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49 results on '"Gabriel, Stacey"'

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

Author

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

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

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

Published
2022

2. Gene expression in African Americans, Puerto Ricans and Mexican Americans reveals ancestry-specific patterns of genetic architecture

Author

Kachuri, Linda, Mak, Angel C. Y., Hu, Donglei, Eng, Celeste, Huntsman, Scott, Elhawary, Jennifer R., Gupta, Namrata, Gabriel, Stacey, Xiao, Shujie, Keys, Kevin L., Oni-Orisan, Akinyemi, Rodríguez-Santana, José R., LeNoir, Michael A., Borrell, Luisa N., Zaitlen, Noah A., Williams, L. Keoki, Gignoux, Christopher R., Burchard, Esteban González, and Ziv, Elad

Published
2023
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3. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian’an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O’Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin D.

Published
2023
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4. Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian’an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O’Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin D.

Published
2023
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5. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

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

Published
2022
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6. Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology

Author

Brody, Jennifer A, Morrison, Alanna C, Bis, Joshua C, O'Connell, Jeffrey R, Brown, Michael R, Huffman, Jennifer E, Ames, Darren C, Carroll, Andrew, Conomos, Matthew P, Gabriel, Stacey, Gibbs, Richard A, Gogarten, Stephanie M, Gupta, Namrata, Jaquish, Cashell E, Johnson, Andrew D, Lewis, Joshua P, Liu, Xiaoming, Manning, Alisa K, Papanicolaou, George J, Pitsillides, Achilleas N, Rice, Kenneth M, Salerno, William, Sitlani, Colleen M, Smith, Nicholas L, Heckbert, Susan R, Laurie, Cathy C, Mitchell, Braxton D, Vasan, Ramachandran S, Rich, Stephen S, Rotter, Jerome I, Wilson, James G, Boerwinkle, Eric, Psaty, Bruce M, and Cupples, L Adrienne

Subjects
Biological Sciences, Genetics, Biotechnology, Networking and Information Technology R&D (NITRD), Lung, Human Genome, 2.5 Research design and methodologies (aetiology), Aetiology, Generic health relevance, Good Health and Well Being, Big Data, Fibrinogen, Genetics, Population, Genome, Humans, Information Dissemination, Mobile Applications, Molecular Epidemiology, Regression Analysis, Software, Workflow, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, TOPMed Hematology and Hemostasis Working Group, CHARGE Analysis and Bioinformatics Working Group, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The exploding volume of whole-genome sequence (WGS) and multi-omics data requires new approaches for analysis. As one solution, we have created a cloud-based Analysis Commons, which brings together genotype and phenotype data from multiple studies in a setting that is accessible by multiple investigators. This framework addresses many of the challenges of multi-center WGS analyses, including data sharing mechanisms, phenotype harmonization, integrated multi-omics analyses, annotation, and computational flexibility. In this setting, the computational pipeline facilitates a sequence-to-discovery analysis workflow illustrated here by an analysis of plasma fibrinogen levels in 3996 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) WGS program. The Analysis Commons represents a novel model for transforming WGS resources from a massive quantity of phenotypic and genomic data into knowledge of the determinants of health and disease risk in diverse human populations.

Published
2017

7. Biallelic mutations in the 3′ exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing

Author

Lardelli, Rea M, Schaffer, Ashleigh E, Eggens, Veerle RC, Zaki, Maha S, Grainger, Stephanie, Sathe, Shashank, Van Nostrand, Eric L, Schlachetzki, Zinayida, Rosti, Basak, Akizu, Naiara, Scott, Eric, Silhavy, Jennifer L, Heckman, Laura Dean, Rosti, Rasim Ozgur, Dikoglu, Esra, Gregor, Anne, Guemez-Gamboa, Alicia, Musaev, Damir, Mande, Rohit, Widjaja, Ari, Shaw, Tim L, Markmiller, Sebastian, Marin-Valencia, Isaac, Davies, Justin H, de Meirleir, Linda, Kayserili, Hulya, Altunoglu, Umut, Freckmann, Mary Louise, Warwick, Linda, Chitayat, David, Blaser, Susan, Çağlayan, Ahmet Okay, Bilguvar, Kaya, Per, Huseyin, Fagerberg, Christina, Christesen, Henrik T, Kibaek, Maria, Aldinger, Kimberly A, Manchester, David, Matsumoto, Naomichi, Muramatsu, Kazuhiro, Saitsu, Hirotomo, Shiina, Masaaki, Ogata, Kazuhiro, Foulds, Nicola, Dobyns, William B, Chi, Neil C, Traver, David, Spaccini, Luigina, Bova, Stefania Maria, Gabriel, Stacey B, Gunel, Murat, Valente, Enza Maria, Nassogne, Marie-Cecile, Bennett, Eric J, Yeo, Gene W, Baas, Frank, Lykke-Andersen, Jens, and Gleeson, Joseph G

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Alleles, Animals, Cerebellar Diseases, Exonucleases, Female, Humans, Male, Mice, Mutation, Neurodegenerative Diseases, Nuclear Proteins, RNA, Messenger, RNA, Small Nuclear, Spliceosomes, Zebrafish, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.

Published
2017

8. Paired exome analysis of Barrett's esophagus and adenocarcinoma

Author

Stachler, Matthew D, Taylor-Weiner, Amaro, Peng, Shouyong, McKenna, Aaron, Agoston, Agoston T, Odze, Robert D, Davison, Jon M, Nason, Katie S, Loda, Massimo, Leshchiner, Ignaty, Stewart, Chip, Stojanov, Petar, Seepo, Sara, Lawrence, Michael S, Ferrer-Torres, Daysha, Lin, Jules, Chang, Andrew C, Gabriel, Stacey B, Lander, Eric S, Beer, David G, Getz, Gad, Carter, Scott L, and Bass, Adam J

Subjects
Biological Sciences, Genetics, Rare Diseases, Digestive Diseases, Cancer, Clinical Research, Adenocarcinoma, Barrett Esophagus, Class I Phosphatidylinositol 3-Kinases, Cyclin-Dependent Kinase Inhibitor p16, DNA Mutational Analysis, Esophageal Neoplasms, Exome, Gene Amplification, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Phosphatidylinositol 3-Kinases, Point Mutation, Tumor Suppressor Protein p53, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Barrett's esophagus is thought to progress to esophageal adenocarcinoma (EAC) through a stepwise progression with loss of CDKN2A followed by TP53 inactivation and aneuploidy. Here we present whole-exome sequencing from 25 pairs of EAC and Barrett's esophagus and from 5 patients whose Barrett's esophagus and tumor were extensively sampled. Our analysis showed that oncogene amplification typically occurred as a late event and that TP53 mutations often occurred early in Barrett's esophagus progression, including in non-dysplastic epithelium. Reanalysis of additional EAC exome data showed that the majority (62.5%) of EACs emerged following genome doubling and that tumors with genomic doubling had different patterns of genomic alterations, with more frequent oncogenic amplification and less frequent inactivation of tumor suppressors, including CDKN2A. These data suggest that many EACs emerge not through the gradual accumulation of tumor-suppressor alterations but rather through a more direct path whereby a TP53-mutant cell undergoes genome doubling, followed by the acquisition of oncogenic amplifications.

