Institution
Broad Institute
Nonprofit•Cambridge, Massachusetts, United States•
About: Broad Institute is a nonprofit organization based out in Cambridge, Massachusetts, United States. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 6584 authors who have published 11618 publications receiving 1522743 citations. The organization is also known as: Eli and Edythe L. Broad Institute of MIT and Harvard.
Papers published on a yearly basis
Papers
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Cardiff University1, Charité2, Harvard University3, King's College London4, Broad Institute5, University of Adelaide6, Centre for Mental Health7, University of Queensland8, University of Münster9, University of Edinburgh10, QIMR Berghofer Medical Research Institute11, University of Vigo12, University of California, Los Angeles13, Icahn School of Medicine at Mount Sinai14, University of Oviedo15, Lundbeck16, Aarhus University17, University of Oslo18, Oslo University Hospital19, Statens Serum Institut20, University of Bergen21, Aarhus University Hospital22, University of Copenhagen23, University of Belgrade24, Tbilisi State Medical University25, deCODE genetics26, University of Verona27, Mental Health Services28, Eli Lilly and Company29, Ludwig Maximilian University of Munich30, Martin Luther University of Halle-Wittenberg31
TL;DR: A new genome-wide association study of schizophrenia is reported, and through meta-analysis with existing data and integrating genomic fine-mapping with brain expression and chromosome conformation data, 50 novel associated loci and 145 loci are identified.
Abstract: Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
1,259 citations
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TL;DR: Using quantitative proteomics, it is found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKzF3, by the CRBN-CRL4 ubiquitin ligase, which are essential transcription factors in multiple myeloma.
Abstract: Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
1,254 citations
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Veterans Health Administration1, Oklahoma Medical Research Foundation2, University of Oklahoma3, Uppsala University4, University of California, San Francisco5, University of Southern California6, University of Alabama at Birmingham7, University of Minnesota8, University of California, Los Angeles9, Hammersmith Hospital10, Wake Forest University11, Broad Institute12, North Shore-LIJ Health System13, Genentech14, University of California, Riverside15, Université de Montréal16, Medical University of South Carolina17, University of California, Davis18, University of Texas Southwestern Medical Center19
TL;DR: The results show that numerous genes, some with known immune-related functions, predispose to SLE, and evidence of association with replication is found at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases.
Abstract: Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 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 x 10(-7) or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
1,253 citations
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TL;DR: Analysis of intratumoral heterogeneity in chronic lymphocytic leukemia cases uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.
1,249 citations
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TL;DR: Results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.
Abstract: Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.
1,248 citations
Authors
Showing all 7146 results
Name | H-index | Papers | Citations |
---|---|---|---|
Eric S. Lander | 301 | 826 | 525976 |
Albert Hofman | 267 | 2530 | 321405 |
Frank B. Hu | 250 | 1675 | 253464 |
David J. Hunter | 213 | 1836 | 207050 |
Kari Stefansson | 206 | 794 | 174819 |
Mark J. Daly | 204 | 763 | 304452 |
Lewis C. Cantley | 196 | 748 | 169037 |
Matthew Meyerson | 194 | 553 | 243726 |
Gad Getz | 189 | 520 | 247560 |
Stacey Gabriel | 187 | 383 | 294284 |
Stuart H. Orkin | 186 | 715 | 112182 |
Ralph Weissleder | 184 | 1160 | 142508 |
Chris Sander | 178 | 713 | 233287 |
Michael I. Jordan | 176 | 1016 | 216204 |
Richard A. Young | 173 | 520 | 126642 |