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Your search keyword '"Barry I, Freedman"' showing total 2 results
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2 results on '"Barry I, Freedman"'

1. Rare variant contribution to the heritability of coronary artery disease

Author

Ghislain Rocheleau, Shoa L. Clarke, Gaëlle Auguste, Natalie R. Hasbani, Alanna C. Morrison, Adam S. Heath, Lawrence F. Bielak, Kruthika R. Iyer, Erica P. Young, Nathan O. Stitziel, Goo Jun, Cecelia Laurie, Jai G. Broome, Alyna T. Khan, Donna K. Arnett, Lewis C. Becker, Joshua C. Bis, Eric Boerwinkle, Donald W. Bowden, April P. Carson, Patrick T. Ellinor, Myriam Fornage, Nora Franceschini, Barry I. Freedman, Nancy L. Heard-Costa, Lifang Hou, Yii-Der Ida Chen, Eimear E. Kenny, Charles Kooperberg, Brian G. Kral, Ruth J. F. Loos, Sharon M. Lutz, JoAnn E. Manson, Lisa W. Martin, Braxton D. Mitchell, Rami Nassir, Nicholette D. Palmer, Wendy S. Post, Michael H. Preuss, Bruce M. Psaty, Laura M. Raffield, Elizabeth A. Regan, Stephen S. Rich, Jennifer A. Smith, Kent D. Taylor, Lisa R. Yanek, Kendra A. Young, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Austin T. Hilliard, Catherine Tcheandjieu, Patricia A. Peyser, Ramachandran S. Vasan, Jerome I. Rotter, Clint L. Miller, Themistocles L. Assimes, Paul S. de Vries, and Ron Do

Subjects
Science
Abstract

Abstract Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Published
2024
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2. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Author

Rebecca Keener, Surya B. Chhetri, Carla J. Connelly, Margaret A. Taub, Matthew P. Conomos, Joshua Weinstock, Bohan Ni, Benjamin Strober, Stella Aslibekyan, Paul L. Auer, Lucas Barwick, Lewis C. Becker, John Blangero, Eugene R. Bleecker, Jennifer A. Brody, Brian E. Cade, Juan C. Celedon, Yi-Cheng Chang, L. Adrienne Cupples, Brian Custer, Barry I. Freedman, Mark T. Gladwin, Susan R. Heckbert, Lifang Hou, Marguerite R. Irvin, Carmen R. Isasi, Jill M. Johnsen, Eimear E. Kenny, Charles Kooperberg, Ryan L. Minster, Take Naseri, Satupa’itea Viali, Sergei Nekhai, Nathan Pankratz, Patricia A. Peyser, Kent D. Taylor, Marilyn J. Telen, Baojun Wu, Lisa R. Yanek, Ivana V. Yang, Christine Albert, Donna K. Arnett, Allison E. Ashley-Koch, Kathleen C. Barnes, Joshua C. Bis, Thomas W. Blackwell, Eric Boerwinkle, Esteban G. Burchard, April P. Carson, Zhanghua Chen, Yii-Der Ida Chen, Dawood Darbar, Mariza de Andrade, Patrick T. Ellinor, Myriam Fornage, Bruce D. Gelb, Frank D. Gilliland, Jiang He, Talat Islam, Stefan Kaab, Sharon L. R. Kardia, Shannon Kelly, Barbara A. Konkle, Rajesh Kumar, Ruth J. F. Loos, Fernando D. Martinez, Stephen T. McGarvey, Deborah A. Meyers, Braxton D. Mitchell, Courtney G. Montgomery, Kari E. North, Nicholette D. Palmer, Juan M. Peralta, Benjamin A. Raby, Susan Redline, Stephen S. Rich, Dan Roden, Jerome I. Rotter, Ingo Ruczinski, David Schwartz, Frank Sciurba, M. Benjamin Shoemaker, Edwin K. Silverman, Moritz F. Sinner, Nicholas L. Smith, Albert V. Smith, Hemant K. Tiwari, Ramachandran S. Vasan, Scott T. Weiss, L. Keoki Williams, Yingze Zhang, Elad Ziv, Laura M. Raffield, Alexander P. Reiner, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group, Marios Arvanitis, Carol W. Greider, Rasika A. Mathias, and Alexis Battle

Subjects
Science
Abstract

Abstract Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Published
2024
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