Published
2015

9. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

Author

Akizu, Naiara, Cantagrel, Vincent, Zaki, Maha S, Al-Gazali, Lihadh, Wang, Xin, Rosti, Rasim Ozgur, Dikoglu, Esra, Gelot, Antoinette Bernabe, Rosti, Basak, Vaux, Keith K, Scott, Eric M, Silhavy, Jennifer L, Schroth, Jana, Copeland, Brett, Schaffer, Ashleigh E, Gordts, Philip LSM, Esko, Jeffrey D, Buschman, Matthew D, Field, Seth J, Napolitano, Gennaro, Abdel-Salam, Ghada M, Ozgul, R Koksal, Sagıroglu, Mahmut Samil, Azam, Matloob, Ismail, Samira, Aglan, Mona, Selim, Laila, Mahmoud, Iman G, Abdel-Hadi, Sawsan, Badawy, Amera El, Sadek, Abdelrahim A, Mojahedi, Faezeh, Kayserili, Hulya, Masri, Amira, Bastaki, Laila, Temtamy, Samia, Müller, Ulrich, Desguerre, Isabelle, Casanova, Jean-Laurent, Dursun, Ali, Gunel, Murat, Gabriel, Stacey B, de Lonlay, Pascale, and Gleeson, Joseph G

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Brain Disorders, Clinical Research, Animals, Atrophy, Autophagy, Cerebellar Diseases, Cerebellum, Child, Preschool, Female, Gene Frequency, Humans, Infant, Lod Score, Lysosomal Storage Diseases, Lysosomes, Male, Mutation, Phagosomes, Sorting Nexins, Spinocerebellar Ataxias, Syndrome, Zebrafish, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology, Genetics
Abstract

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

Published
2015

10. The Cancer Genome Atlas Pan-Cancer analysis project

Author

Chang, Kyle, Creighton, Chad J, Davis, Caleb, Donehower, Lawrence, Drummond, Jennifer, Wheeler, David, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron SN, Chu, Andy, Chuah, Eric, Chun, Hye-Jung E, Dhalla, Noreen, Guin, Ranabir, Hirst, Martin, Hirst, Carrie, Holt, Robert A, Jones, Steven JM, Lee, Darlene, Li, Haiyan I, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Andrew J, Robertson, A Gordon, Schein, Jacqueline E, Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Varhol, Richard J, Beroukhim, Rameen, Bhatt, Ami S, Brooks, Angela N, Cherniack, Andrew D, Freeman, Samuel S, Gabriel, Stacey B, Helman, Elena, Jung, Joonil, Meyerson, Matthew, Ojesina, Akinyemi I, Pedamallu, Chandra Sekhar, Saksena, Gordon, Schumacher, Steven E, Tabak, Barbara, Zack, Travis, Lander, Eric S, Bristow, Christopher A, Hadjipanayis, Angela, Haseley, Psalm, Kucherlapati, Raju, Lee, Semin, Lee, Eunjung, Luquette, Lovelace J, Mahadeshwar, Harshad S, Pantazi, Angeliki, Parfenov, Michael, Park, Peter J, Protopopov, Alexei, Ren, Xiaojia, Santoso, Netty, Seidman, Jonathan, Seth, Sahil, Song, Xingzhi, Tang, Jiabin, Xi, Ruibin, Xu, Andrew W, Yang, Lixing, Zeng, Dong, Auman, J Todd, Balu, Saianand, Buda, Elizabeth, Fan, Cheng, Hoadley, Katherine A, Jones, Corbin D, Meng, Shaowu, Mieczkowski, Piotr A, Parker, Joel S, Perou, Charles M, Roach, Jeffrey, Shi, Yan, Silva, Grace O, Tan, Donghui, Veluvolu, Umadevi, Waring, Scot, Wilkerson, Matthew D, Wu, Junyuan, Zhao, Wei, Bodenheimer, Tom, Hayes, D Neil, Hoyle, Alan P, Jeffreys, Stuart R, Mose, Lisle E, Simons, Janae V, Soloway, Mathew G, Baylin, Stephen B, Berman, Benjamin P, Bootwalla, Moiz S, Danilova, Ludmila, and Herman, James G

Subjects
Biological Sciences, Genetics, Cancer, Human Genome, Rare Diseases, Good Health and Well Being, Gene Expression Profiling, Genome, Humans, Neoplasms, Cancer Genome Atlas Research Network, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

Published
2013

11. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing

Author

Kirby, Andrew, Gnirke, Andreas, Jaffe, David B, Barešová, Veronika, Pochet, Nathalie, Blumenstiel, Brendan, Ye, Chun, Aird, Daniel, Stevens, Christine, Robinson, James T, Cabili, Moran N, Gat-Viks, Irit, Kelliher, Edward, Daza, Riza, DeFelice, Matthew, Hůlková, Helena, Sovová, Jana, Vylet'al, Petr, Antignac, Corinne, Guttman, Mitchell, Handsaker, Robert E, Perrin, Danielle, Steelman, Scott, Sigurdsson, Snaevar, Scheinman, Steven J, Sougnez, Carrie, Cibulskis, Kristian, Parkin, Melissa, Green, Todd, Rossin, Elizabeth, Zody, Michael C, Xavier, Ramnik J, Pollak, Martin R, Alper, Seth L, Lindblad-Toh, Kerstin, Gabriel, Stacey, Hart, P Suzanne, Regev, Aviv, Nusbaum, Chad, Kmoch, Stanislav, Bleyer, Anthony J, Lander, Eric S, and Daly, Mark J

Subjects
Biotechnology, Kidney Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cytosine, Female, Genetic Linkage, Haplotypes, High-Throughput Nucleotide Sequencing, Humans, Male, Minisatellite Repeats, Mucin-1, Mutation, Polycystic Kidney, Autosomal Dominant, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.

