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 Jr; 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

doi:10.1038/s42003-024-06804-3

Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Commun Biol. 2024 Sep 9;7(1):1103. doi: 10.1038/s42003-024-06804-3.

Authors

Shahzad Ahmad^#^{1

2}, Mohammad Aslam Imtiaz^#³, Aniket Mishra⁴, Ruiqi Wang⁵, Marisol Herrera-Rivero^{6

7}, Joshua C Bis⁸, Myriam Fornage⁹, Gennady Roshchupkin¹, Edith Hofer^{10

11}, Mark Logue^{12

13}, W T Longstreth Jr¹⁴, Rui Xia⁹, Vincent Bouteloup⁴, Thomas Mosley¹⁵, Lenore J Launer¹⁶, Michael Khalil¹⁷, Jens Kuhle¹⁸, Robert A Rissman¹⁹, Genevieve Chene⁴, Carole Dufouil⁴, Luc Djoussé²⁰, Michael J Lyons²¹, Kenneth J Mukamal²², William S Kremen²³, Carol E Franz²³, Reinhold Schmidt¹⁰, Stephanie Debette^{4

24}, Monique M B Breteler^{3

25}, Klaus Berger²⁶, Qiong Yang⁵, Sudha Seshadri^{5

27}, N Ahmad Aziz^{3

28}, Mohsen Ghanbari¹, M Arfan Ikram²⁹

Affiliations

¹ Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000, CA, Rotterdam, the Netherlands.
² Oxford-GSK Institute of Computational and Molecular Medicine (IMCM), Centre for Human Genetics, Nuffield Department of Medicine (NDM), University of Oxford, Oxford, OX3 7BN, UK.
³ Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany.
⁴ University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, F-33000, Bordeaux, France.
⁵ Boston University, Boston, MA, 02215, USA.
⁶ Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
⁷ Department of Psychiatry, University of Münster, Münster, Germany.
⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 1730 Minor Ave #1360, Seattle, WA, 98101, USA.
⁹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 1825 Pressler Street Houston, Houston, 77030, TX, USA.
¹⁰ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036, Graz, Austria.
¹¹ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Auenbruggerplatz 2, Fifth Floor, Graz, 8036, Austria.
¹² National Center for PTSD, Behavioral Sciences Division at VA Boston Healthcare System, Boston, 150 South Huntington Avenue, Boston, MA, 02130, USA.
¹³ Department of Psychiatry and Biomedical Genetics, Boston University School of Medicine, Boston, 72 East Concord Street E200, Boston, MA, 02118, USA.
¹⁴ Departments of Neurology and Epidemiology, University of Washington, Seattle, 3980 15th Ave NE Seattle, Seattle, WA, 98195, USA.
¹⁵ MIND Center, University of Mississippi Medical Center, Jackson, 2500 North State Street, Jackson, MS, 39216, USA.
¹⁶ Laboratory of Epidemiology and Population Science, NIA Intramural Research Program, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
¹⁷ Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036, Graz, Austria.
¹⁸ Research Center for Clinical Neuroimmunology and Neuroscience University Hospital, Spitalstrasse 2, CH-4031, Basel, Switzerland.
¹⁹ Department of Physiology and Neuroscience, Alzheimer's Therapeutic Research Institute, Keck School of Medicine of the University of Southern California, California, USA.
²⁰ Brigham and Women's Hospital, Harvard Medical School, Boston, 75 FRANCIS STREET, BOSTON MA 02115, MA, Boston, USA.
²¹ Department of Psychological & Brain Sciences, Boston University, Boston, 64 Cummington Mall # 149, Boston, MA, 02215, USA.
²² Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 330 Brookline Avenue Boston, MA, 02215, USA.
²³ Department of Psychiatry and Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, 92093, USA.
²⁴ CHU de Bordeaux, Department of Neurology, Institute for Neurodegenerative Diseases, F-33000, Bordeaux, France.
²⁵ Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
²⁶ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Institut für Epidemiologie und Sozialmedizin Albert-Schweitzer-Campus 1, Gebäude D3 48149, Münster, Germany.
²⁷ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA.
²⁸ Department of Neurology, Faculty of Medicine, University of Bonn, 53127, Bonn, Germany.
²⁹ Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000, CA, Rotterdam, the Netherlands. m.a.ikram@erasmusmc.nl.

^# Contributed equally.

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.

Publication types

Meta-Analysis

MeSH terms

Alzheimer Disease / blood
Alzheimer Disease / genetics
Biomarkers / blood
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Male
Neurodegenerative Diseases* / blood
Neurodegenerative Diseases* / genetics
Neurofilament Proteins* / blood
Neurofilament Proteins* / genetics
Polymorphism, Single Nucleotide

Substances

Neurofilament Proteins
neurofilament protein L
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding