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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.

SUBMITTER: Gao Y

PROVIDER: S-EPMC7376149 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Gao Yixin Y Wang Ting T Yu Xinghao X Zhao Huashuo H Zeng Ping P

Scientific reports 20200722 1

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 ...[more]

PMID: 32699404

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Project description:Amyotrophic lateral sclerosis is a relatively common and rapidly progressive neurodegenerative disease that, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies combined with the advent of Mendelian randomization is opening significant new opportunities to identify environmental exposures that increase or decrease the risk of amyotrophic lateral sclerosis. Each of these discoveries has the potential to shape new therapeutic interventions. However, to do so, rigorous methodological standards must be applied in the performance of Mendelian randomization. We have reviewed Mendelian randomization studies performed in amyotrophic lateral sclerosis to date. We identified 20 Mendelian randomization studies, including evaluation of physical exercise, adiposity, cognitive performance, immune function, blood lipids, sleep behaviours, educational attainment, alcohol consumption, smoking and type 2 diabetes mellitus. We have evaluated each study using gold standard methodology supported by the Mendelian randomization literature and the STROBE-Mendelian randomization checklist. Where discrepancies exist between Mendelian randomization studies, we suggest the underlying reasons. A number of studies conclude that there is a causal link between blood lipids and risk of amyotrophic lateral sclerosis; replication across different datasets and even different populations adds confidence. For other putative risk factors, such as smoking and immune function, Mendelian randomization studies have provided cause for doubt. We highlight the use of positive control analyses in choosing exposure single nucleotide polymorphisms (SNPs) to make up the Mendelian randomization instrument, use of SNP clumping to avoid false positive results due to SNPs in linkage and the importance of multiple testing correction. We discuss the implications of survival bias for study of late age of onset diseases such as amyotrophic lateral sclerosis and make recommendations to mitigate this potentially important confounder. For Mendelian randomization to be useful to the amyotrophic lateral sclerosis field, high methodological standards must be applied to ensure reproducibility. Mendelian randomization is already an impactful tool, but poor-quality studies will lead to incorrect interpretations by a field that includes non-statisticians, wasted resources and missed opportunities.

Project description:Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study. Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn’s disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran’s Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction. Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66–0.89, and p = 3.66 × 10−4), SS (OR: 0.75, CI: 0.58–0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68–0.88, and p = 9.85 × 10−5), hypothyroidism (OR: 0.84, 95% CI: 0.78–0.91, and p = 7,08 × 10−6), hyperthyroidism (OR: 0.60, 95% CI: 0.44–0.83, and p = 1.90 × 10−3), sarcoidosis (OR: 0.67, 95% CI: 0.54–0.83, and p = 2.60 × 10−4), and IPF (OR: 0.41, 95% CI: 0.29–0.58, and p = 4.11 × 10−7) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18–1.94, and p = 9.66 × 10−4). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62–1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37–2.54, and p = 8.01 × 10−5). Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.

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

Publications

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

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