Published
2013

12. A framework for the interpretation of de novo mutation in human disease

Author

Samocha, Kaitlin E, Robinson, Elise B, Sanders, Stephan J, Stevens, Christine, Sabo, Aniko, McGrath, Lauren M, Kosmicki, Jack A, Rehnström, Karola, Mallick, Swapan, Kirby, Andrew, Wall, Dennis P, MacArthur, Daniel G, Gabriel, Stacey B, DePristo, Mark, Purcell, Shaun M, Palotie, Aarno, Boerwinkle, Eric, Buxbaum, Joseph D, Cook, Jr, Edwin H, Gibbs, Richard A, Schellenberg, Gerard D, Sutcliffe, James S, Devlin, Bernie, Roeder, Kathryn, Neale, Benjamin M, and Daly, Mark J

Published
2014
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13. Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing

Author

Kirby, Andrew, Gnirke, Andreas, Jaffe, David B., Barešová, Veronika, Pochet, Nathalie, Blumenstiel, Brendan, Ye, Chun, Aird, Daniel, Stevens, Christine, Robinson, James T., Cabili, Moran N., Gat-Viks, Irit, Kelliher, Edward, Daza, Riza, DeFelice, Matthew, Hůlková, Helena, Sovová, Jana, Vylet’al, Petr, Antignac, Corinne, Guttman, Mitchell, Handsaker, Robert E., Perrin, Danielle, Steelman, Scott, Sigurdsson, Snaevar, Scheinman, Steven J., Sougnez, Carrie, Cibulskis, Kristian, Parkin, Melissa, Green, Todd, Rossin, Elizabeth, Zody, Michael C., Xavier, Ramnik J., Pollak, Martin R., Alper, Seth L., Lindblad-Toh, Kerstin, Gabriel, Stacey, Hart, P. Suzanne, Regev, Aviv, Nusbaum, Chad, Kmoch, Stanislav, Bleyer, Anthony J., Lander, Eric S., and Daly, Mark J.

Subjects
Male, Cytosine, Haplotypes, Genetic Linkage, Mucin-1, Mutation, High-Throughput Nucleotide Sequencing, Humans, Female, Minisatellite Repeats, Polycystic Kidney, Autosomal Dominant, Article
Abstract

Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.

Published
2013

14. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome

Author

Guemez-Gamboa, Alicia, primary, Nguyen, Long N, additional, Yang, Hongbo, additional, Zaki, Maha S, additional, Kara, Majdi, additional, Ben-Omran, Tawfeg, additional, Akizu, Naiara, additional, Rosti, Rasim Ozgur, additional, Rosti, Basak, additional, Scott, Eric, additional, Schroth, Jana, additional, Copeland, Brett, additional, Vaux, Keith K, additional, Cazenave-Gassiot, Amaury, additional, Quek, Debra Q Y, additional, Wong, Bernice H, additional, Tan, Bryan C, additional, Wenk, Markus R, additional, Gunel, Murat, additional, Gabriel, Stacey, additional, Chi, Neil C, additional, Silver, David L, additional, and Gleeson, Joseph G, additional

Published
2015
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15. RNF43 is frequently mutated in colorectal and endometrial cancers

Author

Giannakis, Marios, primary, Hodis, Eran, additional, Jasmine Mu, Xinmeng, additional, Yamauchi, Mai, additional, Rosenbluh, Joseph, additional, Cibulskis, Kristian, additional, Saksena, Gordon, additional, Lawrence, Michael S, additional, Qian, Zhi Rong, additional, Nishihara, Reiko, additional, Van Allen, Eliezer M, additional, Hahn, William C, additional, Gabriel, Stacey B, additional, Lander, Eric S, additional, Getz, Gad, additional, Ogino, Shuji, additional, Fuchs, Charles S, additional, and Garraway, Levi A, additional

Published
2014
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16. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes

Author

Flannick, Jason, primary, Beer, Nicola L, additional, Bick, Alexander G, additional, Agarwala, Vineeta, additional, Molnes, Janne, additional, Gupta, Namrata, additional, Burtt, Noël P, additional, Florez, Jose C, additional, Meigs, James B, additional, Taylor, Herman, additional, Lyssenko, Valeriya, additional, Irgens, Henrik, additional, Fox, Ervin, additional, Burslem, Frank, additional, Johansson, Stefan, additional, Brosnan, M Julia, additional, Trimmer, Jeff K, additional, Newton-Cheh, Christopher, additional, Tuomi, Tiinamaija, additional, Molven, Anders, additional, Wilson, James G, additional, O'Donnell, Christopher J, additional, Kathiresan, Sekar, additional, Hirschhorn, Joel N, additional, Njølstad, Pål R, additional, Rolph, Tim, additional, Seidman, J G, additional, Gabriel, Stacey, additional, Cox, David R, additional, Seidman, Christine E, additional, Groop, Leif, additional, and Altshuler, David, additional

Published
2013
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17. Pan-cancer patterns of somatic copy number alteration

Author

Zack, Travis I, primary, Schumacher, Steven E, additional, Carter, Scott L, additional, Cherniack, Andrew D, additional, Saksena, Gordon, additional, Tabak, Barbara, additional, Lawrence, Michael S, additional, Zhang, Cheng-Zhong, additional, Wala, Jeremiah, additional, Mermel, Craig H, additional, Sougnez, Carrie, additional, Gabriel, Stacey B, additional, Hernandez, Bryan, additional, Shen, Hui, additional, Laird, Peter W, additional, Getz, Gad, additional, Meyerson, Matthew, additional, and Beroukhim, Rameen, additional

Published
2013
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18. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

Author

Dulak, Austin M, primary, Stojanov, Petar, additional, Peng, Shouyong, additional, Lawrence, Michael S, additional, Fox, Cameron, additional, Stewart, Chip, additional, Bandla, Santhoshi, additional, Imamura, Yu, additional, Schumacher, Steven E, additional, Shefler, Erica, additional, McKenna, Aaron, additional, Carter, Scott L, additional, Cibulskis, Kristian, additional, Sivachenko, Andrey, additional, Saksena, Gordon, additional, Voet, Douglas, additional, Ramos, Alex H, additional, Auclair, Daniel, additional, Thompson, Kristin, additional, Sougnez, Carrie, additional, Onofrio, Robert C, additional, Guiducci, Candace, additional, Beroukhim, Rameen, additional, Zhou, Zhongren, additional, Lin, Lin, additional, Lin, Jules, additional, Reddy, Rishindra, additional, Chang, Andrew, additional, Landrenau, Rodney, additional, Pennathur, Arjun, additional, Ogino, Shuji, additional, Luketich, James D, additional, Golub, Todd R, additional, Gabriel, Stacey B, additional, Lander, Eric S, additional, Beer, David G, additional, Godfrey, Tony E, additional, Getz, Gad, additional, and Bass, Adam J, additional

Published
2013
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19. The genetic landscape of high-risk neuroblastoma

