scholarly journals Association between premorbid body mass index and amyotrophic lateral sclerosis: causal inference through genetic approaches

2019 ◽  
Author(s):  
Ping Zeng ◽  
Xinghao Yu ◽  
Haibo Xu
Keyword(s):  
Body Mass Index ◽  
Amyotrophic Lateral Sclerosis ◽  
Causal Relationship ◽  
Body Mass ◽  
European Population ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Standard Deviation Increase ◽  
Lateral Sclerosis

Background: Inverse association between premorbid body mass index (BMI) and amyotrophic lateral sclerosis (ALS) has been discovered in observational studies; however, whether this association is causal remains largely unknown. Methods: We employed a two-sample Mendelian randomization approach to evaluate the causal relationship of genetically increased BMI with the risk of ALS. The analyses were implemented using summary statistics obtained for the independent instruments identified from large-scale genome-wide association studies of BMI (up to ~770,000 individuals) and ALS (up to ~81,000 individuals). The causal relationship between BMI and ALS was estimated using inverse-variance weighted methods and was further validated through extensive complementary and sensitivity analyses. Findings: Using 1,031 instruments strongly related to BMI, the causal effect of per one standard deviation increase of BMI was estimated to be 1.04 (95% CI 0.97~1.11, p=0.275) in the European population. The null association between BMI and ALS discovered in the European population also held in the East Asian population and was robust against various modeling assumptions and outlier biases. Additionally, the Egger-regression and MR-PRESSO ruled out the possibility of horizontal pleiotropic effects of instruments. Interpretation: Our results do not support the causal role of genetically increased or decreased BMI on the risk of ALS.

scholarly journals Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Gan Zhang ◽  
Yajun Wang ◽  
Tao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Telomere Length ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Leukocyte Telomere Length ◽  
Weighted Median ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. We employed a two-sample Mendelian randomization (MR) approach to explore the causal relationship between leukocyte telomere length (LTL) and ALS based on the most cited and most recent and largest LTL genome-wide association studies (GWASs) that measured LTL with the Southern blot method (n = 9190) and ALS GWAS summary data (n = 80,610). We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR PRESSO method to perform sensitivity analyses. Results We found that genetically determined longer LTL was inversely associated with the risk of ALS (OR = 0.846, 95% CI: 0.744–0.962, P = 0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. In sensitivity analyses, that was confirmed in MR Egger method (OR = 0.647,95% CI = 0.447–0.936, P = 0.050), and a similar trend was shown with the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935 P = 0.535). The MR Egger analyses did not suggest directional pleiotropy, showing an intercept of 0.025 (P = 0.168). Neither the influence of instrumental outliers nor heterogeneity was found. Conclusions Our results suggest that genetically predicted longer LTL has a causal relationship with a lower risk of ALS and underscore the importance of protecting against telomere loss in ALS.

scholarly journals Causal Effects of Blood Lipids on Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2018 ◽  
Author(s):  
Ping Zeng ◽  
Xiang Zhou
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
East Asian ◽  
Density Lipoprotein ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Asian Populations ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per one standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 (95% CI 1.05 - 1.24, p = 1.38E-3) in the European and population and 1.06 (95% CI 1.00 - 1.12, p = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations.

scholarly journals Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Gan Zhang ◽  
Yajun Wang ◽  
Tao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Telomere Length ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Leukocyte Telomere Length ◽  
Weighted Median ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, whether this association is causal remains unclear. In this study, we aimed to explore the causal relationship between leukocyte telomere length (LTL) and ALS by a two-sample Mendelian randomization (MR) approach. Single-nucleotide polymorphisms (SNPs) for LTL were identified through high-quality genome-wide association studies (GWASs). The ALS GWAS summary data (20,806 cases; 59,804 controls) with largest sample size to date was obtained. We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR-PRESSO method to perform sensitivity analyses. Results We found that genetically determined increased LTL was inversely associated with the risk of ALS (odds ratio (OR) = 0.846, 95% confidence interval (CI): 0.744–0.962, P = 0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. The results were further confirmed by sensitivity analysis with the MR Egger method (OR = 0.647, 95% CI = 0.447–0.936, P = 0.050). Analyses by the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935, P = 0.535) also showed a similar trend. The MR Egger analysis did not suggest directional pleiotropy, with an intercept of 0.025 (P = 0.168). Neither the influence of instrumental outliers nor heterogeneity was found. Conclusions Our results suggest that genetically predicted increased LTL has a causal relationship with a lower risk of ALS. Protecting against telomere loss may be of great importance in the prevention and treatment of ALS.

scholarly journals Leukocyte Telomere Length and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Gan Zhang ◽  
Yajun Wang ◽  
Tao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Telomere Length ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Leukocyte Telomere Length ◽  
Weighted Median ◽  
Lateral Sclerosis

