Abstract
Previous genome-wide association studies (GWAS) suggest that rs10489202 in the intron of MPC2 (mitochondrial pyruvate carrier 2) is a risk locus for schizophrenia in Han Chinese populations. To validate this discovery, we conducted a replication analysis in an independent case-control sample of Han Chinese ancestry (437 cases and 2031 controls), followed by a meta-analytic investigation in multiple East Asian samples. In the replication analysis, rs10489202 showed marginal association with schizophrenia (two-tailed P = 0.071, OR = 1.192 for T allele); in the meta-analysis using a total of 14,340 cases and 20,349 controls from ten East Asian samples, rs10489202 was genome-wide significantly associated with schizophrenia (two-tailed P = 3.39 × 10–10, OR = 1.161 for T allele, under the fixed-effect model). We then performed an explorative investigation of the association between this SNP and bipolar disorder, as well as a major depressive disorder, and the schizophrenia-predisposing allele was associated with an increased risk of major depressive disorder in East Asians (two-tailed P = 2.49 × 10–2, OR = 1.103 for T allele). Furthermore, expression quantitative trait loci (eQTL) analysis in lymphoblastoid cell lines from East Asian donors (N = 85 subjects) revealed that rs10489202 was specifically and significantly associated with the expression of TIPRL gene (P = 5.67 × 10–4). Taken together, our data add further support for the genetic involvement of this genomic locus in the susceptibility to schizophrenia in East Asian populations, and also provide preliminary evidence for the underlying molecular mechanisms.
Highlights
With ~0.70–1.10% prevalence worldwide and an estimated heritability of 80%1,2, schizophrenia has been recognized as an emerging public health issue
We examined the linkage disequilibrium (LD) pattern of common single-nucleotide polymorphisms (SNPs) in the MPC2 region in East Asian populations from the 1000-Human-Genomes dataset, and based on the Tagger procedure implemented in Haploview[15], we selected two additional representative tagging SNPs for the following analysis based on the LD structure (Figure S1)
Rs10489202 was nominally significant in a one-tailed test. These results support the contention that rs10489202 is a potential risk SNP for schizophrenia in East Asian populations, but further studies are still required
Summary
With ~0.70–1.10% prevalence worldwide and an estimated heritability of 80%1,2, schizophrenia has been recognized as an emerging public health issue. The genetic components of schizophrenia in East Asians (e.g., Chinese and Japanese), the cohort occupying more than 20% of the world populations, remain less understood. In 2011, two independent schizophrenia genome-wide association studies (GWAS) conducted in Han Chinese populations were published by Yue et al.[4] and Shi et al.[5], and they reported nine single-nucleotide polymorphisms (SNPs) showing genome-wide significant associations with this illness (see Table S1 for details). Two schizophrenia GWAS conducted by Yu et al.[6] and Li et al.[7] in larger sample sets (partially overlapped with those from Yue et al.[4] and Shi et al.5) have identified additional risk loci (see Table S2 for details).
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