Association and functional study of ATP6V1D and GPHN gene polymorphisms with depression in Chinese population

Abstract

Background: Depression is a disease with a significant global social burden. Single nucleotide polymorphisms (SNPs) are correlated with the development of depression. This study investigates the relationship between polymorphisms in the GPHN and ATP6V1D gene promoter regions and susceptibility to depression in the Chinese population.

Aim: To provide new insights into identifying SNPs for predicting depression in the Chinese population.

Methods: We conducted a case-control study involving 555 individuals with depression and 509 healthy controls. GPHN rs8020095 and ATP6V1D rs3759755, rs10144417, rs2031564, and rs8016024 in the promoter region were genotyped using next-generation sequencing. Dual luciferase reporter genes were employed to assess the transcriptional activity of promoter regions for each SNP genotype, with transcription factors binding to each site predicted using the JASPAR database.

Results: Compared to healthy controls, the ATP6V1D promoter rs10144417 AG genotype (P = 0.015), rs3759755 AC/CC genotype (P = 0.036), and GPHN gene rs8020095 GA and AA genotypes (GA: P = 0.028, GG: P = 0.025) were significantly associated with a lower prevalence of depression. Linked disequilibria were present in five SNPs, with the AGATA haplotype frequency in patients significantly lower than in healthy subjects (P = 0.023). Luciferase activity of the rs3759755-A recombinant plasmid was significantly higher than that of the rs3759755-C recombinant plasmid (P = 0.026), and the rs8020095-A recombinant plasmid activity was significantly higher than that of the rs8020095-G recombinant plasmid (P = 0.001). Transcription factors orthodenticle homeobox 2, orthodenticle homeobox 1, forkhead box L1, NK homeobox 3-1, and nuclear factor, interleukin 3 regulated demonstrated binding affinity with rs3759755A > C and rs8020095A > G.

Conclusion: This study demonstrates that SNPs (rs3759755 and rs10144417) in the promoter region of the ATP6V1D and SNP (rs8020095) of GPHN are indeed associated with susceptibility to depression.

Keywords: ATP6V1D; Depression; GPHN; Genetic susceptibility; Single nucleotide polymorphism.

Figure 1

Schematic diagram of rs3759755, rs10144417, rs2031564, rs8020095 and rs8016024 loci, GPHN gene and ATP6V1D gene location. The two arrows in the figure represent transcription start sites for each of the two genes.

Figure 2

Linkage disequilibrium analysis of five single nucleotide polymorphisms loci.

Figure 3

Effect of polymorphisms on rs8020095 and rs3759755 promoter activity. A: The transcriptional activities of different haplotypes in the rs8020095 promoter region; B: Transcriptional activity of rs3759755 promoter with different haplotypes. ^aP < 0.05; ^bP < 0.01. Data are presented as mean ± SD.