe Research Team, White, Tonya, Tiemeier, Henning, Linnarsson, Sten, Hjerling-Leffler, Jens, Polderman, Tinca J. C., Sullivan, Patrick F., van der Sluis, Sophie, and Posthuma, Danielle
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- 2018
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28. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence
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Savage, Jeanne E., Jansen, Philip R., Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A., Nagel, Mats, Awasthi, Swapnil, Barr, Peter B., Coleman, Jonathan R. I., Grasby, Katrina L., Hammerschlag, Anke R., Kaminski, Jakob A., Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A., Trampush, Joey W., Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K., Karlsson, Ida K., Linnarsson, Sten, Montgomery, Grant W., Muñoz-Manchado, Ana B., Quinlan, Erin B., Schumann, Gunter, Skene, Nathan G., Webb, Bradley T., White, Tonya, Arking, Dan E., Avramopoulos, Dimitrios, Bilder, Robert M., Bitsios, Panos, Burdick, Katherine E., Cannon, Tyrone D., Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T., Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J., DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G., Espeseth, Thomas, Freimer, Nelson A., Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C., Hariri, Ahmad R., Hatzimanolis, Alex, Keller, Matthew C., Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C., London, Edythe, Lundervold, Astri J., Malhotra, Anil K., Melle, Ingrid, Morris, Derek, Need, Anna C., Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A., Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W., Scult, Matthew A., Smeland, Olav B., Smyrnis, Nikolaos, Starr, John M., Steen, Vidar M., Stefanis, Nikos C., Straub, Richard E., Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N., Weinberger, Daniel R., Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A., Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M., Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M. Arfan, Kendler, Kenneth S., Martin, Nicholas G., Medland, Sarah E., Pedersen, Nancy L., Plomin, Robert, Polderman, Tinca J. C., Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F., Vrieze, Scott I., Wright, Margaret J., and Posthuma, Danielle
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- 2018
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29. Genetic identification of brain cell types underlying schizophrenia
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Skene, Nathan G., Bryois, Julien, Bakken, Trygve E., Breen, Gerome, Crowley, James J., Gaspar, Héléna A., Giusti-Rodriguez, Paola, Hodge, Rebecca D., Miller, Jeremy A., Muñoz-Manchado, Ana B., O’Donovan, Michael C., Owen, Michael J., Pardiñas, Antonio F., Ryge, Jesper, Walters, James T. R., Linnarsson, Sten, Lein, Ed S., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sullivan, Patrick F., and Hjerling-Leffler, Jens
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- 2018
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30. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression
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Wray, Naomi R., Ripke, Stephan, Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till M. F., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan F. T., Bigdeli, Tim B., Binder, Elisabeth B., Blackwood, Douglas R. H., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan I. R., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Crowley, Cheynna A., Dashti, Hassan S., Davies, Gail, Deary, Ian J., Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Eriksson, Nicholas, Escott-Price, Valentina, Kiadeh, Farnush Hassan Farhadi, Finucane, Hilary K., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Giusti-Rodríguez, Paola, Goes, Fernando S., Gordon, Scott D., Grove, Jakob, Hall, Lynsey S., Hannon, Eilis, Hansen, Christine Søholm, Hansen, Thomas F., Herms, Stefan, Hickie, Ian B., Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Hu, Ming, Hyde, Craig L., Ising, Marcus, Jansen, Rick, Jin, Fulai, Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Krogh, Jesper, Kutalik, Zoltán, Lane, Jacqueline M., Li, Yihan, Li, Yun, Lind, Penelope A., Liu, Xiaoxiao, Lu, Leina, MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mill, Jonathan, Mondimore, Francis M., Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O’Reilly, Paul F., Oskarsson, Hogni, Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Pettersson, Erik, Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Purcell, Shaun M., Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Saeed Mirza, Saira, Saxena, Richa, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant