Faculty, Staff and Student Publications
Publication Date
9-9-2024
Journal
Communications Biology
Abstract
Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer's disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.
Keywords
Humans, Genome-Wide Association Study, Neurofilament Proteins, Neurodegenerative Diseases, Genetic Predisposition to Disease, Genetic Loci, Biomarkers, Polymorphism, Single Nucleotide, Male, Female, Alzheimer Disease
DOI
10.1038/s42003-024-06804-3
PMID
39251807
PMCID
PMC11385583
PubMedCentral® Posted Date
9-9-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Medical Genetics Commons, Nervous System Diseases Commons, Neurology Commons, Public Health Commons