Genome-wide Association Study of Neurofilament Light Levels and Neurodegeneration: Key Insights
Neurofilament light chain (NfL) is emerging as a critical biomarker for neuro-axonal injury, detectable in blood and cerebrospinal fluid (CSF). Elevated levels of NfL indicate neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). The genetic basis of NfL could provide further insight into the molecular pathways underlying neurodegeneration. The article titled "Genome-wide Association Study Meta-analysis of Neurofilament Light (NfL) Levels in Blood Reveals Novel Loci Related to Neurodegeneration" presents a large-scale genome-wide association study (GWAS) aimed at uncovering genetic variants that influence NfL levels and their potential role in neurodegenerative diseases.
The Significance of Neurofilament Light (NfL)
NfL, a cytoskeletal protein found in neurons, helps maintain axonal structure and is released into circulation upon axonal damage. This makes NfL a biomarker for monitoring neurodegeneration across diseases such as AD, PD, Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and MS. Increased blood levels of NfL reflect neuro-axonal damage, with studies showing correlations between NfL levels in CSF and blood, facilitating its use in clinical settings.
Meta-analysis of GWAS: Key Findings
This meta-analysis incorporated data from eleven cohorts of European ancestry and three cohorts of African-American ancestry. The authors identified two significant loci associated with blood NfL levels in European populations—UMOD (16p12) and SLC39A11 (17q24). In participants of African-American ancestry, they identified loci at FMN2 (1q43), 12q14, and 12q21. A trans-ethnic analysis revealed additional loci, notably at 1p32 (FGGY) and 6q14 (TBX18).
UMOD and Kidney Function: The gene UMOD, primarily associated with kidney function, was identified as a locus linked to higher NfL levels. The study suggests a connection between decreased kidney function and elevated blood NfL levels, supported by Mendelian randomization (MR) analysis.
SLC39A11 and Neurodegeneration: Variants in the SLC39A11 gene, which regulates zinc homeostasis, have previously been implicated in ALS and PD. This study showed that a variant within this gene was significantly associated with NfL levels, possibly contributing to neurodegeneration through dysregulated zinc pathways.
Trans-ethnic Analysis: The trans-ethnic meta-analysis uncovered novel loci, including the FGGY gene, which has been linked to ALS in earlier studies. This locus emphasizes the importance of NfL in ALS disease progression and survival.
Polygenic Risk Scores and Alzheimer’s Disease
By analyzing polygenic risk scores (PRS) derived from the identified loci, the authors demonstrated a link between higher PRS for NfL and increased plasma levels of AD biomarkers, such as amyloid-beta (Aβ-40, Aβ-42) and total tau. This suggests shared molecular mechanisms between NfL levels and AD-related neurodegeneration.
The Role of Kidney Function in NfL Levels
One of the most intriguing findings was the potential causal relationship between kidney function and NfL levels. The lead variant in UMOD showed reduced significance when adjusted for kidney function, implying that decreased kidney function could elevate NfL levels in blood. This highlights the necessity of considering kidney function in NfL-related biomarker studies, particularly for diseases like AD and PD, where kidney function might impact neurodegenerative outcomes.
Loci Linked to Blood NfL Levels in African-American Populations
In African-American cohorts, the gene FMN2 was significantly associated with decreased NfL levels. FMN2 plays a role in synaptic plasticity and memory formation, suggesting that this gene may influence cognitive decline in neurodegenerative diseases. Moreover, this finding underscores the importance of studying diverse populations to uncover ancestry-specific genetic factors influencing NfL levels.
Conclusion
This large-scale GWAS meta-analysis offers new insights into the genetic underpinnings of blood NfL levels and their relevance to neurodegeneration. The identification of loci in UMOD and SLC39A11 genes links neurodegeneration with kidney function and zinc homeostasis, respectively. Furthermore, the study emphasizes the value of NfL as a biomarker not only for neurodegenerative diseases but also for understanding genetic risk factors across diverse populations. Future research could explore how these genetic variants contribute to specific pathways of neurodegeneration and potential therapeutic interventions.
References:
Ahmad, S., Imtiaz, M.A., Mishra, A. et al. Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration. Commun Biol 7, 1103 (2024).