B. C., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Stockmeier, Craig A., Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Tian, Chao, Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, eQTLGen, 23andMe, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. C. J., DePaulo, J. Raymond, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Hayward, Caroline, Heath, Andrew C., Hinds, David A., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela F. A., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Penninx, Brenda W. J. H., Perlis, Roy H., Porteous, David J., Potash, James B., Preisig, Martin, Rietschel, Marcella, Schaefer, Catherine, Schulze, Thomas G., Smoller, Jordan W., Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Winslow, Ashley R., Lewis, Cathryn M., Levinson, Douglas F., Breen, Gerome, Børglum, Anders D., Sullivan, Patrick F., and the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
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- 2018
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31. Author Correction: The NCI Genomic Data Commons
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Heath, Allison P., Ferretti, Vincent, Agrawal, Stuti, An, Maksim, Angelakos, James C., Arya, Renuka, Bajari, Rosita, Baqar, Bilal, Barnowski, Justin H. B., Burt, Jeffrey, Catton, Ann, Chan, Brandon F., Chu, Fay, Cullion, Kim, Davidsen, Tanja, Do, Phuong-My, Dompierre, Christian, Ferguson, Martin L., Fitzsimons, Michael S., Ford, Michael, Fukuma, Miyuki, Gaheen, Sharon, Ganji, Gajanan L., Garcia, Tzintzuni I., George, Sameera S., Gerhard, Daniela S., Gerthoffert, Francois, Gomez, Fauzi, Han, Kang, Hernandez, Kyle M., Issac, Biju, Jackson, Richard, Jensen, Mark A., Joshi, Sid, Kadam, Ajinkya, Khurana, Aishmit, Kim, Kyle M. J., Kraft, Victoria E., Li, Shenglai, Lichtenberg, Tara M., Lodato, Janice, Lolla, Laxmi, Martinov, Plamen, Mazzone, Jeffrey A., Miller, Daniel P., Miller, Ian, Miller, Joshua S., Miyauchi, Koji, Murphy, Mark W., Nullet, Thomas, Ogwara, Rowland O., Ortuño, Francisco M., Pedrosa, Jesús, Pham, Phuong L., Popov, Maxim Y., Porter, James J., Powell, Raymond, Rademacher, Karl, Reid, Colin P., Rich, Samantha, Rogel, Bessie, Sahni, Himanso, Savage, Jeremiah H., Schmitt, Kyle A., Simmons, Trevar J., Sislow, Joseph, Spring, Jonathan, Stein, Lincoln, Sullivan, Sean, Tang, Yajing, Thiagarajan, Mathangi, Troyer, Heather D., Wang, Chang, Wang, Zhining, West, Bedford L., Wilmer, Alex, Wilson, Shane, Wu, Kaman, Wysocki, William P., Xiang, Linda, Yamada, Joseph T., Yang, Liming, Yu, Christine, Yung, Christina K., Zenklusen, Jean Claude, Zhang, Junjun, Zhang, Zhenyu, Zhao, Yuanheng, Zubair, Ariz, Staudt, Louis M., and Grossman, Robert L.
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- 2021
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32. Linkage disequilibrium–dependent architecture of human complex traits shows action of negative selection
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Gazal, Steven, Finucane, Hilary K, Furlotte, Nicholas A, Loh, Po-Ru, Palamara, Pier Francesco, Liu, Xuanyao, Schoech, Armin, Bulik-Sullivan, Brendan, Neale, Benjamin M, Gusev, Alexander, and Price, Alkes L
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- 2017
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33. Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
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Jansen, Iris E., Savage, Jeanne E., Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M., Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K., Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S., Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S., Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J., Jonsson, Palmi V., Kiddle, Steven J., Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B., Selbæk, Geir, Shoai, Maryam, Skene, Nathan G., Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D., Wang, Yunpeng, White, Linda R., Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F., van der Flier, Wiesje M., Dobson, Richard, Davis, Lea K., Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L., Ripke, Stephan, Andreassen, Ole A., and Posthuma, Danielle
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- 2020
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34. Author Correction: Linkage disequilibrium–dependent architecture of human complex traits shows action of negative selection
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Gazal, Steven, Finucane, Hilary K., Furlotte, Nicholas A., Loh, Po-Ru, Palamara, Pier Francesco, Liu, Xuanyao, Schoech, Armin, Bulik-Sullivan, Brendan, Neale, Benjamin M., Gusev, Alexander, and Price, Alkes L.
