J G Seidman

Harvard Medical School, Boston, Massachusetts, United States

Are you J G Seidman?

Claim your profile

Publications (398)5535.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.
    Journal of Clinical Investigation 10/2015; DOI:10.1172/JCI82423 · 13.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell–derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.
    Science 08/2015; 349(6251):982-986. DOI:10.1126/science.aaa5458 · 33.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Homozygous cardiac myosin binding protein C-deficient (Mybpct/t) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpct/t myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpct/t myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpct/t mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3+/− individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3−/− mice is primarily myocyte hyperplasia.
    Proceedings of the National Academy of Sciences 07/2015; 112(29). DOI:10.1073/pnas.1511004112 · 9.67 Impact Factor
  • Michael Parfenov · J G Seidman
    [Show abstract] [Hide abstract]
    ABSTRACT: Viruses and bacteria are established as one of the main causes of human diseases from hepatitis to cancer. Recently, the presence of such pathogens has been extensively studied using human whole genome and transcriptome sequencing data. However, detecting and studying pathogens via next generation sequencing data is a challenging task in terms of time and computational resources. In this protocol we give instructions for a simple and quick method to find pathogenic DNA or RNA and detect possible integration of the pathogen genome into the host genome. © 2015 by John Wiley & Sons, Inc. Copyright © 2015 John Wiley & Sons, Inc.
    Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 07/2015; 86:18.9.1-18.9.10. DOI:10.1002/0471142905.hg1809s86
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype-phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. We hypothesized that studying the role of NKX2-5 in inbred populations with homogeneous genetic backgrounds and high consanguinity rates such as Lebanon could help closing this gap. We sequenced NKX2-5 in 188 index CHD cases (25 with ASD). Five variants (three segregated in families) were detected in eleven families including the previously documented p.R25C variant, which was found in seven patients from different families, and in one healthy individual. In 3/5 familial dominant ASD cases, we identified an NKX2-5 mutation. In addition to the heterogeneity of NKX2-5 mutations, a diversity of phenotypes occurred within the families with predominant ASD and AV block. We did in fact identify a large prevalence of Sudden Cardiac Death (SCD) in families with truncating mutations, and two patients with coronary sinus disease. NKX2-5 is thus responsible for dominant familial ASD even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population.
    Scientific Reports 03/2015; 5:8848. DOI:10.1038/srep08848 · 5.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose:Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with nonsyndromic presentations from a broad referral population over 10 years.Methods:Genetic testing was performed by Sanger sequencing for 10 genes from 2004 to 2007, by HCM CardioChip for 11 genes from 2007 to 2011 and by next-generation sequencing for 18, 46, or 51 genes from 2011 onward.Results:The detection rate is ~32% among unselected probands, with inconclusive results in an additional 15%. Detection rates were not significantly different between adult and pediatric probands but were higher in females compared with males. An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels, which examined 11 genes. Familial genetic testing in at-risk family members eliminated the need for longitudinal cardiac evaluations in 691 individuals. Based on the projected costs derived from Medicare fee schedules for the recommended clinical evaluations of HCM family members by the American College of Cardiology Foundation/American Heart Association, our data indicate that genetic testing resulted in a minimum cost savings of about $0.7 million.Conclusion:Clinical HCM genetic testing provides a definitive molecular diagnosis for many patients and provides cost savings to families. Expanded gene panels have not substantively increased the clinical sensitivity of HCM testing, suggesting major additional causes of HCM still remain to be identified.Genet Med advance online publication 22 January 2015Genetics in Medicine (2015); doi:10.1038/gim.2014.205.
    Genetics in medicine: official journal of the American College of Medical Genetics 01/2015; DOI:10.1038/gim.2014.205 · 7.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report a five-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance in all studied affected individuals. As ubiquilin-2 positive inclusions were identified in brain we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 05/2014; 75(5). DOI:10.1002/ana.24164 · 9.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.
    The Journal of clinical investigation 03/2014; 124(4). DOI:10.1172/JCI73140 · 13.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcriptome is subject to multiple changes during pathogenesis, including the use of alternate 5' start-sites that can affect transcription levels and output. Current RNA sequencing techniques can assess mRNA levels, but do not robustly detect changes in 5' start-site use. Here, we developed a transcriptome sequencing strategy that detects genome-wide changes in start-site usage (5'RNA-Seq) and applied this methodology to identify regulatory events that occur in hypertrophic cardiomyopathy (HCM). Compared with transcripts from WT mice, 92 genes had altered start-site usage in a mouse model of HCM, including four-and-a-half LIM domains protein 1 (Fhl1). HCM-induced altered transcriptional regulation of Fhl1 resulted in robust myocyte expression of a distinct protein isoform, a response that was conserved in humans with genetic or acquired cardiomyopathies. Genetic ablation of Fhl1 in HCM mice was deleterious, which suggests that Fhl1 transcriptional changes provide salutary effects on stressed myocytes in this disease. Because Fhl1 is a chromosome X-encoded gene, stress-induced changes in its transcription may contribute to gender differences in the clinical severity of HCM. Our findings indicate that 5'RNA-Seq has the potential to identify genome-wide changes in 5' start-site usage that are associated with pathogenic phenotypes.
    The Journal of clinical investigation 02/2014; 124(3). DOI:10.1172/JCI70108 · 13.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of HDL, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease (CKD). Approximately 14% of African-Americans carry two APOL1 risk alleles, accounting for the high CKD burden in this population. We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African-Americans. We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and CKD were confirmed (p=2.4 x 10-6). Among JHS participants with two APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without vs. 37/280 events among participants with two risk alleles; odds ratio (OR): 2.17, p=9.4 x 10-4). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without vs. 37/101 events among participants with two risk alleles; OR: 1.98, p=8.37 x 10-3; JHS and WHI combined, p=8.5 x 10-5; OR: 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and CKD. APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with two APOL1 risk alleles may benefit from intensive interventions to reduce CVD.