Abstract Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. We employed a two-sample Mendelian randomization (MR) approach to explore the causal relationship between leukocyte telomere length (LTL) and ALS based on the most cited and most recent and largest LTL genome-wide association studies (GWASs) that measured LTL with the Southern blot method (n=9190) and ALS GWAS summary data (n=80,610). We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR PRESSO method to perform sensitivity analyses. We found that genetically determined longer LTL was inversely associated with the risk of ALS (OR=0.846, 95% CI: 0.744-0.962, P=0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. In sensitivity analyses, that was confirmed in MR Egger method (OR=0.647,95% CI=0.447-0.936, P=0.050), and a similar trend was shown with the weighted median method (OR=0.893, P=0.201) and simple median method (OR=0.935 P=0.535). The MR Egger analyses did not suggest directional pleiotropy, showing an intercept of 0.025 (P=0.168). Neither the influence of instrumental outliers nor heterogeneity was found. Our results suggest that genetically predicted longer LTL has a causal relationship with a lower risk of ALS and underscore the importance of protecting against telomere loss in ALS.

Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis

2017 ◽  
Vol 88 (12) ◽  
pp. 1033-1041 ◽  
Author(s):  
Martin Gorges ◽  
Pauline Vercruysse ◽  
Hans-Peter Müller ◽  
Hans-Jürgen Huppertz ◽  
Angela Rosenbohm ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Amyotrophic Lateral Sclerosis ◽  
Body Mass ◽  
Age At Onset ◽  
Lateral Sclerosis

scholarly journals Higher blood high density lipoprotein and apolipoprotein A1 levels are associated with reduced risk of developing amyotrophic lateral sclerosis

2021 ◽  
pp. jnnp-2021-327133
Author(s):  
Alexander G Thompson ◽  
Kevin Talbot ◽  
Martin R Turner
Keyword(s):  
Body Mass Index ◽  
Amyotrophic Lateral Sclerosis ◽  
Body Mass ◽  
Density Lipoprotein ◽  
Apolipoprotein A1 ◽  
Haemoglobin A1c ◽  
Increased Risk ◽  
Prospective Longitudinal ◽  
Lateral Sclerosis ◽  
Reduced Risk

BackgroundPremorbid body mass index, physical activity, diabetes and cardiovascular disease have been associated with an altered risk of developing amyotrophic lateral sclerosis (ALS). There is evidence of shared genetic risk between ALS and lipid metabolism. A very large prospective longitudinal population cohort permits the study of a range of metabolic parameters and the risk of subsequent diagnosis of ALS.MethodsThe risk of subsequent ALS diagnosis in those enrolled prospectively to the UK Biobank (n=502 409) was examined in relation to baseline levels of blood high and low density lipoprotein (HDL, LDL), total cholesterol, total cholesterol:HDL ratio, apolipoproteins A1 and B (apoA1, apoB), triglycerides, glycated haemoglobin A1c (HbA1c) and creatinine, plus self-reported exercise and body mass index.ResultsControlling for age and sex, higher HDL (HR 0.84, 95% CI 0.73 to 0.96, p=0.010) and apoA1 (HR 0.83, 95% CI 0.72 to 0.94, p=0.005) were associated with a reduced risk of ALS. Higher total cholesterol:HDL was associated with an increased risk of ALS (HR 1.17, 95% CI 1.05 to 1.31, p=0.006). In models incorporating multiple metabolic markers, higher LDL or apoB was associated with an increased risk of ALS, in addition to a lower risk with higher HDL or apoA. Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of ALS.ConclusionsThe association of HDL, apoA1 and LDL levels with risk of ALS contributes to an increasing body of evidence that the premorbid metabolic landscape may play a role in pathogenesis. Understanding the molecular basis for these changes will inform presymptomatic biomarker development and therapeutic targeting.

scholarly journals Body Mass Index and Amyotrophic Lateral Sclerosis: A Study of US Military Veterans

2017 ◽  
Vol 185 (5) ◽  
pp. 362-371 ◽  
Author(s):  
Daniela Mariosa ◽  
John D. Beard ◽  
David M. Umbach ◽  
Rino Bellocco ◽  
Jean Keller ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Amyotrophic Lateral Sclerosis ◽  
Body Mass ◽  
Military Veterans ◽  
Us Military ◽  
Lateral Sclerosis

scholarly journals Premorbid body mass index and risk of amyotrophic lateral sclerosis

2012 ◽  
Vol 14 (3) ◽  
pp. 205-211 ◽  
Author(s):  
Éilis J. O'Reilly ◽  
Hao Wang ◽  
Marc G. Weisskopf ◽  
Kathryn C. Fitzgerald ◽  
Guido Falcone ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Amyotrophic Lateral Sclerosis ◽  
Body Mass ◽  
Lateral Sclerosis
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