Herrera-Rivero Marisol, Hofer Edith, Maceski Aleksandra, Leppert David, Benkert Pascal, Kuhle Jens, Schmidt Reinhold, Khalil Michael, Wiendl Heinz, Stoll Monika, Berger Klaus
Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
Department of Neurology, Medical University of Graz, Graz, Austria.
Front Neurol. 2023 Mar 8;14:1145737. doi: 10.3389/fneur.2023.1145737. eCollection 2023.
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.
We performed a discovery genome-wide association study (GWAS) of sNfL in participants of the German BiDirect Study ( = 1,899). A secondary GWAS for meta-analysis was performed in a small Austrian cohort ( = 287). Results from the meta-analysis were investigated in relation with several clinical variables in BiDirect.
Our discovery GWAS identified 12 genomic loci at the suggestive threshold (( < 1 × 10). 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 (, and ) were suggested as genetic factors contributing to baseline sNfL levels.
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.
血液中神经丝轻链（NfL）的测量是神经损伤和疾病的一种很有前景的生物标志物。我们研究了无神经疾病个体血清NfL水平（sNfL）背后的遗传因素。
我们在德国BiDirect研究的参与者（n = 1899）中进行了一项关于sNfL的全基因组关联研究（GWAS）发现阶段。在一个小型奥地利队列（n = 287）中进行了用于荟萃分析的二次GWAS。在BiDirect研究中，对荟萃分析的结果与几个临床变量进行了关联研究。
我们的发现阶段GWAS在提示性阈值（P < 1×10）下鉴定出12个基因组位点。荟萃分析后，7个位点提示与sNfL存在关联。在BiDirect研究参与者中，观察到荟萃分析位点的先导变异（rs34523114、rs114956339、rs529938、rs73198093、rs34372929、rs10982883和rs1842909）在sNfL上存在基因型特异性差异。我们在荟萃分析位点中鉴定出与炎症和肾功能标志物的潜在关联。至少6个蛋白质编码基因（……）被认为是导致基线sNfL水平的遗传因素。
我们的研究结果表明，神经元过程、炎症、代谢和清除的多基因调控调节了循环中NfL的变异性。这些有助于以个性化方式解释sNfL测量结果。
