A functional missense variant in ITIH3 affects protein expression and neurodevelopment and confers schizophrenia risk in the Han Chinese population
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Abstract: The Psychiatric Genomics Consortium (PGC) has recently identified 10 potential functional coding variants for schizophrenia. However, how these coding variants confer schizophrenia risk remains largely unknown. Here, we investigate the associations between eight potential functional coding variants identified by PGC and schizophrenia in a large Han Chinese sample (n = 4022 cases and 9270 controls). Among the eight tested single nucelotide polymorphisms (SNPs), rs3617 (a missense variant, p.K315Q in the ITIH3 gene) showed genome-wide significant association with schizophrenia in the Han Chinese population (P = 8.36 × 10−16), with the same risk allele as in PGC. Interestingly, rs3617 is located in a genomic region that is highly evolutionarily conserved, and its schizophrenia risk allele (C allele) was associated with lower ITIH3 mRNA and protein expression. Intriguingly, mouse neural stem cells stably overexpressing ITIH3 with different alleles of rs3617 exhibited significant differences in proliferation, migration, and differentiation, suggesting the impact of rs3617 on neurodevelopment. Subsequent transcriptome analysis found that the differentially expressed genes in neural stem cells stably overexpressing different alleles of rs3617 were significantly enriched in schizophrenia-related pathways, including cell adhesion, synapse assembly, MAPK and PI3K-AKT pathways. Our study provides convergent lines of evidence suggesting that rs3617 in ITIH3 likely affects protein function and neurodevelopment and thereby confers risk of schizophrenia.
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Key words:
- Schizophrenia /
- ITIH3 /
- Missense variant /
- Association /
- Neurodevelopment /
- Neural stem cells
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Fig. 1. rs3617 is located in an evolutionarily highly conserved region. A: Gene structure of ITIH3 and the location of rs3617. Single Nucleotide Polymorphism (SNP) rs3617 is located in the exon 9 of ITIH3 gene. B: SNP rs3617 is located in the vWFA domain. The C allele (risk allele) of rs3617 encodes glutamine, whereas the A allele encodes lysine. C: SNP rs3617 is located in an evolutionarily highly conserved region. The amino acid at the rs3617 site is lysine in most species. However, a new amino acid (glutamine) has emerged in humans. D and E: 3D structure prediction of ITIH3 protein using the SWISS-MODEL website. The locations of amino acids (lysine and glutamine) encoded by different alleles of rs3617 are shown (arrowheads). vWFA, von Willebrand factor type A; VIT, vault protein inter-alpha-trypsin.
Fig. 2. The C allele of rs3617 is associated with lower ITIH3 protein expression. A: ITIH3 expression vectors (2.5 μg) containing C (pEGFP-ITIH3-C) and A (pEGFP-ITIH3-A allele) alleles of rs3617 were transiently transfected into HEK293 cells. Western blotting (WB) was used to quantify ITIH3 protein expression, and actin was used as an internal control. The normalized ITIH3 expression values (GFP/actin) were compared to test if different alleles of rs3617 affected ITIH3 expression. Total proteins were collected at three time points (24, 48, and 72 h) after transfection, and WB was performed. B‒D: Quantification results of ITIH3 expression at 24 h (B), 48 h (C) and 72 h (D) after transfection. Data are represented as mean ± SD, andP values were calculated using two-tailed Student's t-test, n = 6. E: ITIH3 expression vectors containing different alleles of rs3617 were constructed and Flag was fused to the N-terminus of the ITIH3 coding sequence. The constructed expression vectors (2.5 μg) were transfected into HEK293 cells. Forty-eight hours after transfection, total protein was extracted, and ITIH3 expression was quantified. WB showed that the C allele of rs3617 was associated with lower ITIH3 protein expression. F: Quantification of the WB results shown in E. Data are represented as mean ± SD, and P values were calculated using two-tailed Student's t-test, n= 3. G: Proteins of mNSCs stably overexpressing different alleles of rs3617 were extracted, and WB showed that the C allele of rs3617 was associated with lower ITIH3 protein expression in mNSCs. H: Quantification of the WB results shown in G, n = 3. ∗, P < 0.05; ∗∗∗,P < 0.001. SD, standard deviation; mNSC, mouse neural stem cell.
Fig. 3. The mNSCs stably transfected with different alleles of rs3617 exhibited significant differences in proliferation. A–E: Isolation and characterization of the mNSCs. Immunofluorescence staining with three well-characterized NSC markers (PAX6, NESTIN, and SOX2) confirmed that the cells isolated were NSCs. F: BrdU incorporation assay showed that NSCs stably transfected with the rs3617 C allele had significantly higher proliferation rates than those transfected with the rs3617 A allele. G: The quantified results of the BrdU incorporation assay. H: CCK-8 assay revealed that NSCs stably transfected with the C allele had higher proliferation rates.I: HEK293 cells transiently transfected with the C allele had significantly higher proliferation rates than cells transfected with the A allele. J: Quantified results of the BrdU incorporation assay in I. K: CCK-8 assay revealed that HEK293 cells transiently transfected with ITIH3 expression vector containing the C allele of rs3617 had higher proliferation rates than cells containing the A allele. Data are represented as mean ± SD, and P values are calculated using two-tailed Student's t-test; n = 3 and a total of 10 randomly selected immunostaining images were used for cell counting for G; n = 5 for H; n = 3 and a total of six immunostaining images were used for cell counting for J; n = 5 for K. ∗, P < 0.05; ∗∗,P < 0.01; ∗∗∗,P < 0.001. mNSC, mouse neural stem cell; SD, standard deviation; BrdU, 5-bromo-2-deoxyuridine; CCK-8, Cell Counting Kit-8.
