Polygenic Score for ALS Reflects an Individual’s Cumulative Genetic Risk

A novel scoring system may help predict a person’s risk of developing amyotrophic lateral sclerosis (ALS) by weighing the combined effects of common genetic variants, according to a study published online in Neurology Genetics.

“This polygenic scoring system we developed for ALS allows us to better understand the genetic architecture of the disease,” said study senior author Stephen Goutman, MD, a neurologist and director of the University of Michigan Pranger ALS Clinic, Ann Arbor, Michigan. “This may help to distinguish which populations have greater odds to develop the disease and inform future prevention studies and interventions.”

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The study included 219 patients with ALS from the Pranger ALS Clinic and 223 individuals without ALS who underwent genotyping. Polygenic scores were generated from an independent ALS genome-wide association study (GWAS) involving 20,806 people with ALS and 59,804 controls.

Patients with ALS had higher average polygenic scores compared with healthy control subjects, according to the study. An increase in polygenic score was associated with a greater likelihood of having ALS.

Among the fraction of ALS cases caused by genetic factors, 4.1% were explained by a higher polygenic score, the research team reported. Genetic mutations contributing to the polygenic score were involved in pathways and functions associated with the development and progression of the disease. 

Investigators replicated the findings in an independent cohort from a Spanish study involving 548 people with ALS and 2756 controls.

“By combining all of the common genetic features previously associated with ALS, we improved ALS case status prediction among study populations in Michigan and in Spain,” said study coauthor Kelly M. Bakulski, PhD, assistant professor of epidemiology at the University of Michigan School of Public Health.

“However, there is a lot of room for improvement in ALS prediction so that folks at risk can be identified for prevention and treatment. Future research into additional risk factors, including environmental exposures, will be critical.”

References

Dou J, Bakulski K, Guo K, et al. Cumulative genetic score and C9orf72 repeat status independently contribute to amyotrophic lateral sclerosis risk in 2 case-control studies. Neurol Genet. 2023;9(4):e200079. doi:10.1212/NXG.0000000000200079

Novel genetic scoring system helps determine ALS disease risk. News release. Michigan Medicine - University of Michigan; June 21, 2023. Accessed July 14, 2023.