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Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies.
Dou, John; Bakulski, Kelly; Guo, Kai; Hur, Junguk; Zhao, Lili; Saez-Atienzar, Sara; Stark, Ali; Chia, Ruth; García-Redondo, Alberto; Rojas-Garcia, Ricardo; Vázquez Costa, Juan Francisco; Fernandez Santiago, Ruben; 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, Lucia; Infante Ceberio, Jon; Pastor, Pau; Paradas, Carmen; Dols-Icardo, Oriol; Traynor, Bryan J; Feldman, Eva L; Goutman, Stephen A.
Afiliación
  • Dou J; From 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;
  • Bakulski K; From 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;
  • Guo K; From 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;
  • Hur J; From 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;
  • Zhao L; From 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;
  • Saez-Atienzar S; From 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;
  • Stark A; From 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;
  • Chia R; From 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;
  • García-Redondo A; From 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;
  • Rojas-Garcia R; From 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;
  • Vázquez Costa JF; From 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;
  • Fernandez Santiago R; From 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;
  • Bandres-Ciga S; From 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;
  • Gómez-Garre P; From 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;
  • Periñán MT; From 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;
  • Mir P; From 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;
  • Pérez-Tur J; From 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;
  • Cardona F; From 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;
  • Menendez-Gonzalez M; From 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;
  • Riancho J; From 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;
  • Borrego-Hernández D; From 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;
  • Galán-Dávila L; From 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;
  • Infante Ceberio J; From 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;
  • Pastor P; From 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;
  • Paradas C; From 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;
  • Dols-Icardo O; From 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;
  • Traynor BJ; From 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;
  • Feldman EL; From 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;
  • Goutman SA; From 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;
Neurol Genet ; 9(4): e200079, 2023 Aug.
Article en En | MEDLINE | ID: mdl-37293291
ABSTRACT
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Neurol Genet Año: 2023 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Neurol Genet Año: 2023 Tipo del documento: Article