Association between telomere length and risk of cancer and non-neoplastic diseases a Mendelian randomization study

Haycock, Philip C., Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N., Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J., Evans, David M., Willeit, Peter, Aviv, Abraham, Gaunt, Tomr., Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M., Pooley, Karen A., Eeles, Rosalind A., Lee, Jeffrey E., Fang, Shenying, Chen, Wei V., Law, Matthew H., Bowdler, Lisa M., Iles, Mark M., Yang, Qiong, Worrall, Bradford B., Markus, Hugh Stephen, Hung, Rayjean J., Amos, Chris I., Spurdle, Amanda B., Thompson, Deborah J., O'Mara, Tracy A., Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, Charlotte, Lund, Eiliv, Duell, Eric J., Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J., Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F., Bown, Matthew J., Samani, Nilesh J., van t'Hof, Femke N. G., Tromp, Gerard, Jones, Gregory T., Kuivaniemi, Helena, Elmore, James R., Johansson, Mattias, Mckay, James, Scelo, Ghislaine, carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M., Neale, Rachel E., Olson, Sara H., Gallinger, Steven, Li, Donghui, Petersen, Gloria M., Risch, Harvey A., Klein, Alison P., Han, Jiali, Abnet, Christian C., Freedman, Neal D., Taylor, Philip R., Maris, John M., Aben, Katja K., Kiemeney, Lambertus A., Vermeulen, Sita H., Wiencke, John K., Walsh, Kyle M., Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Goncalo R., SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T., Montgomery, Grant W., Nyholt, Dale R., van Heel, David A., Hunt, Karen, Arking, Dan E., Ashar, Foram N., Sotoodehnia, Nona, Woo, Daniel, Rosand, Jonathan, Comeau, Mary E., Brown, W. Mark, Silverman, Edwin K., Hokanson, John E., Cho, Michael H., Hui, Jennie, Ferreira, Manuel A., Thompson, Philip J., Morrison, Alanna C., Felix, Janine F., Smith, Nicholas L., Christiano, Angela M., Petukhova, Lynn, Betz, Regina C., Fan, Xing, Zhang, Xuejun, Zhu, Caihong, Langefeld, Carl D., Thompson, Susan D., Wang, Feijie, Lin, Xu, Schwartz, David A., Fingerlin, Tasha, Rotter, Jerome I., Cotch, Mary Frances, Jensen, Richard A., Munz, Matthias, Dommisch, Henrik, Schaefer, Arne S., Han, Fang, Ollila, Hanna M., Hillary, Ryan P., Albagha, Omar, Ralston, Stuart H., Zeng, Chenjie, Zheng, Wei, Shu, Xiao-Ou, Reis, Andre, Uebe, Steffen, Hueffmeier, Ulrike, Kawamura, Yoshiya, Otowa, Takeshi, Sasaki, Tsukasa, Hibberd, Martin Lloyd, Davila, Sonia, Xie, Gang, Siminovitch, Katherine, Bei, Jin-Xin, Zeng, Yi-Xin, Foersti, Asta, Chen, Bowang, Landi, Stefano, Franke, Andre, Fischer, Annegret, Ellinghaus, David, Flores, Carlos, Noth, Imre, Ma, Shwu-Fan, Foo, Jia Nee, Liu, Jianjun, Kim, Jong-Won, Cox, David G., Delattre, Olivier, Mirabeau, Olivier, Skibola, Christine F., Tang, Clara S., Garcia-Barcelo, Merce, Chang, Kai-Ping, Su, Wen-Hui, Chang, Yu-Sun, Martin, Nicholas G., Gordon, Scott, Wade, Tracey D., Lee, Chaeyoung, Kubo, Michiaki, Cha, Pei-Chieng, Nakamura, Yusuke, Levy, Daniel, Kimura, Masayuki, Hwang, Shih-Jen, Hunt, Steven, Spector, Tim, Soranzo, Nicole, Manichaikul, Aniw., Barr, Graham, Kahali, Bratati, Speliotes, Elizabeth, Yerges-Armstrong, LauraM., Cheng, Ching-Yu, Jonas, Jost B., Wong, Tien Yin, Fogh, Isabella, Lin, Kuang, Powell, John F., Rice, Kenneth, Relton, Caroline L., Martin, Richard M. and Smith, George Davey (2017) Association between telomere length and risk of cancer and non-neoplastic diseases a Mendelian randomization study. JAMA Oncology, 3 5: 636-651. doi:10.1001/jamaoncol.2016.5945


Author Haycock, Philip C.
Burgess, Stephen
Nounu, Aayah
Zheng, Jie
Okoli, George N.
Bowden, Jack
Wade, Kaitlin Hazel
Timpson, Nicholas J.
Evans, David M.
Willeit, Peter
Aviv, Abraham
Gaunt, Tomr.
Hemani, Gibran
Mangino, Massimo
Ellis, Hayley Patricia
Kurian, Kathreena M.
Pooley, Karen A.
Eeles, Rosalind A.
Lee, Jeffrey E.
Fang, Shenying
Chen, Wei V.
Law, Matthew H.
Bowdler, Lisa M.
Iles, Mark M.
Yang, Qiong
Worrall, Bradford B.
Markus, Hugh Stephen
Hung, Rayjean J.
Amos, Chris I.
Spurdle, Amanda B.
Thompson, Deborah J.
O'Mara, Tracy A.
Wolpin, Brian
Amundadottir, Laufey
Stolzenberg-Solomon, Rachael
Trichopoulou, Antonia
Onland-Moret, Charlotte
Lund, Eiliv
Duell, Eric J.
