Genome-wide Association Study Meta-analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Background: 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 and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders. Methods: To identify the genetic variations underlying blood NfL levels, we conducted an ancestry-specific meta-analyses of genome-wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African-American ancestry. In the post-GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD-regression, and genetic risk score (GRS) association analysis with neurological traits. Results: In the European ancestry GWAS meta-analysis, we identified two genome-wide significant (P < 5x10-8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African-American ancestry GWAS meta-analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta-analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer's disease(AD) (rg = 0.32, P = 1.74x10-6), total-tau (rg = 2.01, P = 1.03x10-6), amyloid-beta (A{beta}-40 (rg = 0.80, P = 6.92x10-6), and A{beta}-42 (rg = 1.03, P = 4.39x10-5). A higher genetic risk score based on NfL-associated genetic variants was also related to increased plasma levels of total-tau (P = 1.97x10-4), A{beta}-40 (P = 2.24x10-5), A{beta}-42 (P = 2.92x10-4) in the Rotterdam Study. Conclusion: This large-scale GWAS meta-analysis revealed multiple novel genetic loci of NFL levels in blood in participants from European and African-American ancestry. Significant genetic correlation of genes underlying NfL with AD, A{beta}-42, and total-tau may indicate a common underlying pathway of neurodegeneration.