Meta-Analysis

. 2024 Sep 9;7(1):1103.

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

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.

PMID: 39251807
PMCID: PMC11385583
DOI: 10.1038/s42003-024-06804-3

Meta-Analysis

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

Shahzad Ahmad et al. Commun Biol. 2024.

. 2024 Sep 9;7(1):1103.

doi: 10.1038/s42003-024-06804-3.

Authors

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.

PMID: 39251807
PMCID: PMC11385583
DOI: 10.1038/s42003-024-06804-3

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Manhattan plots for the meta-analysis of genome-wide association study (GWAS) of the blood levels of neurofilament light (NfL).**
Manhattan plot based on GWAS meta-analysis of the European ancestry (A), African- American ancestry (B), and Trans-ethnic participants (C). The Observed associations of all tested genetic variants on autosomal chromosomes (X-axis) are displayed as –log10(*P values*) on the Y-axis. The red dotted horizontal line indicates a genome-wide significant association (P value < 5 × 10^–8) with NfL levels in blood.

**Fig. 2. Loci identified in the European ancestry.**
Regional plot for two genome-wide significant loci in the *UMOD* (A), and *SLC39A11* (B), and suggestive locus near *TMEM106B/VWDE* genes (C) identified in the meta- analysis of neurofilament light (NfL) genome-wide association study (GWAS) in European ancestry. The genetic variants are denoted as colored circles with their *P values* (-log10) on left Y-axis and genomic location is based on build 37 on X-axis. Lead SNPs (purple diamond) are marked with their genomic location. Recombination rates are plotted on right Y-axis to represent the local linkage disequilibrium (LD) structure. The LD between the genetic variants is provided with a color scale, ranging from blue (r2 = 0) to red (r2 = 1). LD calculations are based on 1000 genome, European ancestry.

**Fig. 3. Loci identified in the African-American ancestry.**
Regional plot for three loci in *FMN2* (A), intergenic region at 12q14 (B) and 12q21 (C) identified in the meta-analysis of neurofilament light (NfL) genome-wide association study (GWAS) in African-American ancestry. The genetic variants are denoted as colored circles with their P values (-log10) on the left Y-axis and genomic location is based on build 37 on the X-axis. Lead SNPs (purple diamond) are marked with their genomic location. Recombination rates are plotted on right Y-axis to represent the local linkage disequilibrium (LD) structure. The LD between the genetic variants is provided with a color scale, ranging from blue (r2 = 0) to red (r2 = 1). LD calculations are based on 1000 genome, African ancestry.

**Fig. 4. Mendelian Randomization and Colocalization analysis.**
Scatter plot of instrumental variable (SNPs) effect size estimates of kidney function (eGFR) on NfL in two sample Mendelian Randomization analysis (A), and Colocalization plot between *UMOD* locus and eGFR (kidney function) in European ancestry (B).

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References

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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