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. 2020 Oct 21;6(43):eabb3063.
doi: 10.1126/sciadv.abb3063. Print 2020 Oct.

The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

Wei Xu  1   2 , Si-Da Han  1 , Can Zhang  3 , Jie-Qiong Li  4 , Yan-Jiang Wang  5 , Chen-Chen Tan  2 , Hong-Qi Li  1 , Qiang Dong  1 , Cui Mei  1 , Lan Tan  2 , Jin-Tai Yu  6
Affiliations

The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

Wei Xu et al. Sci Adv. .

Abstract

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10-12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer's disease, Parkinson's disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

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Figures

Fig. 1
Fig. 1. GWAS results and regional plots for associations with CSF PGRN levels.
(A) Manhattan plots [showing the −log10 (P value) for individual SNP] and q-q plot. (B) Association results after permutation test. EMP1, empiric P value; EMP2, permutation-based corrected empiric family-wise error rate. (C) Regional association results for the GRN-FAM171A2-ITGA2B region. (D) Regional association results after controlling for rs708384.
Fig. 2
Fig. 2. CSF PGRN levels as a function of rs708384 genotype in two samples.
(A) The minor allele (A allele, MAF = 0.41) of rs708384 was significantly associated with lower CSF levels of PGRN in a dose-dependent manner. (B) CSF PGRN levels were compared across the AA, AC, and CC genotypes of rs708384 in a larger independent cohort of 930 nondemented Chinese participants to validate the initial observed top signal. A significant association of decreasing CSF PGRN levels with increased minor allele (A) dose of rs708384 was observed, independent of age, gender, education, APOE ε4 genotype, MMSE score at baseline, CV, and rs5848 genotype.
Fig. 3
Fig. 3. Variability in CSF PGRN levels explained by genetic variants.
(A) Chromosome 17 explained approximately 17.4% of the variability in the CSF levels of PGRN. (B) Most of the significant loci were in LD with rs708384. (C) SNPs in the GRN region explained the most but not all of the variability in CSF PGRN. Analysis of FAM171A2 and ITGA2B region showed that these two regions explained 9.1 and 5.6% of the variability in CSF levels of PGRN, respectively. rs708384 was shown to explain 9.1% of the variability. (D) rs5848 was only in low-to-moderate LD with rs708384 in CEU population (r2 = 0.6), and no loci were in LD with rs5848. Nonetheless, rs5848 was in high LD with rs708384 in CHB population (r2 ≈ 0.8).
Fig. 4
Fig. 4. GO and pathway analysis.
(A) Functional categories were identified that were significantly enriched (P < 0.001), primarily including those involving regulation of nervous system development, molecular transport, signal transduction, cell-cell adhesion, and response to stimuli. GTPase, guanosine triphosphatase. (B) Four clusters were identified in the gene network analysis. The most significant genes (FAM171A2 and GRN) were clustered together. (C) The highest z-scores were achieved by FAM171A2 and GRN. z-score was used by GeneNetwork Assisted Diagnostic Optimization to prioritize the candidate genes: Gene with a higher z-score is more likely to explain the phenotype.
Fig. 5
Fig. 5. FAM171A2 high expression on cerebral vascular endothelium and microglia.
(A and B) The IHC staining of FAM171A2 on mouse cortex and hippocampi. The DAB staining along and around the cerebral vascular (A1 and B1) was marked by tilted arrows. The DAB staining on the cells in a similar form of microglia (A2 and B2) was marked by horizontal arrows. (C and D) The IF staining of FAM171A2 with the CD31 and IBA1 antibodies on mouse cortex and hippocampus. Their colocalization was marked by “*” and “#.” n = 5 mice in these experiments.
Fig. 6
Fig. 6. rs708384 stimulates FAM171A2 expression and subsequently inhibits GRN/PGRN level.
(A) The structure of firefly luciferase reporter plasmid. The sequence containing rs708384 was labeled by a red square. (B) The plasmids with or without rs708384 (c > a), including the empty control, had different expressing levels of firefly luciferase after transfection into the HEK293 cells. The luminous intensity was calibrated by Renilla luciferase, and the result was presented by ratio of firefly/Renilla luciferase. n = 4 per group, the data were analyzed by the one-way analysis of variance (ANOVA) (P < 0.0001) followed by the Tukey post hoc test (P = 0.0002 c > a versus wild type). (C and D) The change of intracellular GRN after FAM171A2 overexpression. n = 5 per group, the data were analyzed by t test (P = 0.0002). (E) The change of the supernatant PGRN levels by FAM171A2 overexpression (OE). n = 5 per group, the data were analyzed by t test (P < 0.0001).
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