Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies

被引：10

作者：

Dou, John ^{[1
]}

Bakulski, Kelly ^{[1
]}

Guo, Kai ^{[2
,3
]}

Hur, Junguk ^{[4
]}

Zhao, Lili ^{[5
]}

Saez-Atienzar, Sara ^{[6
]}

Stark, Ali ^{[6
]}

Chia, Ruth ^{[6
]}

Garcia-Redondo, Alberto ^{[7
,8
]}

Rojas-Garcia, Ricardo ^{[8
,9
,10
]}

Costa, Juan Francisco Vazquez ^{[8
,11
,12
]}

Santiago, Ruben Fernandez ^{[13
,14
,15
,16
]}

Bandres-Ciga, Sara ^{[17
]}

Gomez-Garre, Pilar ^{[13
,18
]}

Perinan, Maria Teresa ^{[13
,18
]}

Mir, Pablo ^{[13
,18
,19
]}

Perez-Tur, Jordi ^{[13
,20
,21
]}

Cardona, Fernando ^{[13
,20
,21
]}

Menendez-Gonzalez, Manuel ^{[22
]}

Riancho, Javier ^{[23
,24
]}

Borrego-Hernandez, Daniel ^{[7
,8
]}

Galan-Davila, Lucia ^{[25
]}

Ceberio, Jon Infante ^{[24
]}

Pastor, Pau ^{[26
,27
]}

Paradas, Carmen ^{[28
]}

Dols-Icardo, Oriol ^{[13
,29
,30
]}

Traynor, Bryan J. ^{[6
]}

Feldman, Eva L. ^{[2
,3
]}

Goutman, Stephen A. ^{[2
,3
]}

机构：

[1] Univ Michigan, Dept Epidemiol, Ann Arbor, MI USA

[2] Univ Michigan, Sch Publ Hlth, Dept Neurol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, NeuroNetwork Emerging Therapies, Ann Arbor, MI 48109 USA

[4] Univ North Dakota, Dept Biomed Sci, Grand Forks, BC, Canada

[5] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI USA

[6] NIH, Neuromuscular Dis Res Sect, Lab Neurogenet, Natl Inst Aging, Bethesda, MD USA

[7] Ctr Networked Biomed Res Rare Dis, ALS Unit, Madrid, Spain

[8] Hosp Univ 12 Octubre Madrid, Ctr Networked Biomed Res Rare Dis, SERMAS, CIBERER,Inst Invest Sanit i 12, Madrid, Spain

[9] Univ Autonoma Barcelona, Hosp Santa Creu I St Pau, Neurol Dept, Neuromuscular Disorders Unit, Barcelona, Spain

[10] Univ Autonoma Barcelona, Hosp Santa Creu I St Pau, St Pau Biomed Res Inst, Neuromuscular Disorders Unit, Barcelona, Spain

[11] Hosp Univ & Politecn La Fe, Neuromuscular Unit, IIS La Fe, Valencia, Spain

[12] Univ Valencia, Dept Med, Valencia, Spain

[13] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain

[14] IDIBAPS Inst Invest Biomed, Labof Parkinsons Dis & Other Neurodegenerat Moveme, Barcelona, Spain

[15] Hosp Clin Barcelona, Serv Neurol, Unitat Parkinson & Trastorns Moviment, Catalonia, Spain

[16] Univ Barcelona, Maria Maetzu Ctr, Inst Neurociencies, Catalonia, Spain

[17] Natl Inst Aging, Ctr Alzheimers & Related Dementias, Bethesda, MD USA

[18] Hosp Univ Virgen Rocio CSIC, Serv Neurol & Neurofisiol Clin, Unidad Trastornos Movimiento, Inst Biomed Sevilla, Seville, Spain

[19] Univ Seville, Dept Med, Seville, Spain

[20] Inst Biomed Valencia CSIC, Neurol & Mol Genet Mixed Invest Unit, Valencia, Spain

[21] Inst Biomed Valencia CSIC, Mol Genet Unit, Inst Invest Sanit La Fe, Valencia, Spain

[22] Univ Oviedo, Dept Med, Oviedo, Spain

[23] IDIVAL Univ Cantabria, Hosp Sierrallana, Serv Neurol, Torrelavega, Spain

[24] Inst Invest Marques de Valdecilla, Santander, Spain

[25] Hosp Clin Univ San Carlos, Dept Neurol, ALS Unit, Madrid, Spain

[26] Univ Hosp Germans Trias I Pujol, Dept Neurol, Unit Neurodegenerat Dis, Badalona, Spain

[27] Germans Trias i Pujol Res Inst IGTP Badalona, Neurosci, Badalona, Spain

[28] Hosp Univ Virgen del Rocio, Dept Neurol, Seville, Spain

[29] Univ Autonoma Barcelona, Hosp Santa Creu I St Pau, Neurol Dept, Memory Unit, Barcelona, Spain

[30] Univ Autonoma Barcelona, Hosp Santa Creu I St Pau, St Pau Biomed Res Inst, Barcelona, Spain

来源：

NEUROLOGY-GENETICS | 2023年 / 9卷 / 04期

关键词：

HEXANUCLEOTIDE REPEAT; ASSOCIATION ANALYSES; ANALYSES IDENTIFY; DISEASE; ALS; VARIANTS; CANCER;

D O I：

10.1212/NXG.0000000000200079

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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.

引用

页数：13

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