To conduct a genome-wide association study (GWAS) of CSF PGRN levels.

Progranulin (PGRN) deficiency has been associated with the development of multiple neurodegenerative diseases and cerebrospinal fluid (CSF) PGRN levels are potentially critical biomarkers for these diseases. The genetic modifiers might be different in CSF and blood.

Here we performed a two-stage GWAS to determine the potential genetic loci that may regulate the CSF PGRN levels, with an association to neurodegenerative diseases. We firstly evaluated genetic loci regulating CSF PGRN in non-demented elders (n = 432) from the well-established Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort and then validated our results in an independent Chinese cohort (n = 613).

We found that single nucleotide polymorphisms (SNPs) reaching the genome-wide significance level were located in FAM171A2, ITGA2B, and GRN. Bioinformatics analyses showed that their expression are highly correlated and are enriched in common pathways associated with cell-cell interactions, axonal transport, and signaling pathways (p < 0.005). As the top signal, the A allele of rs708384 (a transcription factor binding site) on FAM171A2 was significantly associated with lower CSF PGRN levels in a dose-dependent fashion (p = 3.95 ×10^-12). This association was confirmed in a Chinese cohort (p = 1.25 × 10^-5) and further strengthened by meta-analysis (p = 7.76 × 10^-15). Furthermore, the A allele of rs708384 was associated with increased risk for Alzheimer’s disease (p < 0.05), Parkinson’s disease (p = 1.42 × 10^-5), frontotemporal dementia (p < 0.05), poorer global cognition (p < 0.005), and higher levels of CSF tau (p < 0.05). In addition, the expression analyses indicated that rs708384 could influence expression of both GRN and FAM171A2 in brain.

Collectively, these findings suggested that a novel locus in FAM171A2 might be involved in neurodegenerative diseases by regulating CSF PGRN levels.