Author

Pugh, Trevor J, primary, Morozova, Olena, additional, Attiyeh, Edward F, additional, Asgharzadeh, Shahab, additional, Wei, Jun S, additional, Auclair, Daniel, additional, Carter, Scott L, additional, Cibulskis, Kristian, additional, Hanna, Megan, additional, Kiezun, Adam, additional, Kim, Jaegil, additional, Lawrence, Michael S, additional, Lichenstein, Lee, additional, McKenna, Aaron, additional, Pedamallu, Chandra Sekhar, additional, Ramos, Alex H, additional, Shefler, Erica, additional, Sivachenko, Andrey, additional, Sougnez, Carrie, additional, Stewart, Chip, additional, Ally, Adrian, additional, Birol, Inanc, additional, Chiu, Readman, additional, Corbett, Richard D, additional, Hirst, Martin, additional, Jackman, Shaun D, additional, Kamoh, Baljit, additional, Khodabakshi, Alireza Hadj, additional, Krzywinski, Martin, additional, Lo, Allan, additional, Moore, Richard A, additional, Mungall, Karen L, additional, Qian, Jenny, additional, Tam, Angela, additional, Thiessen, Nina, additional, Zhao, Yongjun, additional, Cole, Kristina A, additional, Diamond, Maura, additional, Diskin, Sharon J, additional, Mosse, Yael P, additional, Wood, Andrew C, additional, Ji, Lingyun, additional, Sposto, Richard, additional, Badgett, Thomas, additional, London, Wendy B, additional, Moyer, Yvonne, additional, Gastier-Foster, Julie M, additional, Smith, Malcolm A, additional, Auvil, Jaime M Guidry, additional, Gerhard, Daniela S, additional, Hogarty, Michael D, additional, Jones, Steven J M, additional, Lander, Eric S, additional, Gabriel, Stacey B, additional, Getz, Gad, additional, Seeger, Robert C, additional, Khan, Javed, additional, Marra, Marco A, additional, Meyerson, Matthew, additional, and Maris, John M, additional

Published
2013
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20. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly

Author

Lee, Jeong Ho, primary, Huynh, My, additional, Silhavy, Jennifer L, additional, Kim, Sangwoo, additional, Dixon-Salazar, Tracy, additional, Heiberg, Andrew, additional, Scott, Eric, additional, Bafna, Vineet, additional, Hill, Kiley J, additional, Collazo, Adrienne, additional, Funari, Vincent, additional, Russ, Carsten, additional, Gabriel, Stacey B, additional, Mathern, Gary W, additional, and Gleeson, Joseph G, additional

Published
2012
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21. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer

Author

Barbieri, Christopher E, primary, Baca, Sylvan C, additional, Lawrence, Michael S, additional, Demichelis, Francesca, additional, Blattner, Mirjam, additional, Theurillat, Jean-Philippe, additional, White, Thomas A, additional, Stojanov, Petar, additional, Van Allen, Eliezer, additional, Stransky, Nicolas, additional, Nickerson, Elizabeth, additional, Chae, Sung-Suk, additional, Boysen, Gunther, additional, Auclair, Daniel, additional, Onofrio, Robert C, additional, Park, Kyung, additional, Kitabayashi, Naoki, additional, MacDonald, Theresa Y, additional, Sheikh, Karen, additional, Vuong, Terry, additional, Guiducci, Candace, additional, Cibulskis, Kristian, additional, Sivachenko, Andrey, additional, Carter, Scott L, additional, Saksena, Gordon, additional, Voet, Douglas, additional, Hussain, Wasay M, additional, Ramos, Alex H, additional, Winckler, Wendy, additional, Redman, Michelle C, additional, Ardlie, Kristin, additional, Tewari, Ashutosh K, additional, Mosquera, Juan Miguel, additional, Rupp, Niels, additional, Wild, Peter J, additional, Moch, Holger, additional, Morrissey, Colm, additional, Nelson, Peter S, additional, Kantoff, Philip W, additional, Gabriel, Stacey B, additional, Golub, Todd R, additional, Meyerson, Matthew, additional, Lander, Eric S, additional, Getz, Gad, additional, Rubin, Mark A, additional, and Garraway, Levi A, additional

Published
2012
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22. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion

Author

Bass, Adam J, primary, Lawrence, Michael S, additional, Brace, Lear E, additional, Ramos, Alex H, additional, Drier, Yotam, additional, Cibulskis, Kristian, additional, Sougnez, Carrie, additional, Voet, Douglas, additional, Saksena, Gordon, additional, Sivachenko, Andrey, additional, Jing, Rui, additional, Parkin, Melissa, additional, Pugh, Trevor, additional, Verhaak, Roel G, additional, Stransky, Nicolas, additional, Boutin, Adam T, additional, Barretina, Jordi, additional, Solit, David B, additional, Vakiani, Evi, additional, Shao, Wenlin, additional, Mishina, Yuji, additional, Warmuth, Markus, additional, Jimenez, Jose, additional, Chiang, Derek Y, additional, Signoretti, Sabina, additional, Kaelin, William G, additional, Spardy, Nicole, additional, Hahn, William C, additional, Hoshida, Yujin, additional, Ogino, Shuji, additional, DePinho, Ronald A, additional, Chin, Lynda, additional, Garraway, Levi A, additional, Fuchs, Charles S, additional, Baselga, Jose, additional, Tabernero, Josep, additional, Gabriel, Stacey, additional, Lander, Eric S, additional, Getz, Gad, additional, and Meyerson, Matthew, additional

Published
2011
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23. A framework for variation discovery and genotyping using next-generation DNA sequencing data

Author

DePristo, Mark A, primary, Banks, Eric, additional, Poplin, Ryan, additional, Garimella, Kiran V, additional, Maguire, Jared R, additional, Hartl, Christopher, additional, Philippakis, Anthony A, additional, del Angel, Guillermo, additional, Rivas, Manuel A, additional, Hanna, Matt, additional, McKenna, Aaron, additional, Fennell, Tim J, additional, Kernytsky, Andrew M, additional, Sivachenko, Andrey Y, additional, Cibulskis, Kristian, additional, Gabriel, Stacey B, additional, Altshuler, David, additional, and Daly, Mark J, additional

Published
2011
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24. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency

Author

Calvo, Sarah E, primary, Tucker, Elena J, additional, Compton, Alison G, additional, Kirby, Denise M, additional, Crawford, Gabriel, additional, Burtt, Noel P, additional, Rivas, Manuel, additional, Guiducci, Candace, additional, Bruno, Damien L, additional, Goldberger, Olga A, additional, Redman, Michelle C, additional, Wiltshire, Esko, additional, Wilson, Callum J, additional, Altshuler, David, additional, Gabriel, Stacey B, additional, Daly, Mark J, additional, Thorburn, David R, additional, and Mootha, Vamsi K, additional

Published
2010
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25. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