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- 2019
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35. Author Correction: Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia
- Author
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Cortese, Andrea, Simone, Roberto, Sullivan, Roisin, Vandrovcova, Jana, Tariq, Huma, Yau, Wai Yan, Humphrey, Jack, Jaunmuktane, Zane, Sivakumar, Prasanth, Polke, James, Ilyas, Muhammad, Tribollet, Eloise, Tomaselli, Pedro J., Devigili, Grazia, Callegari, Ilaria, Versino, Maurizio, Salpietro, Vincenzo, Efthymiou, Stephanie, Kaski, Diego, Wood, Nick W., Andrade, Nadja S., Buglo, Elena, Rebelo, Adriana, Rossor, Alexander M., Bronstein, Adolfo, Fratta, Pietro, Marques, Wilson J., Züchner, Stephan, Reilly, Mary M., and Houlden, Henry
- Published
- 2019
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36. Plasmodium cynomolgi genome sequences provide insight into Plasmodium vivax and the monkey malaria clade
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Tachibana, Shin-Ichiro, Sullivan, Steven A, Kawai, Satoru, Nakamura, Shota, Kim, Hyunjae R, Goto, Naohisa, Arisue, Nobuko, Palacpac, Nirianne M Q, Honma, Hajime, Yagi, Masanori, Tougan, Takahiro, Katakai, Yuko, Kaneko, Osamu, Mita, Toshihiro, Kita, Kiyoshi, Yasutomi, Yasuhiro, Sutton, Patrick L, Shakhbatyan, Rimma, Horii, Toshihiro, Yasunaga, Teruo, Barnwell, John W, Escalante, Ananias A, Carlton, Jane M, and Tanabe, Kazuyuki
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- 2012
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37. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
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Võsa, Urmo, Claringbould, Annique, Westra, Harm-Jan, Bonder, Marc Jan, Deelen, Patrick, Zeng, Biao, Kirsten, Holger, Saha, Ashis, Kreuzhuber, Roman, Yazar, Seyhan, Brugge, Harm, Oelen, Roy, de Vries, Dylan H., van der Wijst, Monique G. P., Kasela, Silva, Pervjakova, Natalia, Alves, Isabel, Favé, Marie-Julie, Agbessi, Mawussé, Christiansen, Mark W., Jansen, Rick, Seppälä, Ilkka, Tong, Lin, Teumer, Alexander, Schramm, Katharina, Hemani, Gibran, Verlouw, Joost, Yaghootkar, Hanieh, Sönmez Flitman, Reyhan, Brown, Andrew, Kukushkina, Viktorija, Kalnapenkis, Anette, Rüeger, Sina, Porcu, Eleonora, Kronberg, Jaanika, Kettunen, Johannes, Lee, Bernett, Zhang, Futao, Qi, Ting, Hernandez, Jose Alquicira, Arindrarto, Wibowo, Beutner, Frank, Dmitrieva, Julia, Elansary, Mahmoud, Fairfax, Benjamin P., Georges, Michel, Heijmans, Bastiaan T., Hewitt, Alex W., Kähönen, Mika, Kim, Yungil, Knight, Julian C., Kovacs, Peter, Krohn, Knut, Li, Shuang, Loeffler, Markus, Marigorta, Urko M., Mei, Hailang, Momozawa, Yukihide, Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel G., Penninx, Brenda W. J. H., Pritchard, Jonathan K., Raitakari, Olli T., Rotzschke, Olaf, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ’t