Fig. 4. NSCs stably transfected with different alleles of rs3617 exhibited significant differences in migration. A: Representative photographs for the migration assay. Neurospheres with similar diameters were selected and seeded into laminin-coated 24-well plates. After culturing neurospheres in the differentiation medium for 24 h, the migration distances of neurospheres were measured by subtracting the radius of the original neurosphere from the radius of the neurosphere at 24 h. B: Quantified results of the migration assay in A. Data are represented as mean ± SD, and P value was calculated using two-tailed Student's t-test; 5 independent neurospheres were analyzed for each group. Scale bar represents 500 μm in A. ∗, P < 0.05. NSC, neural stem cell; SD, standard deviation.
Fig. 5. The mNSCs stably transfected with different alleles of rs3617 exhibited significant differences in differentiation. A: Differentiation of mNSCs stably transfected with either the C or A allele of rs3617 into astrocytes. Representative immunostaining for GFAP, a marker for astrocytes. B: The quantification of results in A. Compared with mNSCs stably transfected with the A allele of rs3716, the differentiation of cells stably transfected with the rs3617 C allele into astrocytes (GFAP-positive) was significantly impaired. C: Differentiation of mNSCs into mature neurons. Representative immunostaining images for MAP2, a marker for mature neurons. D: The quantified results in C. Compared with mNSCs stably transfected with the A allele of rs3716, the differentiation of mNSCs stably expressing the rs3617 C allele into neurons (MAP2positive) was significantly increased. E and F: Representative immunostaining images ( E) and corresponding quantification ( F) of immature postmitotic neurons which are TUJ1 positive. Data are represented as mean ± SD, and P values were calculated using two-tailed Student's t-test, n = 3 and a total of 11 immunostaining images were used for cell counting for B; n = 3 and a total of 15 immunostaining images were used for cell counting for D; n = 3 and a total of 15 immunostaining images were used for cell counting for F. Scale bar represents 50 μm in A, C, and E. ∗∗, P < 0.01, ∗∗∗,P < 0.001. mNSC, mouse neural stem cell; SD, standard deviation.
Fig. 6. Transcriptome analysis revealed differentially expressed genes between mNSCs stably transfected with the C and A allele of rs3617. A: Expression heat map showing the differentially expressed genes (n = 669) between mNSCs stably transfected with the C and A allele of rs3617. B: The top 30 genes showing the most significant expression differences. C‒G: Quantitative PCR (qPCR) validation of RNA-Seq results. Genes marked with red color in B were selected for qPCR verification. These genes included Peg10 (C), Sgce (D), Dbx2 (E), Rasgrp3 (F) and Syt1 (G). Data are represented as mean ± SD, and P values were calculated using two-tailed Student's t-test. Average results of three independent biological replicates are presented (three technical replicates for each biological replicate). ∗, P < 0.05; ∗∗,P < 0.01; ∗∗∗,P < 0.001.H: Gene Ontology (GO) analysis for differentially expressed genes identified by RNA-Seq. The differentially expressed genes were significantly enriched in neurodevelopment-related pathways, including cell adhesion, synapse organization, cell migration, and gliogenesis. I: KEGG analysis for differentially expressed genes identified by RNA-Seq. The differentially expressed genes were significantly enriched in MAPK, ECM-receptor interaction, adhesion, and PI3K-AKT signaling pathways. mNSC, mouse neural stem cell; RNA-Seq, RNA sequencing; KEGG, Kyoto Encyclopedia of Genes and Genomes; SD, standard deviation.
Fig. 7. The working model of rs3617 in schizophrenia pathogenesis. The schizophrenia risk C allele of rs3617 downregulates ITIH3 expression. Lower ITIH3 expression promotes proliferation of NSCs but inhibits their migration. Lower ITIH3 expression promotes differentiation of NSCs into glial cells but inhibits their differentiation into neurons. Single Nucleotide Polymorphism (SNP) rs3617 also alters schizophrenia-associated pathways. These results together suggest that rs3617 may confer risk of schizophrenia by affecting neurodevelopment. NSC, neural stem cell.
Table 1. Association significance between the eight nonsynonymous coding SNPs and schizophrenia in the Chinese population.
SNP CHR:BP Gene A1/A2a Amino acid changeb Freq_Casesc Freq_Controlsd ORe P rs3176443 1:177247854 FAM5B G/C V390L 0.172 0.174 0.987 7.15E-01 rs3617 3:52833805 ITIH3 A/C K315Q 0.393 0.446 0.803 8.36E-16 rs3774729 3:63982082 ATXN7 G/A M862V 0.502 0.486 1.067 1.48E-02 rs950169 15:84706461 ADAMTSL3 T/C I1660T 0.062 0.064 0.978 6.80E-01 rs4584886 17:17896205 LRRC48 C/T R191W 0.126 0.129 0.971 4.68E-01 rs2288920 19:50091798 PRRG2 T/G C116G 0.198 0.208 0.943 7.82E-02 rs20551 22:41548008 EP300 G/A V997I 0.080 0.075 1.070 1.74E-01 rs133335 22:42416056 WBP2NL A/G D121G 0.153 0.162 0.935 6.98E-02 aA1/A2 represents the minor allele/major allele of each SNP. bAmino acid change means different alleles encode different amino acids. cFreq_Cases is the frequency of A1 allele in cases. dFreq_Controls is the frequency of A1 allele in controls. eOR (odds ratio) was based on A1 allele. 
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