Author

Valente, Enza Maria, primary, Logan, Clare V, additional, Mougou-Zerelli, Soumaya, additional, Lee, Jeong Ho, additional, Silhavy, Jennifer L, additional, Brancati, Francesco, additional, Iannicelli, Miriam, additional, Travaglini, Lorena, additional, Romani, Sveva, additional, Illi, Barbara, additional, Adams, Matthew, additional, Szymanska, Katarzyna, additional, Mazzotta, Annalisa, additional, Lee, Ji Eun, additional, Tolentino, Jerlyn C, additional, Swistun, Dominika, additional, Salpietro, Carmelo D, additional, Fede, Carmelo, additional, Gabriel, Stacey, additional, Russ, Carsten, additional, Cibulskis, Kristian, additional, Sougnez, Carrie, additional, Hildebrandt, Friedhelm, additional, Otto, Edgar A, additional, Held, Susanne, additional, Diplas, Bill H, additional, Davis, Erica E, additional, Mikula, Mario, additional, Strom, Charles M, additional, Ben-Zeev, Bruria, additional, Lev, Dorit, additional, Sagie, Tally Lerman, additional, Michelson, Marina, additional, Yaron, Yuval, additional, Krause, Amanda, additional, Boltshauser, Eugen, additional, Elkhartoufi, Nadia, additional, Roume, Joelle, additional, Shalev, Stavit, additional, Munnich, Arnold, additional, Saunier, Sophie, additional, Inglehearn, Chris, additional, Saad, Ali, additional, Alkindy, Adila, additional, Thomas, Sophie, additional, Vekemans, Michel, additional, Dallapiccola, Bruno, additional, Katsanis, Nicholas, additional, Johnson, Colin A, additional, Attié-Bitach, Tania, additional, and Gleeson, Joseph G, additional

Published
2010
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26. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot

Author

Greenway, Steven C, primary, Pereira, Alexandre C, additional, Lin, Jennifer C, additional, DePalma, Steven R, additional, Israel, Samuel J, additional, Mesquita, Sonia M, additional, Ergul, Emel, additional, Conta, Jessie H, additional, Korn, Joshua M, additional, McCarroll, Steven A, additional, Gorham, Joshua M, additional, Gabriel, Stacey, additional, Altshuler, David M, additional, de Lourdes Quintanilla-Dieck, Maria, additional, Artunduaga, Maria Alexandra, additional, Eavey, Roland D, additional, Plenge, Robert M, additional, Shadick, Nancy A, additional, Weinblatt, Michael E, additional, De Jager, Philip L, additional, Hafler, David A, additional, Breitbart, Roger E, additional, Seidman, Jonathan G, additional, and Seidman, Christine E, additional

Published
2009
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27. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population

Author

Sabatti, Chiara, primary, Service, Susan K, additional, Hartikainen, Anna-Liisa, additional, Pouta, Anneli, additional, Ripatti, Samuli, additional, Brodsky, Jae, additional, Jones, Chris G, additional, Zaitlen, Noah A, additional, Varilo, Teppo, additional, Kaakinen, Marika, additional, Sovio, Ulla, additional, Ruokonen, Aimo, additional, Laitinen, Jaana, additional, Jakkula, Eveliina, additional, Coin, Lachlan, additional, Hoggart, Clive, additional, Collins, Andrew, additional, Turunen, Hannu, additional, Gabriel, Stacey, additional, Elliot, Paul, additional, McCarthy, Mark I, additional, Daly, Mark J, additional, Järvelin, Marjo-Riitta, additional, Freimer, Nelson B, additional, and Peltonen, Leena, additional

Published
2008
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28. Integrated detection and population-genetic analysis of SNPs and copy number variation

Author

McCarroll, Steven A, primary, Kuruvilla, Finny G, additional, Korn, Joshua M, additional, Cawley, Simon, additional, Nemesh, James, additional, Wysoker, Alec, additional, Shapero, Michael H, additional, de Bakker, Paul I W, additional, Maller, Julian B, additional, Kirby, Andrew, additional, Elliott, Amanda L, additional, Parkin, Melissa, additional, Hubbell, Earl, additional, Webster, Teresa, additional, Mei, Rui, additional, Veitch, James, additional, Collins, Patrick J, additional, Handsaker, Robert, additional, Lincoln, Steve, additional, Nizzari, Marcia, additional, Blume, John, additional, Jones, Keith W, additional, Rava, Rich, additional, Daly, Mark J, additional, Gabriel, Stacey B, additional, and Altshuler, David, additional

Published
2008
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29. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs

Author

Korn, Joshua M, primary, Kuruvilla, Finny G, additional, McCarroll, Steven A, additional, Wysoker, Alec, additional, Nemesh, James, additional, Cawley, Simon, additional, Hubbell, Earl, additional, Veitch, Jim, additional, Collins, Patrick J, additional, Darvishi, Katayoon, additional, Lee, Charles, additional, Nizzari, Marcia M, additional, Gabriel, Stacey B, additional, Purcell, Shaun, additional, Daly, Mark J, additional, and Altshuler, David, additional

Published
2008
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30. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis

Author

Plenge, Robert M, primary, Cotsapas, Chris, additional, Davies, Leela, additional, Price, Alkes L, additional, de Bakker, Paul I W, additional, Maller, Julian, additional, Pe'er, Itsik, additional, Burtt, Noel P, additional, Blumenstiel, Brendan, additional, DeFelice, Matt, additional, Parkin, Melissa, additional, Barry, Rachel, additional, Winslow, Wendy, additional, Healy, Claire, additional, Graham, Robert R, additional, Neale, Benjamin M, additional, Izmailova, Elena, additional, Roubenoff, Ronenn, additional, Parker, Alexander N, additional, Glass, Roberta, additional, Karlson, Elizabeth W, additional, Maher, Nancy, additional, Hafler, David A, additional, Lee, David M, additional, Seldin, Michael F, additional, Remmers, Elaine F, additional, Lee, Annette T, additional, Padyukov, Leonid, additional, Alfredsson, Lars, additional, Coblyn, Jonathan, additional, Weinblatt, Michael E, additional, Gabriel, Stacey B, additional, Purcell, Shaun, additional, Klareskog, Lars, additional, Gregersen, Peter K, additional, Shadick, Nancy A, additional, Daly, Mark J, additional, and Altshuler, David, additional

Published
2007
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31. Erratum: Corrigendum: High-throughput oncogene mutation profiling in human cancer

Author

Thomas, Roman K, primary, Baker, Alissa C, additional, DeBiasi, Ralph M, additional, Winckler, Wendy, additional, LaFramboise, Thomas, additional, Lin, William M, additional, Wang, Meng, additional, Feng, Whei, additional, Zander, Thomas, additional, MacConnaill, Laura E, additional, Lee, Jeffrey C, additional, Nicoletti, Rick, additional, Hatton, Charlie, additional, Goyette, Mary, additional, Girard, Luc, additional, Majmudar, Kuntal, additional, Ziaugra, Liuda, additional, Wong, Kwok-Kin, additional, Gabriel, Stacey, additional, Beroukhim, Rameen, additional, Peyton, Michael, additional, Barretina, Jordi, additional, Dutt, Amit, additional, Emery, Caroline, additional, Greulich, Heidi, additional, Shah, Kinjal, additional, Sasaki, Hidefumi, additional, Gazdar, Adi, additional, Minna, John, additional, Armstrong, Scott A, additional, Mellinghoff, Ingo K, additional, Hodi, F Stephen, additional, Dranoff, Glenn, additional, Mischel, Paul S, additional, Cloughesy, Tim F, additional, Nelson, Stan F, additional, Liau, Linda M, additional, Mertz, Kirsten, additional, Rubin, Mark A, additional, Moch, Holger, additional, Loda, Massimo, additional, Catalona, William, additional, Fletcher, Jonathan, additional, Signoretti, Sabina, additional, Kaye, Frederic, additional, Anderson, Kenneth C, additional, Demetri, George D, additional, Dummer, Reinhard, additional, Wagner, Stephan, additional, Herlyn, Meenhard, additional, Sellers, William R, additional, Meyerson, Matthew, additional, and Garraway, Levi A, additional

