Dataset Information

Education, intelligence, and amyotrophic lateral sclerosis: A Mendelian randomization study.

ABSTRACT: OBJECTIVE:To systematically investigate causal relationships between educational attainment, cognitive-related phenotypes, and amyotrophic lateral sclerosis (ALS). METHODS:Summary statistics from genome-wide association studies for educational attainment, math ability, highest math class taken, cognitive performance, intelligence, and ALS were used. A two-sample Mendelian randomization (MR) design was applied to explore the potential causal associations between them. RESULTS:Genetically predisposition to longer educational attainment and harder math class taken were associated with significantly lower statistical odds ratio of ALS. For per year increase in education completed there was a 21% lower (95% confidence interval [CI] = 27-14%) in risk for ALS. For per 1-SD increase in the highest math class taken obtained there was a 19% lower (95% CI = 9-28%) in risk for ALS. Genetically predisposition to math ability, cognitive performance, and intelligence did not decrease the risk of ALS. INTERPRETATION:This study provides genetic support for a causal association between higher educational attainment and a lower risk of ALS. The genes related to these phenotypes are involved in almost all aspects of neuron-to-neuron communication. ALS patients are occasionally accompanied by varying degrees of cognitive impairment. People with greater cognitive reserve may be better able to offset damages of degenerative brain changes associated with dementia or other brain diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or ALS.

SUBMITTER: Zhang L

PROVIDER: S-EPMC7480912 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Education, intelligence, and amyotrophic lateral sclerosis: A Mendelian randomization study.

Zhang Linjing L Tang Lu L Xia Kailin K Huang Tao T Fan Dongsheng D

Annals of clinical and translational neurology 20200818 9

<h4>Objective</h4>To systematically investigate causal relationships between educational attainment, cognitive-related phenotypes, and amyotrophic lateral sclerosis (ALS).<h4>Methods</h4>Summary statistics from genome-wide association studies for educational attainment, math ability, highest math class taken, cognitive performance, intelligence, and ALS were used. A two-sample Mendelian randomization (MR) design was applied to explore the potential causal associations between them.<h4>Results</h ...[more]

PMID: 32810387

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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:Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS.Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10-5, I2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely.Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.

Dataset Information

Education, intelligence, and amyotrophic lateral sclerosis: A Mendelian randomization study.

Publications

Education, intelligence, and amyotrophic lateral sclerosis: A Mendelian randomization study.

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