Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

  • Public Health Research
March 05, 2020 By:
  • Li C
  • Stoma S
  • Lotta LA
  • Warner S
  • Albrecht E
  • Allione A
  • Arp PP
  • Broer L
  • Buxton JL
  • Da Silva Couto Alves A
  • Deelen J
  • Fedko IO
  • Gordon SD
  • Jiang T
  • Karlsson R
  • Kerrison N
  • Loe TK
  • Mangino M
  • Milaneschi Y
  • Miraglio B
  • Pervjakova N
  • Russo A
  • Surakka I
  • van der Spek A
  • Verhoeven JE
  • Amin N
  • Beekman M
  • Blakemore AI
  • Canzian F
  • Hamby SE
  • Hottenga JJ
  • Jones PD
  • Jousilahti P
  • Magi R
  • Medland SE
  • Montgomery GW
  • Nyholt DR
  • Perola M
  • Pietilainen KH
  • Salomaa V
  • Sillanpaa E
  • Suchiman HE
  • van Heemst D
  • Willemsen G
  • Agudo A
  • Boeing H
  • Boomsma DI
  • Chirlaque MD
  • Fagherazzi G
  • Ferrari P
  • Franks P
  • Gieger C
  • Eriksson JG
  • Gunter M
  • Hagg S
  • Hovatta I
  • Imaz L
  • Kaprio J
  • Kaaks R
  • Key T
  • Krogh V
  • Martin NG
  • Melander O
  • Metspalu A
  • Moreno C
  • Onland-Moret NC
  • Nilsson P
  • Ong KK
  • Overvad K
  • Palli D
  • Panico S
  • Pedersen NL
  • Penninx B
  • Quiros JR
  • Jarvelin MR
  • Rodriguez-Barranco M
  • Scott RA
  • Severi G
  • Slagboom PE
  • Spector TD
  • Tjonneland A
  • Trichopoulou A
  • Tumino R
  • Uitterlinden AG
  • van der Schouw YT
  • van Duijn CM
  • Weiderpass E
  • Denchi EL
  • Matullo G
  • Butterworth AS
  • Danesh J
  • Samani NJ
  • Wareham NJ
  • Nelson CP
  • Langenberg C
  • Codd V.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

2020 Mar. Am J Hum Genet.106(3):389-404. Epub 2020 Feb 27.
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