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Association of ARHGAP 18 polymorphisms with schizophrenia in the Chinese-Han population

View Article: PubMed Central - PubMed

ABSTRACT

Numerous developmental genes have been linked to schizophrenia (SZ) by case-control and genome-wide association studies, suggesting that neurodevelopmental disturbances are major pathogenic mechanisms. However, no neurodevelopmental deficit has been definitively linked to SZ occurrence, likely due to disease heterogeneity and the differential effects of various gene variants across ethnicities. Hence, it is critical to examine linkages in specific ethnic populations, such as Han Chinese. The newly identified RhoGAP ARHGAP18 is likely involved in neurodevelopment through regulation of RhoA/C. Here we describe four single nucleotide polymorphisms (SNPs) in ARHGAP18 associated with SZ across a cohort of >2000 cases and controls from the Han population. Two SNPs, rs7758025 and rs9483050, displayed significant differences between case and control groups both in genotype (P = 0.0002 and P = 7.54×10−6) and allelic frequencies (P = 4.36×10−5 and P = 5.98×10−7), respectively. The AG haplotype in rs7758025−rs9385502 was strongly associated with the occurrence of SZ (P = 0.0012, OR = 0.67, 95% CI = 0.48–0.93), an association that still held following a 1000-times random permutation test (P = 0.022). In an independently collected validation cohort, rs9483050 was the SNP most strongly associated with SZ. In addition, the allelic frequencies of rs12197901 remained associated with SZ in the combined cohort (P = 0.021), although not in the validation cohort alone (P = 0.251). Collectively, our data suggest the ARHGAP18 may confer vulnerability to SZ in the Chinese Han population, providing additional evidence for the involvement of neurodevelopmental dysfunction in the pathogenesis of schizophrenia.

No MeSH data available.


LD structure and the D′ values for the 31 Single Nucleotide Polymorphisms (SNPs).
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pone.0175209.g001: LD structure and the D′ values for the 31 Single Nucleotide Polymorphisms (SNPs).

Mentions: We next performed LD analysis using pairs of SNPs to further analyze the haplotype structure. As shown in Fig 1, Table 2, the LD plot consisted of thrity-five SNPs. Haplotypes GG and GA in the LD block rs7758025−rs9385502 showed minimal difference between the case and control groups (P = 0.175 and P = 0.232, respectively), while haplotype AG was strongly associated with schizophrenia (P = 0.0012, OR = 0.67, 95% CI = 0.48−0.93). These associations remained following a 1000-times random permutation test (P = 0.022). Haplotype CG in the LD block rs11753915−rs9483050 was also associated with schizophrenia (P = 9.6×10−6, OR = 0.58, 95% CI = 0.44−0.78) even after Bonferroni correction (P = 0.0001).


Association of ARHGAP 18 polymorphisms with schizophrenia in the Chinese-Han population
LD structure and the D′ values for the 31 Single Nucleotide Polymorphisms (SNPs).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383423&req=5

pone.0175209.g001: LD structure and the D′ values for the 31 Single Nucleotide Polymorphisms (SNPs).
Mentions: We next performed LD analysis using pairs of SNPs to further analyze the haplotype structure. As shown in Fig 1, Table 2, the LD plot consisted of thrity-five SNPs. Haplotypes GG and GA in the LD block rs7758025−rs9385502 showed minimal difference between the case and control groups (P = 0.175 and P = 0.232, respectively), while haplotype AG was strongly associated with schizophrenia (P = 0.0012, OR = 0.67, 95% CI = 0.48−0.93). These associations remained following a 1000-times random permutation test (P = 0.022). Haplotype CG in the LD block rs11753915−rs9483050 was also associated with schizophrenia (P = 9.6×10−6, OR = 0.58, 95% CI = 0.44−0.78) even after Bonferroni correction (P = 0.0001).

View Article: PubMed Central - PubMed

ABSTRACT

Numerous developmental genes have been linked to schizophrenia (SZ) by case-control and genome-wide association studies, suggesting that neurodevelopmental disturbances are major pathogenic mechanisms. However, no neurodevelopmental deficit has been definitively linked to SZ occurrence, likely due to disease heterogeneity and the differential effects of various gene variants across ethnicities. Hence, it is critical to examine linkages in specific ethnic populations, such as Han Chinese. The newly identified RhoGAP ARHGAP18 is likely involved in neurodevelopment through regulation of RhoA/C. Here we describe four single nucleotide polymorphisms (SNPs) in ARHGAP18 associated with SZ across a cohort of >2000 cases and controls from the Han population. Two SNPs, rs7758025 and rs9483050, displayed significant differences between case and control groups both in genotype (P = 0.0002 and P = 7.54×10−6) and allelic frequencies (P = 4.36×10−5 and P = 5.98×10−7), respectively. The AG haplotype in rs7758025−rs9385502 was strongly associated with the occurrence of SZ (P = 0.0012, OR = 0.67, 95% CI = 0.48–0.93), an association that still held following a 1000-times random permutation test (P = 0.022). In an independently collected validation cohort, rs9483050 was the SNP most strongly associated with SZ. In addition, the allelic frequencies of rs12197901 remained associated with SZ in the combined cohort (P = 0.021), although not in the validation cohort alone (P = 0.251). Collectively, our data suggest the ARHGAP18 may confer vulnerability to SZ in the Chinese Han population, providing additional evidence for the involvement of neurodevelopmental dysfunction in the pathogenesis of schizophrenia.

No MeSH data available.