Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.
Rebecca KeenerSurya B ChhetriCarla J ConnellyMargaret A TaubMatthew P ConomosJoshua S WeinstockBohan NiBenjamin J StroberStella AslibekyanPaul L AuerLucas BarwickLewis C BeckerJohn E BlangeroEugene R BleeckerJennifer A BrodyBrian E CadeJuan C CeledónYi-Cheng ChangL Adrienne CupplesBrian S CusterBarry I FreedmanMark T GladwinSusan R HeckbertLifang HouMarguerite R IrvinCarmen R IsasiJill M JohnsenEimear E KennyCharles KooperbergRyan L MinsterTake NaseriSatupa'itea VialiSergei NekhaiNathan D PankratzPatricia A PeyserKent D TaylorMarilyn J TelenBaojun WuLisa R YanekIvana V YangChristine AlbertDonna K ArnettAllison Elizabeth Ashley-KochKathleen C BarnesJoshua C BisThomas W BlackwellEric BoerwinkleEsteban González BurchardApril P CarsonZhanghua ChenYii-Der Ida ChenDawood DarbarMariza de AndradePatrick T EllinorMyriam FornageBruce D GelbFrank D GillilandJiang HeTalat IslamStefan KääbSharon L R KardiaShannon KellyBarbara A KonkleRajesh KumarRuth J F LoosFernando D MartinezStephen T McGarveyDeborah A MeyersBraxton D MitchellCourtney G MontgomeryKari E NorthNicholette D D AllredJuan M PeraltaBenjamin A RabySusan RedlineStephen S RichDan M RodenJerome I RotterIngo RuczinskiDavid SchwartzFrank SciurbaM Benjamin ShoemakerEdwin K SilvermanMoritz F SinnerNicholas L SmithAlbert Vernon SmithHemant K TiwariRamachandran S VasanScott T WeissL Keoki WilliamsYingze ZhangElad ZivLaura M RaffieldAlexander P Reinernull nullnull nullnull nullMarios ArvanitisCarol W GreiderRasika A MathiasAlexis J BattlePublished in: Nature communications (2024)
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.
Keyphrases
- genome wide
- genome wide association study
- genome wide association
- bioinformatics analysis
- dna methylation
- crispr cas
- endothelial cells
- systematic review
- genome wide identification
- induced apoptosis
- induced pluripotent stem cells
- genome editing
- case control
- pluripotent stem cells
- cell cycle arrest
- cell proliferation
- meta analyses