Frontiers in Neurology (Mar 2023)

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

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

DOI
https://doi.org/10.3389/fneur.2023.1145737
Journal volume & issue
Vol. 14

Abstract

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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 × 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.

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