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. 2014 Jul;40(4):777-86.
doi: 10.1093/schbul/sbt104. Epub 2013 Sep 16.

Common Variants on Xq28 Conferring Risk of Schizophrenia in Han Chinese

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Free PMC article

Common Variants on Xq28 Conferring Risk of Schizophrenia in Han Chinese

Emily H M Wong et al. Schizophr Bull. .
Free PMC article

Abstract

Schizophrenia is a highly heritable, severe psychiatric disorder affecting approximately 1% of the world population. A substantial portion of heritability is still unexplained and the pathophysiology of schizophrenia remains to be elucidated. To identify more schizophrenia susceptibility loci, we performed a genome-wide association study (GWAS) on 498 patients with schizophrenia and 2025 controls from the Han Chinese population, and a follow-up study on 1027 cases and 1005 controls. In the follow-up study, we included 384 single nucleotide polymorphisms (SNPs) which were selected from the top hits in our GWAS (130 SNPs) and from previously implicated loci for schizophrenia based on the SZGene database, NHGRI GWAS Catalog, copy number variation studies, GWAS meta-analysis results from the international Psychiatric Genomics Consortium (PGC) and candidate genes from plausible biological pathways (254 SNPs). Within the chromosomal region Xq28, SNP rs2269372 in RENBP achieved genome-wide significance with a combined P value of 3.98 × 10(-8) (OR of allele A = 1.31). SNPs with suggestive P values were identified within 2 genes that have been previously implicated in schizophrenia, MECP2 (rs2734647, P combined = 8.78 × 10(-7), OR = 1.28; rs2239464, P combined = 6.71 × 10(-6), OR = 1.26) and ARHGAP4 (rs2269368, P combined = 4.74 × 10(-7), OR = 1.25). In addition, the patient sample in our follow-up study showed a significantly greater burden for pre-defined risk alleles based on the SNPs selected than the controls. This indicates the existence of schizophrenia susceptibility loci among the SNPs we selected. This also further supports multigenic inheritance in schizophrenia. Our findings identified a new schizophrenia susceptibility locus on Xq28, which harbor the genes RENBP, MECP2, and ARHGAP4.

Keywords: ARHGAP4; Han Chinese; MECP2; RENBP; genome-wide association study; schizophrenia.

Figures

Fig. 1.
Fig. 1.
Outline of our study design. In this project, we adopted a 2-stage study design, the preliminary discovery phase and a follow-up study. In the discovery phase, we performed a case-control genome-wide association study (GWAS) on schizophrenia by carrying out the single nucleotide polymorphism (SNP) and gene-based association tests. Significant genes defined according to the false discovery rate threshold 0.55 were identified. SNPs from the significant genes and top nongenic significant SNPs were selected for genotyping in the follow-up study. Apart from selecting SNP based on our GWAS results, we also included SNPs based on other schizophrenia research findings. In total, we genotyped 384 SNPs in the follow-up study. We then performed association tests on those successfully genotyped SNPs and risk allele burden tests across samples in the follow-up study. Finally, Our GWAS results and follow-up study results were combined as a meta-analysis on schizophrenia.
Fig. 2.
Fig. 2.
Regional plot of the associated locus on chromosome Xq28. Association results of our Han Chinese genome-wide association study on schizophrenia, together with recombination rates and genes within the 500kb region on Xq28, were plotted using LocusZoom. The index single nucleotide polymorphism (SNP) rs2269368 is represented by a diamond. The remaining SNPs within this region are labeled with different colors according to their linkage disequilibrium with the index SNP, based on the pair-wise r 2 values from HapMap phaseII JPT + CHB. Combined results of the 4 significant SNPs (ie, rs2269368, rs2269372, rs2734647, and rs2239464) are shown as P combined.
Fig. 3.
Fig. 3.
Histograms showing the risk allele burden of patients with schizophrenia (cases) and controls in the follow-up study. Risk allele burden is defined as the count of risk alleles across 358 successfully genotyped single nucleotide polymorphisms (SNPs) in each individual. Cases harbor significantly more risk alleles in the set of 358 SNPs (mean = 331.7) than controls (mean = 329.3) with a P value of 7.78×10−8 in the logistic regression test.

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