Common Variants on Xq28 Conferring Risk of Schizophrenia in Han Chinese

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.

The Sex Chromosome Hypothesis of Schizophrenia: Alive, Dead, or Forgotten? A Commentary and Review

“…Produces RHO GTPase-activating protein that plays a part in growth of axons and mobility of cells during embryonic development [40,48].…”

“…Crucial to the IL-1 receptor signaling pathway [40,49,50]. SRY Y May be involved in dopamine regulation [53].…”

“…DOI: 10.1159/000491489 have been associated with many neurodevelopmental disorders, including autism and schizophrenia [40][41][42]. It is also associated with decreased brain cortical area in at least 2 studies [43,44].…”

“…Of note, GABAergic dysfunction has been long thought to be involved in the pathogenesis of schizophrenia [46,47] [40,49,50]. IL-1β is also hypothesized to participate in immunological reactions involving infections in utero, which may then lead to deleterious effects on a developing neurological system [40,51]. 6.…”

FAPI: Fast and accurate P-value Imputation for genome-wide association study

“…To demonstrate that FAPI also works outside of simulated data, we also analyzed a previously published real in-house GWAS data set of schizophrenia 18 using FAPI. We performed the same quality-control procedure in this data set as in the simulated data.…”