Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes-Reference-Cited by-同舟云学术

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

Published:2024-05-24 Issue:1 Volume:15 Page:
ISSN:2041-1723
Container-title:Nature Communications
language:en
Short-container-title:Nat Commun

Author:

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

Abstract

AbstractGenome-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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

Publisher

Springer Science and Business Media LLC

Link

https://www.nature.com/articles/s41467-024-48394-y.pdf

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