Hoen, Peter A. C., Thiery, Joachim, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, Veldink, Jan H., Völker, Uwe, Warmerdam, Robert, Wijmenga, Cisca, Swertz, Morris, Andiappan, Anand, Montgomery, Grant W., Ripatti, Samuli, Perola, Markus, Kutalik, Zoltan, Dermitzakis, Emmanouil, Bergmann, Sven, Frayling, Timothy, van Meurs, Joyce, Prokisch, Holger, Ahsan, Habibul, Pierce, Brandon L., Lehtimäki, Terho, Boomsma, Dorret I., Psaty, Bruce M., Gharib, Sina A., Awadalla, Philip, Milani, Lili, Ouwehand, Willem H., Downes, Kate, Stegle, Oliver, Battle, Alexis, Visscher, Peter M., Yang, Jian, Scholz, Markus, Powell, Joseph, Gibson, Greg, Esko, Tõnu, and Franke, Lude
- Abstract
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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- 2021
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38. The NCI Genomic Data Commons
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Heath, Allison P., Ferretti, Vincent, Agrawal, Stuti, An, Maksim, Angelakos, James C., Arya, Renuka, Bajari, Rosita, Baqar, Bilal, Barnowski, Justin H. B., Burt, Jeffrey, Catton, Ann, Chan, Brandon F., Chu, Fay, Cullion, Kim, Davidsen, Tanja, Do, Phuong-My, Dompierre, Christian, Ferguson, Martin L., Fitzsimons, Michael S., Ford, Michael, Fukuma, Miyuki, Gaheen, Sharon, Ganji, Gajanan L., Garcia, Tzintzuni I., George, Sameera S., Gerhard, Daniela S., Gerthoffert, Francois, Gomez, Fauzi, Han, Kang, Hernandez, Kyle M., Issac, Biju, Jackson, Richard, Jensen, Mark A., Joshi, Sid, Kadam, Ajinkya, Khurana, Aishmit, Kim, Kyle M. J., Kraft, Victoria E., Li, Shenglai, Lichtenberg, Tara M., Lodato, Janice, Lolla, Laxmi, Martinov, Plamen, Mazzone, Jeffrey A., Miller, Daniel P., Miller, Ian, Miller, Joshua S., Miyauchi, Koji, Murphy, Mark W., Nullet, Thomas, Ogwara, Rowland O., Ortuño, Francisco M., Pedrosa, Jesús, Pham, Phuong L., Popov, Maxim Y., Porter, James J., Powell, Raymond, Rademacher, Karl, Reid, Colin P., Rich, Samantha, Rogel, Bessie, Sahni, Himanso, Savage, Jeremiah H., Schmitt, Kyle A., Simmons, Trevar J., Sislow, Joseph, Spring, Jonathan, Stein, Lincoln, Sullivan, Sean, Tang, Yajing, Thiagarajan, Mathangi, Troyer, Heather D., Wang, Chang, Wang, Zhining, West, Bedford L., Wilmer, Alex, Wilson, Shane, Wu, Kaman, Wysocki, William P., Xiang, Linda, Yamada, Joseph T., Yang, Liming, Yu, Christine, Yung, Christina K., Zenklusen, Jean Claude, Zhang, Junjun, Zhang, Zhenyu, Zhao, Yuanheng, Zubair, Ariz, Staudt, Louis M., and Grossman, Robert L.
- Abstract
The National Cancer Institute (NCI) Genomic Data Commons (GDC) contains more than 2.9 petabytes of genomic and associated clinical data from more than 60 NCI-funded and other contributed cancer genomics research projects. The GDC consists of five applications over a common data model and a common application programming interface.