Published
2007
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32. High-throughput oncogene mutation profiling in human cancer

Author

Thomas, Roman K, primary, Baker, Alissa C, additional, DeBiasi, Ralph M, additional, Winckler, Wendy, additional, LaFramboise, Thomas, additional, Lin, William M, additional, Wang, Meng, additional, Feng, Whei, additional, Zander, Thomas, additional, MacConaill, Laura E, additional, Lee, Jeffrey C, additional, Nicoletti, Rick, additional, Hatton, Charlie, additional, Goyette, Mary, additional, Girard, Luc, additional, Majmudar, Kuntal, additional, Ziaugra, Liuda, additional, Wong, Kwok-Kin, additional, Gabriel, Stacey, additional, Beroukhim, Rameen, additional, Peyton, Michael, additional, Barretina, Jordi, additional, Dutt, Amit, additional, Emery, Caroline, additional, Greulich, Heidi, additional, Shah, Kinjal, additional, Sasaki, Hidefumi, additional, Gazdar, Adi, additional, Minna, John, additional, Armstrong, Scott A, additional, Mellinghoff, Ingo K, additional, Hodi, F Stephen, additional, Dranoff, Glenn, additional, Mischel, Paul S, additional, Cloughesy, Tim F, additional, Nelson, Stan F, additional, Liau, Linda M, additional, Mertz, Kirsten, additional, Rubin, Mark A, additional, Moch, Holger, additional, Loda, Massimo, additional, Catalona, William, additional, Fletcher, Jonathan, additional, Signoretti, Sabina, additional, Kaye, Frederic, additional, Anderson, Kenneth C, additional, Demetri, George D, additional, Dummer, Reinhard, additional, Wagner, Stephan, additional, Herlyn, Meenhard, additional, Sellers, William R, additional, Meyerson, Matthew, additional, and Garraway, Levi A, additional

Published
2007
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34. Assessing the impact of population stratification on genetic association studies

Author

Freedman, Matthew L, primary, Reich, David, additional, Penney, Kathryn L, additional, McDonald, Gavin J, additional, Mignault, Andre A, additional, Patterson, Nick, additional, Gabriel, Stacey B, additional, Topol, Eric J, additional, Smoller, Jordan W, additional, Pato, Carlos N, additional, Pato, Michele T, additional, Petryshen, Tracey L, additional, Kolonel, Laurence N, additional, Lander, Eric S, additional, Sklar, Pamela, additional, Henderson, Brian, additional, Hirschhorn, Joel N, additional, and Altshuler, David, additional

Published
2004
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36. Segregation at three loci explains familial and population risk in Hirschsprung disease

Author

Gabriel, Stacey Bolk, primary, Salomon, Rémi, additional, Pelet, Anna, additional, Angrist, Misha, additional, Amiel, Jeanne, additional, Fornage, Myriam, additional, Attié-Bitach, Tania, additional, Olson, Jane M., additional, Hofstra, Robert, additional, Buys, Charles, additional, Steffann, Julie, additional, Munnich, Arnold, additional, Lyonnet, Stanislas, additional, and Chakravarti, Aravinda, additional

Published
2002
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37. A reference panel of 64,976 haplotypes for genotype imputation

Author

McCarthy, Shane, Das, Sayantan, Kretzschmar, Warren, Delaneau, Olivier, Wood, Andrew R, Teumer, Alexander, Kang, Hyun Min, Fuchsberger, Christian, Danecek, Petr, Sharp, Kevin, Luo, Yang, Sidore, Carlo, Kwong, Alan, Timpson, Nicholas, Koskinen, Seppo, Vrieze, Scott, Scott, Laura J, Zhang, He, Mahajan, Anubha, Veldink, Jan, Peters, Ulrike, Pato, Carlos, van Duijn, Cornelia M, Gillies, Christopher E, Gandin, Ilaria, Mezzavilla, Massimo, Gilly, Arthur, Cocca, Massimiliano, Traglia, Michela, Angius, Andrea, Barrett, Jeffrey C, Boomsma, Dorrett, Branham, Kari, Breen, Gerome, Brummett, Chad M, Busonero, Fabio, Campbell, Harry, Chan, Andrew, Chen, Sai, Chew, Emily, Collins, Francis S, Corbin, Laura J, Smith, George Davey, Dedoussis, George, Dorr, Marcus, Farmaki, Aliki-Eleni, Ferrucci, Luigi, Forer, Lukas, Fraser, Ross M, Gabriel, Stacey, Levy, Shawn, Groop, Leif, Harrison, Tabitha, Hattersley, Andrew, Holmen, Oddgeir L, Hveem, Kristian, Kretzler, Matthias, Lee, James C, McGue, Matt, Meitinger, Thomas, Melzer, David, Min, Josine L, Mohlke, Karen L, Vincent, John B, Nauck, Matthias, Nickerson, Deborah, Palotie, Aarno, Pato, Michele, Pirastu, Nicola, McInnis, Melvin, Richards, J Brent, Sala, Cinzia, Salomaa, Veikko, Schlessinger, David, Schoenherr, Sebastian, Slagboom, P Eline, Small, Kerrin, Spector, Timothy, Stambolian, Dwight, Tuke, Marcus, Tuomilehto, Jaakko, Van den Berg, Leonard H, Van Rheenen, Wouter, Volker, Uwe, Wijmenga, Cisca, Toniolo, Daniela, Zeggini, Eleftheria, Gasparini, Paolo, Sampson, Matthew G, Wilson, James F, Frayling, Timothy, de Bakker, Paul I W, Swertz, Morris A, McCarroll, Steven, Kooperberg, Charles, Dekker, Annelot, Altshuler, David, Willer, Cristen, Iacono, William, Ripatti, Samuli, Soranzo, Nicole, Walter, Klaudia, Swaroop, Anand, Cucca, Francesco, Anderson, Carl A, Myers, Richard M, Boehnke, Michael, McCarthy, Mark I, and Durbin, Richard

Abstract

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

Published
2016
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38. Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery

Author

Scott, Eric M, Halees, Anason, Itan, Yuval, Spencer, Emily G, He, Yupeng, Azab, Mostafa Abdellateef, Gabriel, Stacey B, Belkadi, Aziz, Boisson, Bertrand, Abel, Laurent, Clark, Andrew G, Alkuraya, Fowzan S, Casanova, Jean-Laurent, and Gleeson, Joseph G

Abstract

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized 'genetic purging'. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics.

