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Cumulative Genetic Score and
John Dou1, Kelly Bakulski1, Kai Guo1
1From the Department of Epidemiology (J.D., K.B.), School of Public Health, Department of Neurology (K.G., E.L.F., S.A.G.), NeuroNetwork for Emerging Therapies (K.G., E.L.F., S.A.G.), University of Michigan, Ann Arbor; Department of Biomedical Sciences (J.H.), University of North Dakota, Grand Forks; Department of Biostatistics (L.Z.), School of Public Health, University of Michigan, Ann Arbor; Neuromuscular Diseases Research Section (S.S.-A., A.S., R.C., B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD; ALS Unit (A.G.-R., D.B.-H.), Instituto de Investigación Sanitaria "i + 12" del Hospital Universitario 12 de Octubre de Madrid, SERMAS, CIBERER (A.G.-R., R.R.-G., J.F.V.C., D.B.-H.), Center for Networked Biomedical Research into Rare Diseases, Madrid; Neuromuscular Disorders Unit (R.R.-G.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu I Sant Pau, Universitat Autonoma de Barcelona; Neuromuscular Unit (J.F.V.C.), Hospital Universitario y Politécnico la Fe, IIS La Fe; Department of Medicine (J.F.V.C.), Universitat de València; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) (R.F.S., P.G.-G., M.T.P., P.M., J.P.-T., F.C., O.D.-I.), Madrid; Lab of Parkinson's disease and Other Neurodegenerative Movement Disorders (R.F.S.), IDIBAPS-Institut d'Investigacions Biomèdiques, Barcelona; Unitat de Parkinson i Trastorns del Moviment, Servicio de Neurologia (R.F.S.), Hospital Clínic de Barcelona and Institut de Neurociencies de la Universitat de Barcelona (Maria de Maetzu Center), Catalonia, Spain; Center for Alzheimer's and Related Dementias (S.B.-C.), National Institute on Aging, Bethesda, MD; Unidad de Trastornos del Movimiento (P.G.-G., M.T.P., P.M.), Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC; Departamento de Medicina (P.M.), Universidad de Sevilla; Neurology and Molecular Genetics Mixed Investigation Unit (J.P.-T., F.C.), Instituto de Investigación Sanitaria La Fe, Molecular Genetics Unit (J.P.-T., F.C.), Institut de Biomedicina de València-CSIC; Department of Medicine (M.M.-G.), Universidad de Oviedo; Department of Neurology (M.M.-G.), Hospital Universitario Central de Asturias; Instituto de Investigación Sanitaria del Principado de Asturias (M.M.-G.), Oviedo, Spain; Service of Neurology (J.R.), Hospital Sierrallana, IDIVAL University of Cantabria, Torrelavega; Instituto de Investigación Marqués de Valdecilla (J.R., J.I.C.), Santander; Department of Neurology (L.G.-D.), ALS Unit, Hospital Clínico Universitario "San Carlos," Madrid; Unit of Neurodegenerative Diseases (P.P.), Department of Neurology, University Hospital Germans Trias I Pujol; Neurosciences (P.P.), The Germans Trias i Pujol Research Institute (IGTP) Badalona; Department of Neurology (C.P.), Hospital Universitario Virgen del Rocio, Sevilla; and Memory Unit (O.D.-I.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu I Sant Pau, Universitat Autonoma de Barcelona, Spain.
Background And Objectives:
Most patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores.
Methods:
Participant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort size was 219 ALS and 223 healthy controls after genotyping and participant filtering. 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 variation (SNV) had the best model fit in the Michigan cohort. An SD 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 vs a model without the ALS polygenic score (p value = 1 × 10-6). The population attributable fraction of the highest 20th percentile of ALS polygenic scores, relative to the lowest 80th percentile, 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 variation polygenic score, yielded similar logistic regression findings (odds ratio: 1.13, 95% CI 1.04-1.23).
Discussion:
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.
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