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Sekar Kathiresan
Broad Institute
521Publications
106H-index
60.9kCitations
Publications 528
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Polygenic risk scores (PRSs) capture the polygenic architecture of common diseases by aggregating genome-wide genetic variation into a single score that reflects individual9s disease risk, affording a new opportunity to identify downstream molecular pathways involved in disease pathogenesis. We performed an integrative analysis to characterise associations of PRSs of five cardiometabolic diseases with 3,442 plasma proteins in 3,175 healthy individuals. Through polygenic association scans we iden...
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Inherited susceptibility to common, complex diseases may be caused by rare, pathogenic variants (“monogenic”) or by the cumulative effect of numerous common variants (“polygenic”). Comprehensive genome interpretation should enable assessment for both monogenic and polygenic components of inherited risk. The traditional approach requires two distinct genetic testing technologies—high coverage sequencing of known genes to detect monogenic variants and a genome-wide genotyping array followed by imp...
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Background: Genetic variation can predispose to disease both through (i) monogenic risk variants in specific genes that disrupt a specific physiologic pathway and have a large effect on disease risk and (ii) polygenic risk that involves large numbers of variants of small effect that affect many different pathways. Few studies have explored the interaction between monogenic risk variants and polygenic risk. Methods: We identified monogenic risk variants and calculated polygenic scores for three d...
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Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells due to acquired leukemic mutations in genes such as DNMT3A or TET2. In huma...
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Abstract Background Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. Objectives This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and ...
1 CitationsSource
Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We...
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Summary Although human genetic studies have implicated many susceptible genes associated with plasma lipid levels, their physiological and molecular functions are not fully characterized. Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2) through activation of the extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating hepatic very low-density lipoprotein (VLDL) secret...
2 CitationsSource
#1Benjamin Georgi (Bayer)
#2Johanna Mielke (Bayer)
Last.Daniel F. Freitag (Bayer)H-Index: 16
view all 11 authors...
Background and Purpose— Coagulation factor XI (FXI) is a novel target for antithrombotic therapy addressed by various therapeutic modalities currently in clinical development. The expected magnitud...
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#1Erik L. Bao (Harvard University)H-Index: 4
#2Satish K Nandakumar (Boston Children's Hospital)H-Index: 1
Last.Vijay G. Sankaran (Boston Children's Hospital)H-Index: 33
view all 33 authors...
Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs). While substantial progress has been made to define the causal somatic mutation profile for MPNs, epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers. However, only a limited set of genetic risk loci have been i...
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