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- 2021
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39. Genome-wide association study identifies 30 loci associated with bipolar disorder
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Stahl, Eli A., Breen, Gerome, Forstner, Andreas J., McQuillin, Andrew, Ripke, Stephan, Trubetskoy, Vassily, Mattheisen, Manuel, Wang, Yunpeng, Coleman, Jonathan R. I., Gaspar, Héléna A., de Leeuw, Christiaan A., Steinberg, Stacy, Pavlides, Jennifer M. Whitehead, Trzaskowski, Maciej, Byrne, Enda M., Pers, Tune H., Holmans, Peter A., Richards, Alexander L., Abbott, Liam, Agerbo, Esben, Akil, Huda, Albani, Diego, Alliey-Rodriguez, Ney, Als, Thomas D., Anjorin, Adebayo, Antilla, Verneri, Awasthi, Swapnil, Badner, Judith A., Bækvad-Hansen, Marie, Barchas, Jack D., Bass, Nicholas, Bauer, Michael, Belliveau, Richard, Bergen, Sarah E., Pedersen, Carsten Bøcker, Bøen, Erlend, Boks, Marco P., Boocock, James, Budde, Monika, Bunney, William, Burmeister, Margit, Bybjerg-Grauholm, Jonas, Byerley, William, Casas, Miquel, Cerrato, Felecia, Cervantes, Pablo, Chambert, Kimberly, Charney, Alexander W., Chen, Danfeng, Churchhouse, Claire, Clarke, Toni-Kim, Coryell, William, Craig, David W., Cruceanu, Cristiana, Curtis, David, Czerski, Piotr M., Dale, Anders M., de Jong, Simone, Degenhardt, Franziska, Del-Favero, Jurgen, DePaulo, J. Raymond, Djurovic, Srdjan, Dobbyn, Amanda L., Dumont, Ashley, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Fan, Chun Chieh, Fischer, Sascha B., Flickinger, Matthew, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Fraser, Christine, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Gage, Diane, Garnham, Julie, Giambartolomei, Claudia, Pedersen, Marianne Giørtz, Goldstein, Jaqueline, Gordon, Scott D., Gordon-Smith, Katherine, Green, Elaine K., Green, Melissa J., Greenwood, Tiffany A., Grove, Jakob, Guan, Weihua, Guzman-Parra, José, Hamshere, Marian L., Hautzinger, Martin, Heilbronner, Urs, Herms, Stefan, Hipolito, Maria, Hoffmann, Per, Holland, Dominic, Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Juréus, Anders, Kandaswamy, Radhika, Karlsson, Robert, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koller, Anna C., Kupka, Ralph, Lavebratt, Catharina, Lawrence, Jacob, Lawson, William B., Leber, Markus, Lee, Phil H., Levy, Shawn E., Li, Jun Z., Liu, Chunyu, Lucae, Susanne, Maaser, Anna, MacIntyre, Donald J., Mahon, Pamela B., Maier, Wolfgang, Martinsson, Lina, McCarroll, Steve, McGuffin, Peter, McInnis, Melvin G., McKay, James D., Medeiros, Helena, Medland, Sarah E., Meng, Fan, Milani, Lili, Montgomery, Grant W., Morris, Derek W., Mühleisen, Thomas W., Mullins, Niamh, Nguyen, Hoang, Nievergelt, Caroline M., Adolfsson, Annelie Nordin, Nwulia, Evaristus A., O’Donovan, Claire, Loohuis, Loes M. Olde, Ori, Anil P. S., Oruc, Lilijana, Ösby, Urban, Perlis, Roy H., Perry, Amy, Pfennig, Andrea, Potash, James B., Purcell, Shaun M., Regeer, Eline J., Reif, Andreas, Reinbold, Céline S., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roussos, Panos, Ruderfer, Douglas M., Ryu, Euijung, Sánchez-Mora, Cristina, Schatzberg, Alan F., Scheftner, William A., Schork, Nicholas J., Shannon Weickert, Cynthia, Shehktman, Tatyana, Shilling, Paul D., Sigurdsson, Engilbert, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Søholm Hansen, Christine, Spijker, Anne T., St Clair, David, Steffens, Michael, Strauss, John S., Streit, Fabian, Strohmaier, Jana, Szelinger, Szabolcs, Thompson, Robert C., Thorgeirsson, Thorgeir E., Treutlein, Jens, Vedder, Helmut, Wang, Weiqing, Watson, Stanley J., Weickert, Thomas W., Witt, Stephanie H., Xi, Simon, Xu, Wei, Young, Allan H., Zandi, Peter, Zhang, Peng, Zöllner, Sebastian, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Berrettini, Wade H., Biernacka, Joanna M., Blackwood, Douglas H. R., Boehnke, Michael, Børglum, Anders D., Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Dannlowski, Udo, Esko, Tõnu, Etain, Bruno, Frye, Mark, Fullerton, Janice M., Gershon, Elliot S., Gill, Michael, Goes, Fernando, Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Hougaard, David M., Hultman, Christina M., Jones, Ian, Jones, Lisa A., Kahn, René S., Kirov, George, Landén, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Martin, Nicholas G., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Metspalu, Andres, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nimgaonkar, Vishwajit, Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Owen, Michael J., Paciga, Sara A., Pato, Carlos, Pato, Michele T., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Ribasés, Marta, Rietschel, Marcella, Rouleau, Guy A., Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Serretti, Alessandro, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Werge, Thomas, Nurnberger, John I., Wray, Naomi R., Di Florio, Arianna, Edenberg, Howard J., Cichon, Sven, Ophoff, Roel A., Scott, Laura J., Andreassen, Ole A., Kelsoe, John, and Sklar, Pamela