Published
2016
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39. Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction.

Author

Shea, Jessica, Agarwala, Vineeta, Philippakis, Anthony A, Maguire, Jared, Banks, Eric, DePristo, Mark, Thomson, Brian, Guiducci, Candace, Onofrio, Robert C., M. I. G.C., Kathiresan, Sekar, Gabriel, Stacey, Burtt, Noël P., Daly, Mark J., Groop, Leif, and Altshuler, David

Subjects
HUMAN genetic variation, MYOCARDIAL infarction, GENETIC polymorphisms, BAYESIAN analysis, PEOPLE with diabetes
Abstract

Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes, myocardial infarction, aneurysm, vertical cup disc ratio and at least five cancers. Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing and from 1000 Genomes Project low-coverage data. Polymorphisms with frequency >5% were captured well by all strategies. Imputation of intermediate-frequency polymorphisms required a higher density of tag SNPs in disease samples than is available on first-generation genome-wide association study (GWAS) arrays. Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals. [ABSTRACT FROM AUTHOR]

Published
2011
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40. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.

Author

Sabatti, Chiara, Service, Susan K., Hartikainen, Anna-Liisa, Pouta, Anneli, Ripatti, Samuli, Brodsky, Jae, Jones, Chris G., Zaitlen, Noah A., Varilo, Teppo, Kaakinen, Marika, Sovio, Ulla, Ruokonen, Aimo, Laitinen, Jaana, Jakkula, Eveliina, Coin, Lachlan, Hoggart, Clive, Collins, Andrew, Turunen, Hannu, Gabriel, Stacey, and Elliot, Paul

Subjects
LONGITUDINAL method, HIGH density lipoproteins, LOW density lipoproteins, GLUCOSE, INSULIN, BODY mass index
Abstract

Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene–environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci. [ABSTRACT FROM AUTHOR]

Published
2009
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41. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci.

Author

Harley, John B., Alarcón-Riquelme, Marta E., Criswell, Lindsey A., Jacob, Chaim O., Kimberly, Robert P., Moser, Kathy L., Tsao, Betty P., Vyse, Timothy J., Langefeld, Carl D., Nath, Swapan K., Guthridge, Joel M., Cobb, Beth L., Mirel, Daniel B., Marion, Miranda C., Williams, Adrienne H., Divers, Jasmin, Wei Wang, Frank, Summer G., Namjou, Bahram, and Gabriel, Stacey B.

Subjects
SYSTEMIC lupus erythematosus, ETIOLOGY of diseases, DISEASES in women, ALLERGIC encephalomyelitis, IMMUNOLOGIC diseases
Abstract

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ∼30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10−7 < Poverall < 1.6 × 10−23; odds ratio = 0.82–1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10−5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at 9 other loci (P < 2 × 10−7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE. [ABSTRACT FROM AUTHOR]

Published
2008
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42. New models of collaboration in genome-wide association studies: the Genetic Association Information Network.

Author

Manolio, Teri A., Rodriguez, Laura Lyman, Brooks, Lisa, Abecasis, Gonçalo, Ballinger, Dennis, Daly, Mark, Donnelly, Peter, Faraone, Stephen V., Frazer, Kelly, Gabriel, Stacey, Gejman, Pablo, Guttmacher, Alan, Harris, Emily L., Insel, Thomas, Kelsoe, John R., Lander, Eric, McCowin, Norma, Mailman, Matthew D., Nabel, Elizabeth, and Ostell, James

Subjects
GENOMES, GENETICS, GENOTYPE-environment interaction, ETIOLOGY of diseases, GENES
Abstract

The Genetic Association Information Network (GAIN) is a public-private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases. [ABSTRACT FROM AUTHOR]

Published
2007
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43. Common deletion polymorphisms in the human genome.

Author

McCarroll, Steven A., Hadnott, Tracy N., Perry, George H., Sabeti, Pardis C., Zody, Michael C., Barrett, Jeffrey C., Dallaire, Stephanie, Gabriel, Stacey B., Lee, Charles, Daly, Mark J., and Altshuler, David M.

Subjects
GENETIC polymorphisms, HUMAN genome, STEROIDS, SMELL, GENETIC mutation, METABOLISM
Abstract

The locations and properties of common deletion variants in the human genome are largely unknown. We describe a systematic method for using dense SNP genotype data to discover deletions and its application to data from the International HapMap Consortium to characterize and catalogue segregating deletion variants across the human genome. We identified 541 deletion variants (94% novel) ranging from 1 kb to 745 kb in size; 278 of these variants were observed in multiple, unrelated individuals, 120 in the homozygous state. The coding exons of ten expressed genes were found to be commonly deleted, including multiple genes with roles in sex steroid metabolism, olfaction and drug response. These common deletion polymorphisms typically represent ancestral mutations that are in linkage disequilibrium with nearby SNPs, meaning that their association to disease can often be evaluated in the course of SNP-based whole-genome association studies. [ABSTRACT FROM AUTHOR]

Published
2006
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44. Corrigendum: High-throughput oncogene mutation profiling in human cancer.

Author

Thomas, Roman K., Baker, Alissa C., DeBiasi, Ralph M., Winckler, Wendy, LaFramboise, Thomas, Lin, William M., Wang, Meng, Feng, Whei, Zander, Thomas, MacConnaill, Laura E., Lee, Jeffrey C., Nicoletti, Rick, Hatton, Charlie, Goyette, Mary, Girard, Luc, Majmudar, Kuntal, Ziaugra, Liuda, Wong, Kwok-Kin, Gabriel, Stacey, and Beroukhim, Rameen

Subjects
ONCOGENES
Abstract

A correction to the article "High-throughput oncogene mutation profiling in human cancer" that was published in the previous issue is presented.

Published
2007
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45. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

