Biomaterial Database

Genetic Modifiers of Age at Onset for Amyotrophic Lateral Sclerosis: A Genome-Wide Association Study. 2023

Chunyu Li, and Junyu Lin, and Qirui Jiang, and Tianmi Yang, and Yi Xiao, and Jingxuan Huang, and Yanbing Hou, and Qianqian Wei, and Yiyuan Cui, and Shichan Wang, and Xiaoting Zheng, and Ruwei Ou, and Kuncheng Liu, and Xueping Chen, and Wei Song, and Bi Zhao, and Huifang Shang

Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China.

Age at onset (AAO) is an essential clinical feature associated with disease progression and mortality in amyotrophic lateral sclerosis (ALS). Identification of genetic variants and environmental risk factors influencing AAO of ALS could help better understand the disease's biological mechanism and provide clinical guidance. However, most genetic studies focused on the risk of ALS, while the genetic background of AAO is less explored. This study aimed to identify genetic and environmental determinants for AAO of ALS. We performed a genome-wide association analysis using a Cox proportional hazards model on AAO of ALS in 10,068 patients. We further conducted colocalization analysis and in-vitro functional exploration for the target variants, as well as Mendelian randomization analysis to identify risk factors influencing AAO of ALS. The total heritability of AAO of ALS was ~0.16 (standard error [SE] = 0.03). One novel locus rs2046243 (CTIF) was significantly associated with earlier AAO by ~1.29 years (p = 1.68E-08, beta = 0.10, SE = 0.02). Functional exploration suggested this variant was associated with increased expression of CTIF in multiple tissues including the brain. Colocalization analysis detected a colocalization signal at the locus between AAO of ALS and expression of CTIF. Causal inference indicated higher education level was associated with later AAO. These findings improve the current knowledge of the genetic and environmental etiology of AAO of ALS, and provide a novel target CTIF for further research on ALS pathogenesis and potential therapeutic options to delay the disease onset. ANN NEUROL 2023;94:933-941.

UI	MeSH Term	Description	Entries
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000690	Amyotrophic Lateral Sclerosis	A degenerative disorder affecting upper MOTOR NEURONS in the brain and lower motor neurons in the brain stem and SPINAL CORD. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous ASTROCYTES and atrophy of anterior SPINAL NERVE ROOTS and corticospinal tracts. (From Adams et al., Principles of Neurology, 6th ed, pp1089-94)	ALS - Amyotrophic Lateral Sclerosis,Lou Gehrig Disease,Motor Neuron Disease, Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis With Dementia,Amyotrophic Lateral Sclerosis, Guam Form,Amyotrophic Lateral Sclerosis, Parkinsonism-Dementia Complex of Guam,Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex 1,Charcot Disease,Dementia With Amyotrophic Lateral Sclerosis,Gehrig's Disease,Guam Disease,Guam Form of Amyotrophic Lateral Sclerosis,Lou Gehrig's Disease,Lou-Gehrigs Disease,ALS Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis Parkinsonism Dementia Complex 1,Amyotrophic Lateral Sclerosis, Parkinsonism Dementia Complex of Guam,Disease, Guam,Disease, Lou-Gehrigs,Gehrig Disease,Gehrigs Disease,Sclerosis, Amyotrophic Lateral
D012307	Risk Factors	An aspect of personal behavior or lifestyle, environmental exposure, inborn or inherited characteristic, which, based on epidemiological evidence, is known to be associated with a health-related condition considered important to prevent.	Health Correlates,Risk Factor Scores,Risk Scores,Social Risk Factors,Population at Risk,Populations at Risk,Correlates, Health,Factor, Risk,Factor, Social Risk,Factors, Social Risk,Risk Factor,Risk Factor Score,Risk Factor, Social,Risk Factors, Social,Risk Score,Score, Risk,Score, Risk Factor,Social Risk Factor
D017668	Age of Onset	The age, developmental stage, or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual.	Age-at-Onset,Age at Onset,Onset Age
D055106	Genome-Wide Association Study	An analysis comparing the allele frequencies of all available (or a whole GENOME representative set of) polymorphic markers to identify gene candidates or quantitative trait loci associated with a specific organism trait or specific disease or condition.	Genome Wide Association Analysis,Genome Wide Association Study,GWA Study,Genome Wide Association Scan,Genome Wide Association Studies,Whole Genome Association Analysis,Whole Genome Association Study,Association Studies, Genome-Wide,Association Study, Genome-Wide,GWA Studies,Genome-Wide Association Studies,Studies, GWA,Studies, Genome-Wide Association,Study, GWA,Study, Genome-Wide Association
D020641	Polymorphism, Single Nucleotide	A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.	SNPs,Single Nucleotide Polymorphism,Nucleotide Polymorphism, Single,Nucleotide Polymorphisms, Single,Polymorphisms, Single Nucleotide,Single Nucleotide Polymorphisms