Canzian, Federico
Severi, Gianluca
Overvad, Kim
Gunter, Marc J.
Tumino, Rosario
Svenson, Ulrika
van Rij, Andre
Baas, Annette F.
Bown, Matthew J.
Samani, Nilesh J.
van t'Hof, Femke N. G.
Tromp, Gerard
Jones, Gregory T.
Kuivaniemi, Helena
Elmore, James R.
Johansson, Mattias
Mckay, James
Scelo, Ghislaine
carreras-Torres, Robert
Gaborieau, Valerie
Brennan, Paul
Bracci, Paige M.
Neale, Rachel E.
Olson, Sara H.
Gallinger, Steven
Li, Donghui
Petersen, Gloria M.
Risch, Harvey A.
Klein, Alison P.
Han, Jiali
Abnet, Christian C.
Freedman, Neal D.
Taylor, Philip R.
Maris, John M.
Aben, Katja K.
Kiemeney, Lambertus A.
Vermeulen, Sita H.
Wiencke, John K.
Walsh, Kyle M.
Wrensch, Margaret
Rice, Terri
Turnbull, Clare
Litchfield, Kevin
Paternoster, Lavinia
Standl, Marie
Abecasis, Goncalo R.
SanGiovanni, John Paul
Li, Yong
Mijatovic, Vladan
Sapkota, Yadav
Low, Siew-Kee
Zondervan, Krina T.
Montgomery, Grant W.
Nyholt, Dale R.
van Heel, David A.
Hunt, Karen
Arking, Dan E.
Ashar, Foram N.
Sotoodehnia, Nona
Woo, Daniel
Rosand, Jonathan
Comeau, Mary E.
Brown, W. Mark
Silverman, Edwin K.
Hokanson, John E.
Cho, Michael H.
Hui, Jennie
Ferreira, Manuel A.
Thompson, Philip J.
Morrison, Alanna C.
Felix, Janine F.
Smith, Nicholas L.
Christiano, Angela M.
Petukhova, Lynn
Betz, Regina C.
Fan, Xing
Zhang, Xuejun
Zhu, Caihong
Langefeld, Carl D.
Thompson, Susan D.
Wang, Feijie
Lin, Xu
Schwartz, David A.
Fingerlin, Tasha
Rotter, Jerome I.
Cotch, Mary Frances
Jensen, Richard A.
Munz, Matthias
Dommisch, Henrik
Schaefer, Arne S.
Han, Fang
Ollila, Hanna M.
Hillary, Ryan P.
Albagha, Omar
Ralston, Stuart H.
Zeng, Chenjie
Zheng, Wei
Shu, Xiao-Ou
Reis, Andre
Uebe, Steffen
Hueffmeier, Ulrike
Kawamura, Yoshiya
Otowa, Takeshi
Sasaki, Tsukasa
Hibberd, Martin Lloyd
Davila, Sonia
Xie, Gang
Siminovitch, Katherine
Bei, Jin-Xin
Zeng, Yi-Xin
Foersti, Asta
Chen, Bowang
Landi, Stefano
Franke, Andre
Fischer, Annegret
Ellinghaus, David
Flores, Carlos
Noth, Imre
Ma, Shwu-Fan
Foo, Jia Nee
Liu, Jianjun
Kim, Jong-Won
Cox, David G.
Delattre, Olivier
Mirabeau, Olivier
Skibola, Christine F.
Tang, Clara S.
Garcia-Barcelo, Merce
Chang, Kai-Ping
Su, Wen-Hui
Chang, Yu-Sun
Martin, Nicholas G.
Gordon, Scott
Wade, Tracey D.
Lee, Chaeyoung
Kubo, Michiaki
Cha, Pei-Chieng
Nakamura, Yusuke
Levy, Daniel
Kimura, Masayuki
Hwang, Shih-Jen
Hunt, Steven
Spector, Tim
Soranzo, Nicole
Manichaikul, Aniw.
Barr, Graham
Kahali, Bratati
Speliotes, Elizabeth
Yerges-Armstrong, LauraM.
Cheng, Ching-Yu
Jonas, Jost B.
Wong, Tien Yin
Fogh, Isabella
Lin, Kuang
Powell, John F.
Rice, Kenneth
Relton, Caroline L.
Martin, Richard M.
Smith, George Davey
Title Association between telomere length and risk of cancer and non-neoplastic diseases a Mendelian randomization study
Journal name JAMA Oncology   Check publisher's open access policy
ISSN 2374-2445
2374-2437
Publication date 2017-05-01
Sub-type Article (original research)
DOI 10.1001/jamaoncol.2016.5945
Open Access Status Not yet assessed
Volume 3
Issue 5
Start page 636
End page 651
Total pages 16
Place of publication Chicago, IL, United States
Publisher American Medical Association
Language eng
Subject 2730 Oncology
1306 Cancer Research
Abstract IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
Formatted abstract
Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions and Relevance:
 It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
Keyword Genome-Wide Association
Abdominal Aortic-Aneurysm
Incident Colorectal-Carcinoma
Multiple Susceptibility Loci
Peripheral-Blood Leukocytes
Nonmelanoma Skin-Cancer
Squamous-Cell Carcinoma
Shanghai Womens Health
Lung-Cancer
Endometrial Cancer
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID DK063491
HL044682
HL044682
HL064310
MC-UU-12013/1
MC-UU-12013/2
MC-UU-12013/3
HL064310
R01HL105756
U01HG006382
UL1TR001881
UL1TR001881
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
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