Communications Biology (Sep 2024)
Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration
- Shahzad Ahmad,
- Mohammad Aslam Imtiaz,
- Aniket Mishra,
- Ruiqi Wang,
- Marisol Herrera-Rivero,
- Joshua C. Bis,
- Myriam Fornage,
- Gennady Roshchupkin,
- Edith Hofer,
- Mark Logue,
- W. T. Longstreth,
- Rui Xia,
- Vincent Bouteloup,
- Thomas Mosley,
- Lenore J. Launer,
- Michael Khalil,
- Jens Kuhle,
- Robert A. Rissman,
- Genevieve Chene,
- Carole Dufouil,
- Luc Djoussé,
- Michael J. Lyons,
- Kenneth J. Mukamal,
- William S. Kremen,
- Carol E. Franz,
- Reinhold Schmidt,
- Stephanie Debette,
- Monique M. B. Breteler,
- Klaus Berger,
- Qiong Yang,
- Sudha Seshadri,
- N. Ahmad Aziz,
- Mohsen Ghanbari,
- M. Arfan Ikram
Affiliations
- Shahzad Ahmad
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040
- Mohammad Aslam Imtiaz
- Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99
- Aniket Mishra
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219
- Ruiqi Wang
- Boston University
- Marisol Herrera-Rivero
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster
- Joshua C. Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 1730 Minor Ave #1360
- Myriam Fornage
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 1825 Pressler Street Houston
- Gennady Roshchupkin
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040
- Edith Hofer
- Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Auenbruggerplatz 22
- Mark Logue
- National Center for PTSD, Behavioral Sciences Division at VA Boston Healthcare System, Boston, 150 South Huntington Avenue
- W. T. Longstreth
- Departments of Neurology and Epidemiology, University of Washington, Seattle, 3980 15th Ave NE Seattle
- Rui Xia
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 1825 Pressler Street Houston
- Vincent Bouteloup
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219
- Thomas Mosley
- MIND Center, University of Mississippi Medical Center, Jackson, 2500 North State Street
- Lenore J. Launer
- Laboratory of Epidemiology and Population Science, NIA Intramural Research Program, 251 Bayview Blvd
- Michael Khalil
- Department of Neurology, Medical University of Graz, Auenbruggerplatz 22
- Jens Kuhle
- Research Center for Clinical Neuroimmunology and Neuroscience University Hospital, Spitalstrasse 2
- Robert A. Rissman
- Department of Physiology and Neuroscience, Alzheimer’s Therapeutic Research Institute, Keck School of Medicine of the University of Southern California
- Genevieve Chene
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219
- Carole Dufouil
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219
- Luc Djoussé
- Brigham and Women’s Hospital, Harvard Medical School, Boston, 75 FRANCIS STREET, BOSTON MA 02115
- Michael J. Lyons
- Department of Psychological & Brain Sciences, Boston University, Boston, 64 Cummington Mall # 149
- Kenneth J. Mukamal
- Beth Israel Deaconess Medical Center, Harvard Medical School
- William S. Kremen
- Department of Psychiatry and Center for Behavior Genetics of Aging, University of California, San Diego
- Carol E. Franz
- Department of Psychiatry and Center for Behavior Genetics of Aging, University of California, San Diego
- Reinhold Schmidt
- Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Auenbruggerplatz 22
- Stephanie Debette
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219
- Monique M. B. Breteler
- Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99
- Klaus Berger
- Institute of Epidemiology and Social Medicine, University of Münster, Münster, Institut für Epidemiologie und Sozialmedizin Albert-Schweitzer-Campus 1, Gebäude D3 48149
- Qiong Yang
- Boston University
- Sudha Seshadri
- Boston University
- N. Ahmad Aziz
- Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99
- Mohsen Ghanbari
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040
- M. Arfan Ikram
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040
- DOI
- https://doi.org/10.1038/s42003-024-06804-3
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 12
Abstract
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.
