Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum

Marisol Herrera-Rivero; Edith Hofer; Aleksandra Maceski; David Leppert; Pascal Benkert; Jens Kuhle; Reinhold Schmidt; Michael Khalil; Heinz Wiendl; Monika Stoll; Klaus Berger

doi:10.3389/fneur.2023.1145737

Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum

Front Neurol. 2023 Mar 8:14:1145737. doi: 10.3389/fneur.2023.1145737. eCollection 2023.

Authors

Marisol Herrera-Rivero¹, Edith Hofer^{2

3}, Aleksandra Maceski⁴, David Leppert⁴, Pascal Benkert⁵, Jens Kuhle⁴, Reinhold Schmidt², Michael Khalil², Heinz Wiendl⁶, Monika Stoll^{1

7}, Klaus Berger⁸

Affiliations

¹ Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
² Department of Neurology, Medical University of Graz, Graz, Austria.
³ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
⁴ Neurologic Clinic and Polyclinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital of Basel, Basel, Switzerland.
⁵ Clinical Trial Unit, Department of Clinical Research, University Hospital of Basel, Basel, Switzerland.
⁶ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
⁷ Department of Biochemistry, Genetic Epidemiology and Statistical Genetics, Maastricht University, Maastricht, Netherlands.
⁸ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

Abstract

Introduction: The measurement of neurofilament light chain (NfL) in blood is a promising biomarker of neurological injury and disease. We investigated the genetic factors that underlie serum NfL levels (sNfL) of individuals without neurological conditions.

Methods: We performed a discovery genome-wide association study (GWAS) of sNfL in participants of the German BiDirect Study (N = 1,899). A secondary GWAS for meta-analysis was performed in a small Austrian cohort (N = 287). Results from the meta-analysis were investigated in relation with several clinical variables in BiDirect.

Results: Our discovery GWAS identified 12 genomic loci at the suggestive threshold ((p < 1 × 10^-5). After meta-analysis, 7 loci were suggestive of an association with sNfL. Genotype-specific differences in sNfL were observed for the lead variants of meta-analysis loci (rs34523114, rs114956339, rs529938, rs73198093, rs34372929, rs10982883, and rs1842909) in BiDirect participants. We identified potential associations in meta-analysis loci with markers of inflammation and renal function. At least 6 protein-coding genes (ACTG2, TPRKB, DMXL1, COL23A1, NAT1, and RIMS2) were suggested as genetic factors contributing to baseline sNfL levels.

Discussion: Our findings suggest that polygenic regulation of neuronal processes, inflammation, metabolism and clearance modulate the variability of NfL in the circulation. These could aid in the interpretation of sNfL measurements in a personalized manner.

Keywords: GWAS; genetics; neurofilament light chain; neuropathology; serum biomarkers.

Grants and funding

ASPS-Fam was funded by the Austrian Science Fund (FWF, grant number PI904). The Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft support the ASPS-Fam databank. The BiDirect Study was funded by the German Federal Ministry of Education and Research (BMBF, grant numbers FKZ-01ER0816 and -01ER1506).