Cumulative genetic risk andC9orf72repeat status independently associate with ALS status in two case-control studies
Authors: Dou John F. , Bakulski Kelly M. , Guo Kai , Hur Junguk , Zhou Lili , Saez-Atienzar Sara , Stark Ali R , Chia Ruth , García-Redondo Alberto , Rojas-García Ricardo , Vázquez-Costa Juan Francisco , Santiago Ruben Fernandez , Bandres-Ciga Sara , Gómez-Garre Pilar , Periñán Maria Teresa , Mir Pablo , Pérez-Tur Jordi , Cardona Fernando , Menendez-Gonzalez Manuel , Riancho Javier , Borrego-Hernández Daniel , Galán-Dávila Lucía , Ceberio Jon Infante , Pastor Pau ,   Spanish Neurological Consortium, Traynor Bryan J. , Feldman Eva L. , Goutman Stephen A ,   Members of the Spanish Neurological Consortium:, Esteban-Pérez Jesús , Cordero-Vázquez Pilar , Teresa Sevilla , López de Munain Adolfo , Pardo-Fernández Julio , Jericó-Pascual Ivonne , Dols-Icardo Oriol , Mantius Ellen Gelpi , Hoenicka Janet , Martinez Victoria Alvarez , de Rivera Garrido Francisco Javier Rodríguez , Beyer Katrin , Clarimón Echevarría Jordi 
Published: October 2022

Background

Most amyotrophic lateral sclerosis (ALS) patients lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores.

Methods

ALS (n=219) and healthy control (n=223) participant samples from University of Michigan were genotyped and assayed for theC9orf72hexanucleotide expansion. Polygenic scores excluding the C9 region were generated using an independent ALS genome-wide association study (20,806 cases, 59,804 controls). Adjusted logistic regression and receiver operating characteristic curves evaluated the association and classification between polygenic scores and ALS status, respectively. Population attributable fractions and pathway analyses were conducted. An independent Spanish study sample (548 cases, 2,756 controls) was used for replication.

Results

Polygenic scores constructed from 275 single nucleotide polymorphisms had the best model fit in the Michigan cohort. A standard deviation increase in ALS polygenic score associated with 1.28 (95%CI 1.04-1.57) times higher odds of ALS with area under the curve of 0.663 versus a model without the ALS polygenic score (p-value=1×10−6). The population attributable fraction of the highest 20thpercentile of ALS polygenic scores, relative to the lowest 80thpercentile, was 4.1% of ALS cases. Genes annotated to this polygenic score enriched for important ALS pathomechanisms. Meta-analysis with the Spanish study, using a harmonized 132 single nucleotide polymorphism polygenic score, yielded similar logistic regression findings (odds ratio: 1.13, 95%CI 1.04-1.23).

Conclusion

ALS polygenic scores can account for cumulative genetic risk in populations and reflect disease-relevant pathways. If further validated, this polygenic score will inform future ALS risk models.

What is already known on this topic

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease caused in part by genetic factors, and methods to account for ALS polygenic disease risk are needed.

What this study adds

An ALS polygenic score reflects disease risk in the population and helps ascribe the magnitude of the risk.

How this study might affect research, practice or policy

ALS polygenic scores can assign the overall distribution of genetic risk in a population and can be used to screen individuals at higher risk.