TY - JOUR
T1 - Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum
AU - Herrera-Rivero, M.
AU - Hofer, E.
AU - Maceski, A.
AU - Leppert, D.
AU - Benkert, P.
AU - Kuhle, J.
AU - Schmidt, R.
AU - Khalil, M.
AU - Wiendl, H.
AU - Stoll, M.
AU - Berger, K.
N1 - Funding Information:
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).
Funding Information:
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).
Publisher Copyright:
Copyright © 2023 Herrera-Rivero, Hofer, Maceski, Leppert, Benkert, Kuhle, Schmidt, Khalil, Wiendl, Stoll and Berger.
PY - 2023/3/8
Y1 - 2023/3/8
N2 - IntroductionThe 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. MethodsWe 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. ResultsOur discovery GWAS identified 12 genomic loci at the suggestive threshold ((p < 1 x 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. DiscussionOur 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.
AB - IntroductionThe 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. MethodsWe 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. ResultsOur discovery GWAS identified 12 genomic loci at the suggestive threshold ((p < 1 x 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. DiscussionOur 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.
KW - GWAS
KW - neurofilament light chain
KW - serum biomarkers
KW - neuropathology
KW - genetics
KW - DEFINITION
U2 - 10.3389/fneur.2023.1145737
DO - 10.3389/fneur.2023.1145737
M3 - Article
C2 - 36970523
SN - 1664-2295
VL - 14
JO - Frontiers in Neurology
JF - Frontiers in Neurology
IS - 1
M1 - 1145737
ER -