Ursula M. Schick
Icahn School of Medicine at Mount Sinai
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Featured researches published by Ursula M. Schick.
The New England Journal of Medicine | 2014
Nathan O. Stitziel; Hong-Hee Won; Alanna C. Morrison; Gina M. Peloso; Ron Do; Leslie A. Lange; Pierre Fontanillas; Namrata Gupta; Stefano Duga; Anuj Goel; Martin Farrall; Danish Saleheen; Paola G. Ferrario; Inke R. König; Rosanna Asselta; Piera Angelica Merlini; Nicola Marziliano; Maria Francesca Notarangelo; Ursula M. Schick; Paul L. Auer; Themistocles L. Assimes; Muredach P. Reilly; Robert L. Wilensky; Daniel J. Rader; G. Kees Hovingh; Thomas Meitinger; Thorsten Kessler; Adnan Kastrati; Karl-Ludwig Laugwitz; David S. Siscovick
BACKGROUND Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. METHODS We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. RESULTS With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). CONCLUSIONS Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).
Nature Genetics | 2014
Paul L. Auer; Alexander Teumer; Ursula M. Schick; Andrew O'Shaughnessy; Ken Sin Lo; Nathalie Chami; Christopher S. Carlson; Simon de Denus; Marie-Pierre Dubé; Jeff Haessler; Rebecca D. Jackson; Charles Kooperberg; Louis-Philippe Lemieux Perreault; Matthias Nauck; Ulrike Peters; John D. Rioux; Frank Schmidt; Valérie Turcot; Uwe Völker; Henry Völzke; Andreas Greinacher; Li Hsu; Jean-Claude Tardif; George A. Diaz; Alex P. Reiner; Guillaume Lettre
Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10−13). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10−22) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10−7) and WBC count (P = 3.1 × 10−5). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.
Human Molecular Genetics | 2013
Zhao Chen; Hua Tang; Rehan Qayyum; Ursula M. Schick; Michael A. Nalls; Robert E. Handsaker; Jin Li; Yingchang Lu; Lisa R. Yanek; Brendan J. Keating; Yan Meng; Frank J. A. van Rooij; Yukinori Okada; Michiaki Kubo; Laura J. Rasmussen-Torvik; Margaux F. Keller; Leslie A. Lange; Michele K. Evans; Erwin P. Bottinger; Michael D. Linderman; Douglas M. Ruderfer; Hakon Hakonarson; George J. Papanicolaou; Alan B. Zonderman; Omri Gottesman; Cynthia A. Thomson; Elad Ziv; Andrew B. Singleton; Ruth J. F. Loos; Patrick Sleiman
Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.
Molecular Psychiatry | 2016
Emily Olfson; Nancy L. Saccone; E. O. Johnson; Li-Shiun Chen; Robert Culverhouse; Kimberly F. Doheny; S. M. Foltz; Louis Fox; Stephanie M. Gogarten; Sarah M. Hartz; K. Hetrick; Cathy C. Laurie; B. Marosy; Najaf Amin; Donna K. Arnett; R. G. Barr; Traci M. Bartz; Sarah Bertelsen; Ingrid B. Borecki; Michael R. Brown; Daniel I. Chasman; C. M. van Duijn; Mary F. Feitosa; Ervin R. Fox; Nora Franceschini; Oscar H. Franco; Megan L. Grove; Xiuqing Guo; A. Hofman; Sharon L.R. Kardia
The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10−11; African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.
Human Molecular Genetics | 2015
Ursula M. Schick; Paul L. Auer; Joshua C. Bis; Honghuang Lin; Peng Wei; Nathan Pankratz; Leslie A. Lange; Jennifer A. Brody; Nathan O. Stitziel; Daniel S. Kim; Christopher S. Carlson; Myriam Fornage; Jeffery Haessler; Li Hsu; Rebecca D. Jackson; Charles Kooperberg; Suzanne M. Leal; Bruce M. Psaty; Eric Boerwinkle; Russell P. Tracy; Diego Ardissino; Svati H. Shah; Cristen J. Willer; Ruth J. F. Loos; Olle Melander; Ruth McPherson; Kees Hovingh; Muredach P. Reilly; Hugh Watkins; Domenico Girelli
C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.
PLOS ONE | 2013
Ursula M. Schick; Andrew McDavid; Paul K. Crane; Noah Weston; Kelly Ehrlich; Katherine M. Newton; Robert B. Wallace; Ebony Bookman; Tabitha A. Harrison; Aaron K. Aragaki; David R. Crosslin; Sophia S. Wang; Alex P. Reiner; Rebecca D. Jackson; Ulrike Peters; Eric B. Larson; Gail P. Jarvik; Christopher S. Carlson
Chromosomal abnormalities provide clinical utility in the diagnosis and treatment of hematologic malignancies, and may be predictive of malignant transformation in individuals without apparent clinical presentation of a hematologic cancer. In an effort to confirm previous reports of an association between clonal mosaicism and incident hematologic cancer, we applied the anomDetectBAF algorithm to call chromosomal anomalies in genotype data from previously conducted Genome Wide Association Studies (GWAS). The genotypes were initially collected from DNA derived from peripheral blood of 12,176 participants in the Group Health electronic Medical Records and Genomics study (eMERGE) and the Women’s Health Initiative (WHI). We detected clonal mosaicism in 169 individuals (1.4%) and large clonal mosaic events (>2 mb) in 117 (1.0%) individuals. Though only 9.5% of clonal mosaic carriers had an incident diagnosis of hematologic cancer (multiple myeloma, myelodysplastic syndrome, lymphoma, or leukemia), the carriers had a 5.5-fold increased risk (95% CI: 3.3–9.3; p-value = 7.5×10−11) of developing these cancers subsequently. Carriers of large mosaic anomalies showed particularly pronounced risk of subsequent leukemia (HR = 19.2, 95% CI: 8.9–41.6; p-value = 7.3×10−14). Thus we independently confirm the association between detectable clonal mosaicism and hematologic cancer found previously in two recent publications.