- Abstract
Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P< 1 × 10−4in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P< 5 × 10−8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
- Published
- 2019
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40. Biallelic expansion of an intronic repeat in RFC1is a common cause of late-onset ataxia
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Cortese, Andrea, Simone, Roberto, Sullivan, Roisin, Vandrovcova, Jana, Tariq, Huma, Yau, Wai Yan, Humphrey, Jack, Jaunmuktane, Zane, Sivakumar, Prasanth, Polke, James, Ilyas, Muhammad, Tribollet, Eloise, Tomaselli, Pedro J., Devigili, Grazia, Callegari, Ilaria, Versino, Maurizio, Salpietro, Vincenzo, Efthymiou, Stephanie, Kaski, Diego, Wood, Nick W., Andrade, Nadja S., Buglo, Elena, Rebelo, Adriana, Rossor, Alexander M., Bronstein, Adolfo, Fratta, Pietro, Marques, Wilson J., Züchner, Stephan, Reilly, Mary M., and Houlden, Henry
- Abstract
Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11allele, does not affect RFC1expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1is a frequent cause of late-onset ataxia.
- Published
- 2019
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41. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways
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Jansen, Philip R., Watanabe, Kyoko, Stringer, Sven, Skene, Nathan, Bryois, Julien, Hammerschlag, Anke R., de Leeuw, Christiaan A., Benjamins, Jeroen S., Muñoz-Manchado, Ana B., Nagel, Mats, Savage, Jeanne E., Tiemeier, Henning, White, Tonya, Tung, Joyce Y., Hinds, David A., Vacic, Vladimir, Wang, Xin, Sullivan, Patrick F., van der Sluis, Sophie, Polderman, Tinca J. C., Smit, August B., Hjerling-Leffler, Jens, Van Someren, Eus J. W., and Posthuma, Danielle
- Abstract
Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited. Here, we use a large genetic association sample (n= 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.
- Published
- 2019
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42. Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia
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Li, Zhiqiang, Chen, Jianhua, Yu, Hao, He, Lin, Xu, Yifeng, Zhang, Dai, Yi, Qizhong, Li, Changgui, Li, Xingwang, Shen, Jiawei, Song, Zhijian, Ji, Weidong, Wang, Meng, Zhou, Juan, Chen, Boyu, Liu, Yahui, Wang, Jiqiang, Wang, Peng, Yang, Ping, Wang, Qingzhong, Feng, Guoyin, Liu, Benxiu, Sun, Wensheng, Li, Baojie, He, Guang, Li, Weidong, Wan, Chunling, Xu, Qi, Li, Wenjin, Wen, Zujia, Liu, Ke, Huang, Fang, Ji, Jue, Ripke, Stephan, Yue, Weihua, Sullivan, Patrick F, O'Donovan, Michael C, and Shi, Yongyong
- Abstract
We conducted a genome-wide association study (GWAS) with replication in 36,180 Chinese individuals and performed further transancestry meta-analyses with data from the Psychiatry Genomics Consortium (PGC2). Approximately 95% of the genome-wide significant (GWS) index alleles (or their proxies) from the PGC2 study were overrepresented in Chinese schizophrenia cases, including ∼50% that achieved nominal significance and ∼75% that continued to be GWS in the transancestry analysis. The Chinese-only analysis identified seven GWS loci; three of these also were GWS in the transancestry analyses, which identified 109 GWS loci, thus yielding a total of 113 GWS loci (30 novel) in at least one of these analyses. We observed improvements in the fine-mapping resolution at many susceptibility loci. Our results provide several lines of evidence supporting candidate genes at many loci and highlight some pathways for further research. Together, our findings provide novel insight into the genetic architecture and biological etiology of schizophrenia.