    Circulation Research 12/2013; 114(5). DOI:10.1161/CIRCRESAHA.114.302347 · 11.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: -Integrin-linked kinase (ILK) is a serine-threonine kinase that has been linked to human and experimental heart failure, but its role in the heart is not fully understood. -To define the role of cardiomyocyte ILK, we generated cardiac-specific ILK knockout mice (CSILK-KO) using α-MHC-driven Cre expression. CSILK-KO spontaneously developed lethal dilated cardiomyopathy and heart failure with an early increase in apoptosis, fibrosis, and cardiac inflammation. To identify downstream effectors, we used deep sequence analysis of gene expression (DSAGE) to compare comprehensive transcriptional profiles of CSILK-KO and WT hearts from 10 day old mice before the development of cardiac dysfunction. ~2x10(6) cDNA clones from each genotype were sequenced, corresponding to 33,274 independent transcripts. 93 genes were altered, using nominal thresholds of >1.4-fold change and p<0.001. The most highly upregulated gene was osteopontin (47-fold increase, p=9.6x10(-45)), an inflammatory chemokine implicated in heart failure pathophysiology. ILK also regulated osteopontin expression in cardiomyocytes in vitro. Importantly, blocking antibodies to osteopontin mitigated but did not fully rescue the functional decline in CSILK-KO mice. -Cardiomyocyte-specific ILK deletion leads to a lethal cardiomyopathy characterized by cardiomyocyte death, fibrosis, and inflammation. Comprehensive profiling identifies ILK-dependent transcriptional effects and implicates osteopontin as a contributor to these phenotypes.
    Circulation Heart Failure 12/2013; 7(1). DOI:10.1161/CIRCHEARTFAILURE.113.000649 · 5.89 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
    Nature Genetics 10/2013; 45(11). DOI:10.1038/ng.2794 · 29.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. We found that expression of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of HCM, for at least 6 months. Because inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.
    Science 10/2013; 342(6154):111-114. DOI:10.1126/science.1236921 · 33.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rapid advancement of next-generation sequencing technologies has made it possible to study expression profiles of microRNAs (miRNAs) comprehensively and efficiently. Multiplexing miRNA libraries by barcoding can significantly reduce sequencing cost per sample without compromising library quality. This unit provides a step-by-step protocol for isolating miRNAs and constructing multiplexed miRNA libraries. Also described is a custom computational pipeline for analyzing the multiplexed miRNA library sequencing reads generated by Illumina-based technology. Curr. Protoc. Mol. Biol. 103:4.17.1-4.17.14. © 2013 by John Wiley & Sons, Inc.
    Current protocols in molecular biology / edited by Frederick M. Ausubel ... [et al.] 07/2013; Chapter 4:Unit4.17. DOI:10.1002/0471142727.mb0417s103
  • A. C. Fahed · B. D. Gelb · J. G. Seidman · C. E. Seidman
    Circulation Research 06/2013; 112(12):E182-E182. DOI:10.1161/RES.0b013e31829ae2ed · 11.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Valvular Interstitial Cells (VICs) are a common substrate for congenital and adult heart disease yet the signaling mechanisms governing their formation during early valvulogenesis are incompletely understood. We developed an unbiased strategy to identify genes important in endocardial epithelial-to-mesenchymal transformation (EMT) using a spatial transcriptional profile. Endocardial cells overlaying the cushions of the atrioventricular canal (AVC) and outflow tract (OFT) undergo an EMT to yield VICs. RNA sequencing (RNA-seq) analysis of gene expression between AVC, OFT, and ventricles (VEN) isolated from chick and mouse embryos at comparable stages of development (chick HH18; mouse E11.0) was performed. EMT occurs in the AVC and OFT cushions, but not VEN at this time. 198 genes in the chick (n=1) and 105 genes in the mouse (n=2) were enriched 2-fold in the cushions. Gene regulatory networks (GRN) generated from cushion-enriched gene lists confirmed TGFβ as a nodal point and identified NF-κB as a potential node. To reveal previously unrecognized regulators of EMT four candidate genes, Hapln1, Id1, Foxp2, and Meis2, and a candidate pathway, NF-κB, were selected. In vivo spatial expression of each gene was confirmed by in situ hybridization and a functional role for each in endocardial EMT was determined by siRNA knockdown in a collagen gel assay. Our spatial-transcriptional profiling strategy yielded gene lists which reflected the known biology of the system. Further analysis accurately identified and validated previously unrecognized novel candidate genes and the NF-κB pathway as regulators of endocardial cell EMT in vitro.
    Journal of Molecular and Cellular Cardiology 04/2013; 59. DOI:10.1016/j.yjmcc.2013.03.016 · 4.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.
    Circulation Research 02/2013; 112(4):707-20. DOI:10.1161/CIRCRESAHA.112.300853 · 11.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dilated cardiomyopathy (DCM) is a disease characterized by dilation of the ventricular chambers and reduced contractile function. We examined the contractile performance of chemically-skinned ventricular strips from two heterozygous murine models of DCM-causing missense mutations of myosin, F764L/+ and S532P/+, in an α-myosin heavy chain (MyHC) background. In Ca(2+)-activated skinned myocardial strips, the maximum developed tension in F764L/+ was only ~50% that of litter-mate controls (+/+). The F764L/+ also exhibited significantly reduced rigor stiffness, loaded shortening velocity and power output. Corresponding indices for S532P/+ strips were not different from controls. Manipulation of MgATP concentration in conjunction with measures of viscoelasticity, which provides estimates of myosin detachment rate 2πc, allowed us to probe the molecular basis of changes in crossbridge kinetics that occur with the myosin mutations. By examining the response of detachment rate to varying MgATP we found the rate of MgADP release was unaffected by the myosin mutations. However, MgATP binding rate was higher in the DCM groups compared to controls (422±109 mM(-1).s(-1) in F764L/+, 483±74 mM(-1).s(-1) in S532P/+ and 303±18 mM(-1).s(-1) in +/+). In addition, the rate constant of force development, 2πb, was significantly higher in DCM groups compared to controls (at 5 mM MgATP: 36.9±4.9 s(-1) in F764L/+, 32.9±4.5 s(-1) in S532P/+ and 18.2±1.7 s(-1) in +/+). These results suggest that elevated rates of force development and MgATP binding are features of cardiac myofilament function that underlie the development of DCM.
    Journal of Molecular and Cellular Cardiology 01/2013; 57(1). DOI:10.1016/j.yjmcc.2012.12.022 · 4.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with serious adverse outcomes, including heart failure, arrhythmias, and sudden cardiac death. The discovery that mutations in sarcomere protein genes cause HCM has enabled the development of mouse models that recapitulate clinical manifestations of disease. Studies in these models have provided unexpected insights into the biophysical and biochemical properties of mutated contractile proteins and may help to improve clinical diagnosis and management of patients with HCM.
    The Journal of Cell Biology 10/2012; 199(3):417-21. DOI:10.1083/jcb.201207033 · 9.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis.
    The American Journal of Human Genetics 09/2012; 91(3):513-9. DOI:10.1016/j.ajhg.2012.07.017 · 10.93 Impact Factor

