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. 2020 Mar 5;106(3):389-404.
doi: 10.1016/j.ajhg.2020.02.006. Epub 2020 Feb 27.

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

Chen Li  1 , Svetlana Stoma  2 , Luca A Lotta  3 , Sophie Warner  4 , Eva Albrecht  5 , Alessandra Allione  6 , Pascal P Arp  7 , Linda Broer  7 , Jessica L Buxton  8 , Alexessander Da Silva Couto Alves  9 , Joris Deelen  10 , Iryna O Fedko  11 , Scott D Gordon  12 , Tao Jiang  13 , Robert Karlsson  14 , Nicola Kerrison  3 , Taylor K Loe  15 , Massimo Mangino  16 , Yuri Milaneschi  17 , Benjamin Miraglio  18 , Natalia Pervjakova  19 , Alessia Russo  6 , Ida Surakka  20 , Ashley van der Spek  21 , Josine E Verhoeven  17 , Najaf Amin  21 , Marian Beekman  22 , Alexandra I Blakemore  23 , Federico Canzian  24 , Stephen E Hamby  2 , Jouke-Jan Hottenga  11 , Peter D Jones  4 , Pekka Jousilahti  25 , Reedik Mägi  19 , Sarah E Medland  12 , Grant W Montgomery  26 , Dale R Nyholt  27 , Markus Perola  28 , Kirsi H Pietiläinen  29 , Veikko Salomaa  25 , Elina Sillanpää  30 , H Eka Suchiman  22 , Diana van Heemst  31 , Gonneke Willemsen  11 , Antonio Agudo  32 , Heiner Boeing  33 , Dorret I Boomsma  11 , Maria-Dolores Chirlaque  34 , Guy Fagherazzi  35 , Pietro Ferrari  36 , Paul Franks  37 , Christian Gieger  38 , Johan Gunnar Eriksson  39 , Marc Gunter  36 , Sara Hägg  14 , Iiris Hovatta  40 , Liher Imaz  41 , Jaakko Kaprio  42 , Rudolf Kaaks  43 , Timothy Key  44 , Vittorio Krogh  45 , Nicholas G Martin  12 , Olle Melander  46 , Andres Metspalu  19 , Concha Moreno  47 , N Charlotte Onland-Moret  48 , Peter Nilsson  49 , Ken K Ong  50 , Kim Overvad  51 , Domenico Palli  52 , Salvatore Panico  53 , Nancy L Pedersen  14 , Brenda W J H Penninx  17 , J Ramón Quirós  54 , Marjo Riitta Jarvelin  55 , Miguel Rodríguez-Barranco  56 , Robert A Scott  3 , Gianluca Severi  57 , P Eline Slagboom  10 , Tim D Spector  58 , Anne Tjonneland  59 , Antonia Trichopoulou  60 , Rosario Tumino  61 , André G Uitterlinden  7 , Yvonne T van der Schouw  48 , Cornelia M van Duijn  62 , Elisabete Weiderpass  36 , Eros Lazzerini Denchi  63 , Giuseppe Matullo  6 , Adam S Butterworth  64 , John Danesh  65 , Nilesh J Samani  2 , Nicholas J Wareham  3 , Christopher P Nelson  2 , Claudia Langenberg  66 , Veryan Codd  67
Affiliations

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

Chen Li et al. Am J Hum Genet. .

Abstract

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.

Keywords: Mendelian randomisation; age-related disease; biological aging; telomere length.

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Conflict of interest statement

A.S.B. holds grants unrelated to this work from AstraZeneca, Merck, Novartis, Biogen, and Bioverativ/Sanofi.

J.D. reports personal fees and non-financial support from Merck Sharpe and Dohme UK Atherosclerosis; personal fees and non-financial support from Novartis Cardiovascular and Metabolic Advisory Board; personal fees and non-financial support from Pfizer Population Research Advisory Panel; and grants from the British Heart Foundation, the European Research Council, Merck, the NIHR, NHS Blood and Transplant, Novartis, Pfizer, the UK Medical Research Council, Health Data Research UK, and the Wellcome Trust outside the submitted work.

Figures

Figure 1
Figure 1
Loci with Established Roles in Telomere Biology Candidate genes found in this study are shown in red. These include genes that encode components of the SHELTERIN complex (A), regulate the formation and activity of telomerase (B), and regulate telomere structure (C).
Figure 2
Figure 2
Pathways Enriched for Telomere-Associated Genes (A) Gene sets significantly (false discovery rate [FDR] < 0.05) enriched for prioritised LTL-associated genes. Color intensity of the nodes (gene sets), classified into three levels, reflects enrichment strengths (FDR). Edge width indicates Pearson correlation coefficient (r2) between each pair of the gene sets. Some of the most significantly associated gene sets include telomere maintenance along with DNA replication and repair pathways as may be expected. How other enriched pathways may influence LTL is unclear. (B) Role of LTL-associated genes in nucleotide metabolism. Five enzymatic reactions and genes encoding the corresponding enzymes prioritized from this GWAS are highlighted in bold.
Figure 3
Figure 3
Mendelian Randomization Results for the Effect of Shorter LTL on the Risk of 122 Diseases in the UK Biobank Data shown are odds ratios and 95% confidence intervals for a 1 standard deviation shorter LTL. Diseases are classified into groups, as indicated by the boxing, and sorted alphabetically within disease group. Nominally significant (p < 0.05) associations estimated via inverse-variance-weighted Mendelian randomization are shown in green for a reduction in risk and purple for an increase in risk due to shorter LTL. O indicates nominal (p < 0.05) evidence of pleiotropy estimated by MR-Eggers intercept. Full results are also shown in Table S16 along with the full MR sensitivity analysis.
See this image and copyright information in PMC

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