- Published
- 2017
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43. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability
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Singh, Tarjinder, Walters, James T R, Johnstone, Mandy, Curtis, David, Suvisaari, Jaana, Torniainen, Minna, Rees, Elliott, Iyegbe, Conrad, Blackwood, Douglas, McIntosh, Andrew M, Kirov, Georg, Geschwind, Daniel, Murray, Robin M, Di Forti, Marta, Bramon, Elvira, Gandal, Michael, Hultman, Christina M, Sklar, Pamela, Palotie, Aarno, Sullivan, Patrick F, O'Donovan, Michael C, Owen, Michael J, and Barrett, Jeffrey C
- Abstract
By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.
- Published
- 2017
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44. Single-molecule sequencing and chromatin conformation capture enable de novo reference assembly of the domestic goat genome
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Bickhart, Derek M, Rosen, Benjamin D, Koren, Sergey, Sayre, Brian L, Hastie, Alex R, Chan, Saki, Lee, Joyce, Lam, Ernest T, Liachko, Ivan, Sullivan, Shawn T, Burton, Joshua N, Huson, Heather J, Nystrom, John C, Kelley, Christy M, Hutchison, Jana L, Zhou, Yang, Sun, Jiajie, Crisà, Alessandra, Ponce de León, F Abel, Schwartz, John C, Hammond, John A, Waldbieser, Geoffrey C, Schroeder, Steven G, Liu, George E, Dunham, Maitreya J, Shendure, Jay, Sonstegard, Tad S, Phillippy, Adam M, Van Tassell, Curtis P, and Smith, Timothy P L
- Abstract
The decrease in sequencing cost and increased sophistication of assembly algorithms for short-read platforms has resulted in a sharp increase in the number of species with genome assemblies. However, these assemblies are highly fragmented, with many gaps, ambiguities, and errors, impeding downstream applications. We demonstrate current state of the art for de novo assembly using the domestic goat (Capra hircus) based on long reads for contig formation, short reads for consensus validation, and scaffolding by optical and chromatin interaction mapping. These combined technologies produced what is, to our knowledge, the most continuous de novo mammalian assembly to date, with chromosome-length scaffolds and only 649 gaps. Our assembly represents a ∼400-fold improvement in continuity due to properly assembled gaps, compared to the previously published C. hircus assembly, and better resolves repetitive structures longer than 1 kb, representing the largest repeat family and immune gene complex yet produced for an individual of a ruminant species.
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- 2017
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45. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias
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Dunford, Andrew, Weinstock, David M, Savova, Virginia, Schumacher, Steven E, Cleary, John P, Yoda, Akinori, Sullivan, Timothy J, Hess, Julian M, Gimelbrant, Alexander A, Beroukhim, Rameen, Lawrence, Michael S, Getz, Gad, and Lane, Andrew A
- Abstract
There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate < 0.1), in comparison to zero of 18,055 autosomal and PAR genes (Fisher's exact P < 0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.
- Published
- 2017
- Full Text
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46. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population
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Robinson, Elise B, St Pourcain, Beate, Anttila, Verneri, Kosmicki, Jack A, Bulik-Sullivan, Brendan, Grove, Jakob, Maller, Julian, Samocha, Kaitlin E, Sanders, Stephan J, Ripke, Stephan, Martin, Joanna, Hollegaard, Mads V, Werge, Thomas, Hougaard, David M, Neale, Benjamin M, Evans, David M, Skuse, David, Mortensen, Preben Bo, Børglum, Anders D, Ronald, Angelica, Smith, George Davey, and Daly, Mark J
- Abstract
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.
