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

IF 3 3区医学 Q2 CLINICAL NEUROLOGY Neurology-Genetics Pub Date : 2023-05-31 eCollection Date: 2023-08-01 DOI:10.1212/NXG.0000000000200079

John Dou, Kelly Bakulski, Kai Guo, Junguk Hur, Lili Zhao, Sara Saez-Atienzar, Ali Stark, Ruth Chia, Alberto García-Redondo, Ricardo Rojas-Garcia, Juan Francisco Vázquez Costa, Ruben Fernandez Santiago, Sara Bandres-Ciga, Pilar Gómez-Garre, Maria Teresa Periñán, Pablo Mir, Jordi Pérez-Tur, Fernando Cardona, Manuel Menendez-Gonzalez, Javier Riancho, Daniel Borrego-Hernández, Lucia Galán-Dávila, Jon Infante Ceberio, Pau Pastor, Carmen Paradas, Oriol Dols-Icardo, Bryan J Traynor, Eva L Feldman, Stephen A Goutman

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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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在2项病例对照研究中，累积遗传评分和C9orf72重复状态对肌萎缩侧索硬化症风险的独立贡献。

背景和目的：大多数肌萎缩侧索硬化症（ALS）患者缺乏单基因突变。这项研究使用多基因评分评估了密歇根州和西班牙独立复制队列中ALS的累积遗传风险。方法：对来自密歇根大学的参与者样本进行基因分型，并测定9号染色体开放阅读框72六核苷酸扩增。基因分型和参与者筛选后，最终队列规模为219名ALS和223名健康对照。使用一项独立的ALS全基因组关联研究（20806例病例，59804例对照）生成除C9区域外的多基因评分。调整后的逻辑回归和受试者操作特征曲线分别评估了多基因评分和ALS状态之间的关联和分类。进行了群体可归因组分和通路分析。一个独立的西班牙研究样本（548例，2756例对照）用于复制。结果：由275个单核苷酸变异（SNV）构建的多基因评分在密歇根队列中具有最佳的模型拟合性。ALS多基因评分的SD增加与曲线下面积为0.663的ALS发生几率高1.28倍（95%CI 1.04-1.57）相关（p值=1×10-6）。相对于最低的第80百分位，ALS多基因评分最高的第20百分位的人群归因分数为ALS病例的4.1%。注释到该多基因评分的基因丰富了重要的ALS病理机制。与西班牙研究的荟萃分析，使用统一的132个单核苷酸变异多基因评分，得出了类似的逻辑回归结果（比值比：1.13，95%CI 1.04-1.23）。讨论：ALS多基因评分可以解释人群的累积遗传风险，并反映疾病相关途径。如果进一步验证，这个多基因评分将为未来的ALS风险模型提供信息。

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来源期刊

Neurology-Genetics Medicine-Neurology (clinical)

CiteScore

6.30

自引率

3.20%

发文量

107

审稿时长

15 weeks

期刊介绍： Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.