Browsing by Author "Schadt, Eric E."

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    Correction to: Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
    (BioMed Central, 2019-11-05) Glicksberg, Benjamin S.; Amadori, Letizia; Akers, Nicholas K.; Sukhavasi, Katyayani; Franzén, Oscar; Li, Li; Belbin, Gillian M.; Ayers, Kristin L.; Shameer, Khader; Badgeley, Marcus A.; Johnson, Kipp W.; Readhead, Ben; Darrow, Bruce J.; Kenny, Eimear E.; Betsholtz, Christer; Ermel, Raili; Skogsberg, Josefin; Ruusalepp, Arno; Schadt, Eric E.; Dudley, Joel T.; Ren, Hongxia; Kovacic, Jason C.; Giannarelli, Chiara; Li, Shuyu D.; Björkegren, Johan L. M.; Chen, Rong; Pediatrics, School of Medicine
    Erratum for Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. [BMC Med Genomics. 2019]
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    Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease
    (American Association for the Advancement of Science, 2018-01-10) Hui, Ken Y.; Fernandez-Hernandez, Heriberto; Hu, Jianzhong; Schaffner, Adam; Pankratz, Nathan; Hsu, Nai-Yun; Chuang, Ling-Shiang; Carmi, Shai; Villaverde, Nicole; Li, Xianting; Rivas, Manual; Levine, Adam P.; Bao, Xiuliang; Labrias, Philippe R.; Haritunians, Talin; Ruane, Darren; Gettler, Kyle; Chen, Ernie; Li, Dalin; Schiff, Elena R.; Pontikos, Nikolas; Barzilai, Nir; Brant, Steven R.; Bressman, Susan; Cheifetz, Adam S.; Clark, Lorraine N.; Daly, Mark J.; Desnick, Robert J.; Duerr, Richard H.; Katz, Seymour; Lencz, Todd; Myers, Richard H.; Ostrer, Harry; Ozelius, Laurie; Payami, Haydeh; Peter, Yakov; Rioux, John D.; Segal, Anthony W.; Scott, William K.; Silverberg, Mark S.; Vance, Jeffery M.; Ubarretxena-Belandia, Iban; Foroud, Tatiana; Atzmon, Gil; Pe’er, Itsik; Ioannou, Yiannis; McGovern, Dermot P.B.; Yue, Zhenyu; Schadt, Eric E.; Cho, Judy H.; Peter, Inga; Medical and Molecular Genetics, School of Medicine
    Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10-10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10-8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson's disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.
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    Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
    (Biomed Central, 2019-07-25) Glicksberg, Benjamin S.; Amadori, Letizia; Akers, Nicholas K.; Sukhavasi, Katyayani; Franzén, Oscar; Li, Li; Belbin, Gillian M.; Akers, Kristin L.; Shameer, Khader; Badgeley, Marcus A.; Johnson, Kipp W.; Readhead, Ben; Darrow, Bruce J.; Kenny, Eimear E.; Betsholtz, Christer; Ermel, Raili; Skogsberg, Josefin; Ruusalepp, Arno; Schadt, Eric E.; Dudley, Joel T.; Ren, Hongxia; Kovacic, Jason C.; Giannarelli, Chiara; Li, Shuyu D.; Björkegren, Johan L. M.; Chen, Rong; Pediatrics, IU School of Medicine
    BACKGROUND: Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. RESULTS: We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. CONCLUSION: In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.