- Published
- 2016
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47. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis
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Loh, Po-Ru, Bhatia, Gaurav, Gusev, Alexander, Finucane, Hilary K, Bulik-Sullivan, Brendan K, Pollack, Samuela J, de Candia, Teresa R, Lee, Sang Hong, Wray, Naomi R, Kendler, Kenneth S, O'Donovan, Michael C, Neale, Benjamin M, Patterson, Nick, and Price, Alkes L
- Abstract
Heritability analyses of genome-wide association study (GWAS) cohorts have yielded important insights into complex disease architecture, and increasing sample sizes hold the promise of further discoveries. Here we analyze the genetic architectures of schizophrenia in 49,806 samples from the PGC and nine complex diseases in 54,734 samples from the GERA cohort. For schizophrenia, we infer an overwhelmingly polygenic disease architecture in which ≥71% of 1-Mb genomic regions harbor ≥1 variant influencing schizophrenia risk. We also observe significant enrichment of heritability in GC-rich regions and in higher-frequency SNPs for both schizophrenia and GERA diseases. In bivariate analyses, we observe significant genetic correlations (ranging from 0.18 to 0.85) for several pairs of GERA diseases; genetic correlations were on average 1.3 tunes stronger than the correlations of overall disease liabilities. To accomplish these analyses, we developed a fast algorithm for multicomponent, multi-trait variance-components analysis that overcomes prior computational barriers that made such analyses intractable at this scale.
- Published
- 2015
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48. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux
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Sanyanusin, Phaikasame, Schimmenti, Lisa A., McNoe, Leslie A., Ward, Teresa A., Pierpont, Mary Ella M., Sullivan, Michael J., Dobyns, William B., and Eccles, Michael R.
- Abstract
Paired box (PAX) genes play a critical role in human development and disease. The PAX2 gene is expressed in primitive cells of the kidney, ureter, eye, ear and central nervous system. We have conducted a mutational analysis of PAX2 in a family with optic nerve colobomas, renal hypoplasia, mild proteinuria and vesicoureteral reflux. We report a single nucleotide deletion in exon five, causing a frame–shift of the PAX2 coding region in the octapeptide domain. The phenotype resulting from the PAX2 mutation in this family was very similar to abnormalities that have been reported in Krd mutant mice. These data suggest that PAX2 is required for normal kidney and eye development.
- Published
- 1995
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49. Identification of the remains of the Romanov family by DNA analysis
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Gill, Peter, Ivanov, Pavel L., Kimpton, Colin, Piercy, Romelle, Benson, Nicola, Tully, Gillian, Evett, Ian, Hagelberg, Erika, and Sullivan, Kevin
- Abstract
Nine skeletons found in a shallow grave in Ekaterinburg, Russia, in July 1991, were tentatively identified by Russian forensic authorities as the remains of the last Tsar, Tsarina, three of their five children, the Royal Physician and three servants. We have performed DNA based sex testing and short tandem repeat (STR) analysis and confirm that a family group was present in the grave. Analysis of mitochondrial (mt) DNA reveals an exact sequence match between the putative Tsarina and the three children with a living maternal relative. Amplified mtDNA extracted from the remains of the putative Tsar has been cloned to demonstrate heteroplasmy at a single base within the mtDNA control region. One of these sequences matches two living maternal relatives of the Tsar. We conclude that the DNA evidence supports the hypothesis that the remains are those of the Romanov family.
- Published
- 1994
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50. A high observed substitution rate in the human mitochondrial DNA control region
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Parsons, Thomas J., Muniec, David S., Sullivan, Kevin, Woodyatt, Nicola, Alliston-Greiner, Rosemary, Wilson, Mark R., Berry, Dianna L., Holland, Koren A., Weedn, Victor W., Gill, Peter, and Holland, Mitchell M.
- Abstract
The rate and pattern of sequence substitutions in the mitochondrial DNA (mtDNA) control region (CR) is of central importance to studies of human evolution and to forensic identity testing. Here, we report a direct measurement of the intergenerational substitution rate in the human CR. We compared DNA sequences of two CR hypervariable segments from close maternal relatives, from 134 independent mtDNA lineages spanning 327 generational events. Ten substitutions were observed, resulting in an empirical rate of 1/33 generations, or 2.5/site/Myr. This is roughly twenty-fold higher than estimates derived from phylogenetic analyses. This disparity cannot be accounted for simply by substitutions at mutational hot spots, suggesting additional factors that produce the discrepancy between very near-term and long-term apparent rates of sequence divergence. The data also indicate that extremely rapid segregation of CR sequence variants between generations is common in humans, with a very small mtDNA bottleneck. These results have implications for forensic applications and studies of human evolution.
- Published
- 1997
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