Publication Stats

50k Citations
5,535.78 Total Impact Points


  • 1983–2015
    • Harvard Medical School
      • • Department of Genetics
      • • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, Massachusetts, United States
  • 1992–2013
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 2002–2005
    • Minneapolis Heart Institute
      Minneapolis, Minnesota, United States
  • 1987–2005
    • Brigham and Women's Hospital
      • • Center for Brain Mind Medicine
      • • Department of Medicine
      • • Division of Urology
      Boston, Massachusetts, United States
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States
    • Netherlands Cancer Institute
      • Division of Immunology
      Amsterdamo, North Holland, Netherlands
    • The Children's Hospital of Philadelphia
      • Department of Pediatrics
      Filadelfia, Pennsylvania, United States
  • 2004
    • University of Vermont
      • Department of Molecular Physiology and Biophysics
      Burlington, Vermont, United States
  • 1995–2002
    • Cornell University
      Итак, New York, United States
  • 1999
    • Weill Cornell Medical College
      • Division of Cardiology
      New York City, New York, United States
  • 1989–1998
    • Boston Children's Hospital
      • Division of Infectious Diseases
      Boston, Massachusetts, United States
  • 1986–1991
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
    • McGill University
      Montréal, Quebec, Canada
    • National Institutes of Health
      • Branch of Metabolism
      베서스다, Maryland, United States
  • 1990
    • LSU Medical Center
      • Department of Medicine
      Shreveport, Louisiana, United States
  • 1986–1989
    • University of Toronto
      • Banting and Best Department of Medical Research
      Toronto, Ontario, Canada
  • 1988
    • Sinai Hospital
      Baltimore, Maryland, United States
  • 1984
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
    • Aarhus University
      • Institute of Human Genetics
      Aarhus, Central Jutland, Denmark
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 1977–1982
    • National Institute of Child Health and Human Development
      베서스다, Maryland, United States
  • 1981
    • National Cancer Institute (USA)
      • Laboratory of Cell Biology
      Maryland, United States
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 1979
    • Uniformed Services University of the Health Sciences
      Maryland, United States