Author

Keith K. Vaux, Mahmut Şamil Sağıroğlu, Laila Bastaki, Seth J. Field, Pascale de Lonlay, Sawsan Abdel-Hadi, Lihadh Al-Gazali, Hülya Kayserili, Ali Dursun, Jeffrey D. Esko, Eric Scott, Xin Wang, Faezeh Mojahedi, Ashleigh E. Schaffer, R. Köksal Özgül, Iman G. Mahmoud, Isabelle Desguerre, Matthew D. Buschman, Laila Selim, Samia A. Temtamy, Jean-Laurent Casanova, Murat Gunel, Abdelrahim Abdrabou Sadek, Philip L.S.M. Gordts, Brett Copeland, Mona Aglan, Amira Masri, Maha S. Zaki, Joseph G. Gleeson, Matloob Azam, Naiara Akizu, Vincent Cantagrel, Antoinette Gelot, Basak Rosti, Jennifer L. Silhavy, Esra Dikoglu, Ulrich Müller, Amera El Badawy, Gennaro Napolitano, Stacey Gabriel, Rasim Ozgur Rosti, Jana Schroth, Samira Ismail, Ghada M H Abdel-Salam, İç Hastalıkları, Akizu, Naiara, Cantagrel, Vincent, Zaki, Maha S., Al-Gazali, Lihadh, Wang, Xin, Rosti, Rasim Ozgur, Dikoglu, Esra, Gelot, Antoinette Bernabe, Rosti, Basak, Vaux, Keith K., Scott, Eric M., Silhavy, Jennifer L., Schroth, Jana, Copeland, Brett, Schaffer, Ashleigh E., Gordts, Philip L. S. M., Esko, Jeffrey D., Buschman, Matthew D., Field, Seth J., Napolitano, Gennaro, Abdel-Salam, Ghada M., Ozgul, R Koksal, Saglroglu, Mahmut Samil, Azam, Matloob, Ismail, Samira, Aglan, Mona, Selim, Laila, Mahmoud, Iman G., Abdel-Hadi, Sawsan, Badawy, Amera El, Sadek, Abdelrahim A., Mojahedi, Faezeh, Kayserili, Hulya, Masri, Amira, Bastaki, Laila, Temtamy, Samia, Müller, Ulrich, Desguerre, Isabelle, Casanova, Jean-Laurent, Dursun, Ali, Gunel, Murat, Gabriel, Stacey B., De Lonlay, Pascale, and Gleeson, Joseph G.

Subjects
Male, Autophagosome, medicine.disease_cause, Medical and Health Sciences, Lysosomal Storage Disease, Gene Frequency, Cerebellum, Phagosomes, Child, Sorting Nexins, Phagosome, Zebrafish, 2. Zero hunger, Genetics, Mutation, Cerebellar Disease, Syndrome, Biological Sciences, Lysosome, Cell biology, medicine.anatomical_structure, Child, Preschool, Female, Cerebellar atrophy, medicine.symptom, Human, Ataxia, Endosome, Biology, Article, Cerebellar Diseases, Clinical Research, Autophagy, medicine, Animals, Humans, Spinocerebellar Ataxias, Preschool, Spinocerebellar Ataxia, Animal, Sorting Nexin, Infant, Brain Disorders, Lysosomal Storage Diseases, Sorting nexin, Atrophy, Lod Score, Lysosomes, Developmental Biology
Abstract

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

Published
2015

46. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Author

Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsén T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jørgensen T, Jørgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee JY, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel-Madsen R, Richard AM, Rolph T, Salomaa V, Segrè AV, Skärstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njølstad PR, Pedersen O, Groop L, Cox DR, Stefansson K, and Altshuler D

Subjects
Animals, Base Sequence, Blood Glucose genetics, Genetic Association Studies, Genotype, Humans, Ion Transport genetics, Mice, Mice, Knockout, Molecular Sequence Data, Proinsulin blood, Sequence Analysis, DNA, Zinc Transporter 8, Cation Transport Proteins genetics, Diabetes Mellitus, Type 2 genetics, Mutation, Missense genetics
Abstract

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

Published
2014
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47. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.

Author

Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, Boucher G, Ripke S, Ellinghaus D, Burtt N, Fennell T, Kirby A, Latiano A, Goyette P, Green T, Halfvarson J, Haritunians T, Korn JM, Kuruvilla F, Lagacé C, Neale B, Lo KS, Schumm P, Törkvist L, Dubinsky MC, Brant SR, Silverberg MS, Duerr RH, Altshuler D, Gabriel S, Lettre G, Franke A, D'Amato M, McGovern DP, Cho JH, Rioux JD, Xavier RJ, and Daly MJ

Subjects
Case-Control Studies, Cell Line, Genetic Predisposition to Disease, Humans, Nod2 Signaling Adaptor Protein genetics, RNA Splicing, Receptors, Interleukin genetics, Genome-Wide Association Study, Inflammatory Bowel Diseases genetics, Sequence Analysis, DNA
Abstract

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

Published
2011
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48. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

Author

Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Samani NJ, Schunkert H, Erdmann J, Reilly MP, Rader DJ, Morgan T, Spertus JA, Stoll M, Girelli D, McKeown PP, Patterson CC, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Ardissino D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Casari G, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Mannucci PM, Schwartz SM, Siscovick DS, Yee J, Friedlander Y, Elosua R, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Kathiresan S, Meigs JB, Williams G, Nathan DM, MacRae CA, O'Donnell CJ, Salomaa V, Havulinna AS, Peltonen L, Melander O, Berglund G, Voight BF, Kathiresan S, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Musunuru K, Daly MJ, Purcell S, Voight BF, Purcell S, Nemesh J, Korn JM, McCarroll SA, Schwartz SM, Yee J, Kathiresan S, Lucas G, Subirana I, Elosua R, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, Samani NJ, Thompson JR, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall A, Schunkert H, Erdmann J, Linsel-Nitschke P, Lieb W, Ziegler A, König I, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Schunkert H, Samani NJ, Erdmann J, Ouwehand W, Hengstenberg C, Deloukas P, Scholz M, Cambien F, Reilly MP, Li M, Chen Z, Wilensky R, Matthai W, Qasim A, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Scheffold T, Berger K, Stoll M, Huge A, Girelli D, Martinelli N, Olivieri O, Corrocher R, Morgan T, Spertus JA, McKeown P, Patterson CC, Schunkert H, Erdmann E, Linsel-Nitschke P, Lieb W, Ziegler A, König IR, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Hólm H, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Engert JC, Do R, Xie C, Anand S, Kathiresan S, Ardissino D, Mannucci PM, Siscovick D, O'Donnell CJ, Samani NJ, Melander O, Elosua R, Peltonen L, Salomaa V, Schwartz SM, and Altshuler D

Subjects
Adult, Age of Onset, Algorithms, Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Mutation physiology, Myocardial Infarction epidemiology, Risk Factors, Gene Dosage, Myocardial Infarction genetics, Polymorphism, Single Nucleotide
Abstract

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.

Published
2009
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49. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.

Author

Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Chambert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, Breen G, Gill M, Morris DW, Elkin A, Muir WJ, McGhee KA, Williamson R, MacIntyre DJ, MacLean AW, St CD, Robinson M, Van Beck M, Pereira AC, Kandaswamy R, McQuillin A, Collier DA, Bass NJ, Young AH, Lawrence J, Ferrier IN, Anjorin A, Farmer A, Curtis D, Scolnick EM, McGuffin P, Daly MJ, Corvin AP, Holmans PA, Blackwood DH, Gurling HM, Owen MJ, Purcell SM, Sklar P, and Craddock N

Subjects
Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 15, Genetic Predisposition to Disease, Humans, Logistic Models, Polymorphism, Single Nucleotide, Ankyrins genetics, Bipolar Disorder genetics, Calcium Channels, L-Type genetics, Genome-Wide Association Study
Abstract

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Published
2008
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