Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum [Nachweis einer polygenen Regulierung des physiologischen Vorhandenseins der leichten Kette des Neurofilaments im menschlichen Serum]

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

Abstract

Neurofilament light chain (NfL) is a subunit of neurofilaments (NFs), cytoskeletal components found exclusively in neurons and particularly abundant in axons. NfL is a major component of the backbone of NFs in the central and peripheral nervous systems (1). Axonal damage and neuronal death due to neurological diseases, including those of inflammatory, neurodegenerative, traumatic and cerebrovascular nature, result in NfL release into the cerebrospinal fluid (CSF) and blood. Recent technological advances in immunoassay detection have enabled the accurate measurement of the small amounts of NfL that reach the circulation, facilitating its application as a universal peripheral biomarker of the presence and progression of neurological conditions, and of treatment responses (1–3). Therefore, investigating the factors that influence concentrations of NfL in the periphery becomes crucial for the interpretation of results. To date, it has been demonstrated that NfL serum levels (sNfL) increase with age (4) and potential confounding factors, such as body mass index and cardiovascular risk factors, have been suggested (5, 6). Studies in population-based cohorts have shown a polygenic nature of numerous health-related serum biomarkers, including alanine transaminase (liver function), fibrinogen (clot formation) and glycated hemoglobin (type 2 diabetes mellitus), among many others. These findings can provide novel biological insights and facilitate disease diagnosis and stratification (7). Nevertheless, to our knowledge, no genetic associations with sNfL have been investigated. We hypothesized that the identification of genetic factors that modulate sNfL in physiological conditions will help interpretation on an individual basis, consequently improving the clinical applications of sNfL as a biomarker. To test our hypothesis, we performed a genome-wide association study (GWAS) and meta-analysis of sNfL in a total of 2,186 individuals of European descent without known neurological conditions, and correlated our findings with clinical data to identify potential sources of sNfL variability.