PLOS Genetics | 2017
Chani J. Hodonsky; Deepti Jain; Ursula M. Schick; Jean Morrison; Lisa Brown; Caitlin P. McHugh; Diane D. Chen; Yongmei Liu; Paul L. Auer; Cecilia A. Laurie; Kent D. Taylor; Brian L. Browning; Yun Li; George J. Papanicolaou; Jerome I. Rotter; Ryo Kurita; Yukio Nakamura; Sharon R. Browning; Ruth J. F. Loos; Kari E. North; Cathy C. Laurie; Timothy A. Thornton; Nathan Pankratz; Daniel E. Bauer; Tamar Sofer; Alex P. Reiner
Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/SOL Hispanics/Latinos, including African ancestral alpha- and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 (which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element harboring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos.
Journal of Clinical Medicine Research | 2012
Samuel M. Lancaster; Ursula M. Schick; Morwan M. Osman; Daniel A. Enquobahrie
Background Identify variables associated with intrapartum epidural use. Methods Odds ratios were calculated to quantify associations between selected variables and epidural use using a population-based case-control study of Washington State birth certificate data from 2009. Results Non-Whites had 10 - 45% lower odds of epidural use relative to Whites. Foreign-born women had 25 - 45% lower odds of epidural use compared to their US-born counterparts, except for Asians. Women who smoked or induced labor had higher roughly 2-fold higher odds of epidural use compared with non-smokers or women giving birth spontaneously, respectively. Women without a high school diploma or equivalent had lower odds of epidural use relative to those who graduated. Delivering at perinatal units, rural hospitals, or non-profit hospitals had ~50% lower odds of epidural use compared with secondary/teritiary perinatal units, urban hospitals or for-profit hospitals, respectively. Conclusion Several individual and health service-related variables were associated with epidural use. These findings elucidate the clinical relevance of epidural use, and dispariaties in its utilization and in quality of care during delivery. Keywords Epidural use; Foreign birth; Labor; Racial disparities
Human Molecular Genetics | 2017
Deepti Jain; Chani J. Hodonsky; Ursula M. Schick; Jean Morrison; Sharon Minnerath; Lisa Brown; Yongmei Liu; Paul L. Auer; Cecelia A. Laurie; Kent D. Taylor; Brian L. Browning; George J. Papanicolaou; Sharon R. Browning; Ruth J. F. Loos; Kari E. North; Bharat Thyagarajan; Cathy C. Laurie; Timothy A. Thornton; Tamar Sofer; Alex P. Reiner
Circulating white blood cell (WBC) counts (neutrophils, monocytes, lymphocytes, eosinophils, basophils) differ by ethnicity. The genetic factors underlying basal WBC traits in Hispanics/Latinos are unknown. We performed a genome-wide association study of total WBC and differential counts in a large, ethnically diverse US population sample of Hispanics/Latinos ascertained by the Hispanic Community Health Study and Study of Latinos (HCHS/SOL). We demonstrate that several previously known WBC-associated genetic loci (e.g. the African Duffy antigen receptor for chemokines null variant for neutrophil count) are generalizable to WBC traits in Hispanics/Latinos. We identified and replicated common and rare germ-line variants at FLT3 (a gene often somatically mutated in leukemia) associated with monocyte count. The common FLT3 variant rs76428106 has a large allele frequency differential between African and non-African populations. We also identified several novel genetic loci involving or regulating hematopoietic transcription factors (CEBPE-SLC7A7, CEBPA and CRBN-TRNT1) associated with basophil count. The minor allele of the CEBPE variant associated with lower basophil count has been previously associated with Amerindian ancestry and higher risk of acute lymphoblastic leukemia in Hispanics. Together, these data suggest that germline genetic variation affecting transcriptional and signaling pathways that underlie WBC development and lineage specification can contribute to inter-individual as well as ethnic differences in peripheral blood cell counts (normal hematopoiesis) in addition to susceptibility to leukemia (malignant hematopoiesis).
American Journal of Hematology | 2018
Chani J. Hodonsky; Ursula M. Schick; Jonathan Kocarnik; Ran Tao; Frank J. A. van Rooij; Christina L. Wassel; Steve Buyske; Myriam Fornage; Lucia A. Hindorff; James S. Floyd; Santhi K. Ganesh; D. Y. Lin; Kari E. North; Alex P. Reiner; Ruth J. F. Loos; Charles Kooperberg; Christy L. Avery
Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome‐wide association studies were performed primarily in European‐ or Asian‐ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine‐mapping. Here, we report the first fine‐mapping of 6 correlated (Pearsons r range: |0.04‐0.92|) RBC traits in up to 19 036 African Americans and 19 562 Hispanic/Latino participants of the Population Architecture using Genomics and Epidemiology consortium. Trans‐ethnic meta‐analysis of race/ethnic‐ and study‐specific estimates for approximately 11 000 SNPs flanking 13 previously identified association signals as well as 150 000 additional array‐wide SNPs was performed using inverse‐variance meta‐analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP‐RBC trait associations generalized to the trans‐ethnic study population (p < 1.7 × 10−4); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans‐ethnic fine‐mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p = 1.9 × 10−7). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations.