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Association Study of the KCNJ3 Gene As a Susceptibility Candidate for Schizophrenia in the Chinese Population

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Association Study of the KCNJ3 Gene As a Susceptibility Candidate for Schizophrenia in the Chinese Population Hum Genet (2012) 131:443–451 DOI 10.1007/s00439-011-1089-3 ORIGINAL INVESTIGATION Association study of the KCNJ3 gene as a susceptibility candidate for schizophrenia in the Chinese population Kazuo Yamada • Yoshimi Iwayama • Tomoko Toyota • Tetsuo Ohnishi • Hisako Ohba • Motoko Maekawa • Takeo Yoshikawa Received: 26 July 2011 / Accepted: 2 September 2011 / Published online: 17 September 2011 Ó The Author(s) 2011. This article is published with open access at Springerlink.com Abstract We recently reported the results of a genome- in postmortem brains from schizophrenic and bipolar wide association study (GWAS) of schizophrenia in the patients compared with controls. These data suggest that Japanese population. In that study, a single nucleotide the KCNJ3 gene is genetically associated with schizo- polymorphism (SNP) (rs3106653) in the KCNJ3 (potas- phrenia in Asian populations and add further evidence to sium inwardly rectifying channel, subfamily J, member 3) the ‘‘channelopathy theory of psychiatric illnesses’’. gene located at 2q24.1 showed association with schizo- phrenia in two independent sample sets. KCNJ3, also Abbreviations termed GIRK1 or Kir3.1, is a member of the G protein- GWAS Genome-wide association study activated inwardly rectifying K? channel (GIRK) group. SNP Single nucleotide polymorphism GIRKs are widely distributed in the brain and play an KCNJ3 Potassium inwardly rectifying channel, important role in regulating neural excitability through the subfamily J, member 3 activation of various G protein-coupled receptors. In this GIRK G protein-activated inwardly rectifying K? study, we set out to examine this association using a dif- channel ferent population. We first performed a gene-centric asso- GPCRs G protein-coupled receptors ciation study of the KCNJ3 gene, by genotyping 38 GABA c-Aminobutyric acid tagSNPs in the Chinese population. We detected nine SNPs PMI Postmortem interval that displayed significant association with schizophrenia LD Linkage disequilibrium (lowest P = 0.0016 for rs3106658, Global signifi- HWE Hardy–Weinberg equilibrium cance = 0.036). The initial marker SNP (rs3106653) SE Standard error examined in our prior GWAS in the Japanese population NMDA N-methyl-D-aspartate also showed nominally significant association in the Chi- nese population (P = 0.028). Next, we analyzed transcript levels in the dorsolateral prefrontal cortex of postmortem brains from patients with schizophrenia and bipolar disor- Introduction der and from healthy controls, using real-time quantitative RT-PCR. We found significantly lower KCNJ3 expression Schizophrenia is a highly heritable neurodevelopmental disorder, with a complex pathophysiology. It is thought that multiple susceptibility genes, each with a small effect, Electronic supplementary material The online version of this act in conjunction with epigenetic processes and environ- article (doi:10.1007/s00439-011-1089-3) contains supplementary material, which is available to authorized users. mental factors. Identifying these susceptibility genes is still challenging and the underlying mechanisms of disease K. Yamada (&) Á Y. Iwayama Á T. Toyota Á T. Ohnishi Á remain largely elusive. H. Ohba Á M. Maekawa Á T. Yoshikawa In a search for schizophrenia susceptibility genes, we Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan recently carried out a whole genome association survey and e-mail: [email protected] replication study, analyzing two sets of samples from 123 444 Hum Genet (2012) 131:443–451 Japanese cohorts. This approach revealed novel candidate Materials and methods genes associated with schizophrenia in the Japanese popu- lation (Yamada et al. 2011). Among the top hit signals in Samples the two-stage association analyses, the KCNJ3 gene drew special attention because several other genome-wide Chinese samples consisted of 293 pedigrees (1,163 sub- association studies (GWASs) (O’Donovan et al. 2009; Tam jects: 9 trios and 284 quads) collected by the NIMH ini- et al. 2010; Williams et al. 2011) and gene expression tiative (http://nimhgenetics.org/). studies (Arion and Lewis 2011; Bigos et al. 2010; Huffaker RNA from the dorsolateral prefrontal cortex (Brod- et al. 2009; Kalkman 2011) of schizophrenia and other mann’s area 46) was obtained from the Stanley Medical psychiatric illnesses have revealed a potential role in dis- Research Institute (http://sncid.stanleyresearch.org/) (Kim ease etiology for ion channel genes. Genes for calcium and Webster 2009, 2010). Brain samples were taken from 35 channel [CACNA1C: calcium channel, voltage-dependent, schizophrenics (26 males, 9 