Genome‐wide Association Study Meta‐analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration
Year: 2023
Type: article
Study design: Observational Study
Abstract: 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. Method 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. Result In the European ancestry GWAS meta‐analysis, we identified two genome‐wide significant (P< 5×10−8) 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 = 1.74×10−6), total‐tau (rg = 2.01, P = 1.03×10−6), amyloid‐beta (Aβ)‐40 (rg = 0.80, P = 6.92×10−6),and Aβ‐42 (rg = 1.03, P = 4.39×10−5). A higher genetic risk score based on NfL‐associated genetic variants was also related to increased plasma levels of total‐tau (P = 1.97×10−4), Aβ‐ 40 (P = 2.24×10−5), Aβ‐42 (P = 2.92×10−4) 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, Aβ‐42, and total‐tau may indicate a common underlying pathway of neurodegeneration.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.073349
Authors: Shahzad Ahmad, Mohammed Aslam Imtiaz, Aniket Mishra, Ruiqi Wang, Marisol Herrera‐ Rivero, Joshua C Bis, Myriam Fornage, Gennady V. Roshchupkin, Edith Hofer, Mark W. Logue, W.T. Longstreth, Rui Xia, Vincent Bouteloup, Thomas H. Mosley, Lenore J J. Launer, Michael Khalil, Jens Kuhle, Robert A Rissman, Geneviève Chêne, Carole Dufouil, Luc Djoussé, Michael J. Lyons, Kenneth J Mukamal, William Seth Stone, Carol E Franz, Reinhold Schmidt, Stéphanie Debette, Monique M.B. Breteler, Klaus Berger, Qiong Yang, Sudha Seshadri, N. Ahmad Aziz, Mohsen Ghanbari, M. Arfan Ikram
Institutions: Leiden University, Erasmus MC, German Center for Neurodegenerative Diseases, Université de Bordeaux, Boston University, University of Münster, University of Washington, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Medical University of Graz, VA Boston Healthcare System, Inserm, Bordeaux Population Health, University of Mississippi Medical Center, National Institute on Aging, University Hospital of Basel, University of California San Diego, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, University of Bonn, Institut für Medizinische Biometrie, Informatik und Epidemiologie
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4390198745