Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

International FTD-Genomics Consortium (IFGC)

doi:10.1038/s41598-020-68848-9

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

International FTD-Genomics Consortium (IFGC)

Physical Medicine and Rehabilitation

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Original language	English (US)
Article number	12184
Journal	Scientific reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-68848-9
State	Published - Dec 1 2020

Funding

We thank the ENGAGE Telomere Consortium, AVS, IFGC and all other GWAS consortium studies for making summary statistics datasets publicly available for us and are grateful to all the investigators and participants who contributed to those studies. Further acknowledgements for IFGC can be found in the Supplementary Acknowledgment. This study was supported by Youth Foundation of Humanity and Social Science funded by Ministry of Education of China (18YJC910002), the Natural Science Foundation of Jiangsu (BK20181472), the China Postdoctoral Science Foundation (2018M630607 and 2019T120465), the QingLan Research Project of Jiangsu for Outstanding Young Teachers, the Six-Talent Peaks Project in Jiangsu of China (WSN-087), the Social Development Project of Xuzhou (KC19017), the Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, the National Natural Science Foundation of China (81402765), the Statistical Science Research Project from National Bureau of Statistics of China (2014LY112) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University.

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@article{e7e6a6896c3a4e62be3d0808f0316fa9,

title = "Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis",

abstract = "We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.",

author = "{International FTD-Genomics Consortium (IFGC)} and Yixin Gao and Ting Wang and Xinghao Yu and Raffaele Ferrari and Hernandez, {Dena G.} and Nalls, {Michael A.} and Rohrer, {Jonathan D.} and Adaikalavan Ramasamy and Kwok, {John B.J.} and Carol Dobson-Stone and Brooks, {William S.} and Schofield, {Peter R.} and Halliday, {Glenda M.} and Hodges, {John R.} and Olivier Piguet and Lauren Bartley and Elizabeth Thompson and Eric Haan and Isabel Hern{\'a}ndez and Agust{\'i}n Ruiz and Merc{\`e} Boada and Barbara Borroni and Alessandro Padovani and Carlos Cruchaga and Cairns, {Nigel J.} and Luisa Benussi and Giuliano Binetti and Roberta Ghidoni and Gianluigi Forloni and Diego Albani and Daniela Galimberti and Chiara Fenoglio and Maria Serpente and Elio Scarpini and Jordi Clarim{\'o}n and Alberto Lle{\'o} and Rafael Blesa and Wald{\"o}, {Maria Landqvist} and Karin Nilsson and Christer Nilsson and Mackenzie, {Ian R.A.} and Hsiung, {Ging Yuek R.} and Mann, {David M.A.} and Jordan Grafman and Morris, {Christopher M.} and Johannes Attems and Griffiths, {Timothy D.} and McKeith, {Ian G.} and Thomas, {Alan J.} and Pietro Pietrini",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41598-020-68848-9",

language = "English (US)",

volume = "10",

journal = "Scientific reports",

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T1 - Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

AU - International FTD-Genomics Consortium (IFGC)

AU - Gao, Yixin

AU - Wang, Ting

AU - Yu, Xinghao

AU - Ferrari, Raffaele

AU - Hernandez, Dena G.

AU - Nalls, Michael A.

AU - Rohrer, Jonathan D.

AU - Ramasamy, Adaikalavan

AU - Kwok, John B.J.

AU - Dobson-Stone, Carol

AU - Brooks, William S.

AU - Schofield, Peter R.

AU - Halliday, Glenda M.

AU - Hodges, John R.

AU - Piguet, Olivier

AU - Bartley, Lauren

AU - Thompson, Elizabeth

AU - Haan, Eric

AU - Hernández, Isabel

AU - Ruiz, Agustín

AU - Boada, Mercè

AU - Borroni, Barbara

AU - Padovani, Alessandro

AU - Cruchaga, Carlos

AU - Cairns, Nigel J.

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Ghidoni, Roberta

AU - Forloni, Gianluigi

AU - Albani, Diego

AU - Galimberti, Daniela

AU - Fenoglio, Chiara

AU - Serpente, Maria

AU - Scarpini, Elio

AU - Clarimón, Jordi

AU - Lleó, Alberto

AU - Blesa, Rafael

AU - Waldö, Maria Landqvist

AU - Nilsson, Karin

AU - Nilsson, Christer

AU - Mackenzie, Ian R.A.

AU - Hsiung, Ging Yuek R.

AU - Mann, David M.A.

AU - Grafman, Jordan

AU - Morris, Christopher M.

AU - Attems, Johannes

AU - Griffiths, Timothy D.

AU - McKeith, Ian G.

AU - Thomas, Alan J.

AU - Pietrini, Pietro

PY - 2020/12/1

Y1 - 2020/12/1

N2 - We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

AB - We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

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DO - 10.1038/s41598-020-68848-9

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AN - SCOPUS:85088385622

SN - 2045-2322

VL - 10

JO - Scientific reports

JF - Scientific reports

IS - 1

M1 - 12184

ER -

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

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