females; mean ± SD age, L type, alpha 1C subunit], potassium channels [KCNE1: 42.6 ± 8.5 years; postmortem interval (PMI), 31.4 ± potassium voltage-gated channel, Isk-related family, 15.5 h; brain pH, 6.5 ± 0.2), 35 bipolar disorder patients (17 member 1, KCNE2: potassium voltage-gated channel, males, 18 females; mean ± SD age, 45.3 ± 10.5 years; Isk-related family, member 2, KCNH2: potassium voltage- PMI, 37.9 ± 18.3 h; brain pH, 6.4 ± 0.3), and 35 controls gated channel, subfamily H (eag-related), member 2] and (26 males, 9 females; mean ± SD age, 44.2 ± 7.6 years; chloride transporters [NKCC1: sodium/potassium/chloride PMI, 29.4 ± 12.9 h; brain pH, 6.6 ± 0.3). Diagnoses were cotransporter 1, also known as SLC12A2 (solute carrier made in accordance with DSM-IV criteria. There were no family 12, member 2), KCC2: potassium/chloride co- significant demographic differences between the schizo- transporter 2, also known as SLC12A5 (solute carrier phrenia, bipolar disorder, and control brains, in terms of age, family 12, member 5)] have emerged from these studies. PMI, and sample pH. All the patients with schizophrenia and However, the role of the KCNJ3 gene in schizophrenia bipolar disorder had previously received therapeutic drugs to pathogenesis has not been evaluated so far. treat their disease. KCNJ3, also known as GIRK1/Kir3.1, belongs to the family of G protein-gated inwardly rectifying potassium Gene-centric association study (GIRK/Kir3) channels. GIRK channels play an important role in controlling neuronal excitability, by generating slow SNP information was based on the UCSC database inhibitory potentials, following the activation of G protein- (http://genome.ucsc.edu/). Using ldSelect software (Carlson coupled receptors (GPCRs). These GPCRs, are in turn et al. 2004), tag SNPs were selected according to the fol- stimulated by various neurotransmitters, such as dopamine, lowing criteria: alleles captured with r2 C 0.8 and minor serotonin, opioids and c-aminobutyric acid (GABA). The allele frequency (MAF) C 10% in the Han Chinese popu- involvement of these neurotransmitters and cognate GPCRs lation. In the gene-centric association study, SNP genotyping in schizophrenia has been suggested by multiple lines of was performed using the TaqMan system (Applied Biosys- evidence (Karam et al. 2010). GIRK channels are also tems, Foster City, CA, USA), following the manufacturer’s implicated in the pathophysiology of several other diseases, recommendation. PCR was performed using an ABI 9700 such as epilepsy, addiction, Down’s syndrome, ataxia and thermocycler, and fluorescent signals were analyzed on an Parkinson’s disease (Luscher and Slesinger 2010). There- ABI 7900HT Fast real-time PCR System using Sequence fore, it is tempting to speculate that any of these systems Detection Software (SDS) v2.3 (Applied Biosystems). related to GIRK channels may contribute to the psychiatric Linkage disequilibrium (LD) between markers and symptoms and cognitive defects seen in schizophrenia. departures from the assumption of Hardy–Weinberg equi- To corroborate the association of KCNJ3 with schizo- librium (HWE) were evaluated based on data from inde- phrenia in Asian populations, we examined the gene using pendent parents. the following approaches: (1) we performed gene-centric analyses using tag SNPs that span the entire KCNJ3 gene Brain tissue and quantitative RT-PCR region to achieve greater coverage of genetic variations; (2) we resequenced and analyzed the coding region of the Real-time quantitative RT-PCR analysis was conducted using gene; (3) we analyzed patient–parent pedigrees of Chinese an ABI7900HT Fast Real-Time PCR System (Applied Bio- descent, an ethnically similar but different population (Kim systems). TaqMan probes and primers for KCNJ3 and GAPDH et al. 2005; Tian et al. 2008); (4) we performed an (an internal control) were Assay-on-DemandTM or Assay-by- expression study of the gene using postmortem brains from DesignTM gene expression products (Applied Biosystems). All patients with schizophrenia and bipolar disorder and from real-time quantitative RT-PCR reactions were performed in controls. triplicate, based on the standard curve method. 123 Hum Genet (2012) 131:443–451 445 Resequencing analysis of KCNJ3 Table 1 SNP information dbSNPa Positionb Allelec P valued The exons of KCNJ3 were screened for genomic variants by direct sequencing of PCR products, using 58 unrelated rs4571015 155545670 G/T 0.0522 Chinese schizophrenia samples. Information on the primers rs3111037 155548559 A/C 0.0339 and conditions for amplification are available upon request. rs3106658 155568062 A/G 0.0016 Direct sequencing of PCR products was performed using rs11895478 155571123 C/T 0.0684 the BigDye Terminator Cycle Sequencing FS Ready rs3106653 155575560 A/C 0.0289 Reaction kit (Applied Biosystems) and the ABI PRISM rs3106652 155578422 C/T 0.2100
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