AANEM News Express

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Science News: Shared Polygenic Risk and Causal Inferences in Amyotrophic Lateral Sclerosis

Submitted by Clark Pinyan, MD, MPH
Edited by Lisa Williams, MD

Bandres-Ciga S et al. Shared Polygenic Risk and Causal Inferences in Amyotrophic Lateral Sclerosis. Ann Neurol 2019;85:470-481

Epidemiological studies of ALS can be limited by the sometimes rapid progression of the disease. New methods of risk analysis including genome-wide association studies were reviewed in reference to the recently published ALS-GWAS. Analysis of whole genome data with linkage disequilibrium score regression on over 20,000 (mostly European) ALS patients and 59,000 controls looked at correlations with over 700 phenotypic traits. Positive correlations for ALS were seen with smoking status and moderate physical activity. Negative correlations were seen with higher cognitive performance, higher educational attainment and light physical activity. Secondarily, Mendelian randomization suggests a causative relationship between hyperlipidemia and ALS.

Genome linkage studies use genetic markers associated with a risk (such as tendency to smoke, cancer, or hypercholesterolemia), compared with incidence of a particular condition, in this case ALS. This can overcome some limitations of traditional epidemiology such as recall or selection bias, by being independent of patient self-reporting or selection. Furthermore, Mendelian randomization can suggest a causative link if certain conditions are met. 

Comments: In this no-hypothesis exploratory study, there is some genetic confirmation of epidemiologically suggested risks for ALS including smoking, lower education and hyperlipidemia, though the traditional epidemiological studies for low-density lipoprotein and ALS are somewhat mixed. The positive correlation with moderate exercise was unexpected and needs further explanation. Use of whole genomic data to determine risk for ALS may be useful in overcoming limitations in epidemiological studies of ALS in both research and clinical practice.

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