Meta-analysis of data from the Psychiatric Genomics Consortium and additional samples supports association of CACNA1C with risk for schizophrenia

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Abstract

Recently, numerous genome-wide association studies (GWASs) have identified numerous risk loci for schizophrenia, but follow-up studies are still essential to confirm those results. Therefore, we followed up on top GWAS hits by genotyping implicated loci in additional schizophrenia family samples from our own collection. Five-hundred thirty-six Asian families (comprising 1633 members including 698 schizophrenics) were genotyped in this study. We analyzed 12 single nucleotide polymorphisms (SNPs) in strongly implicated candidate genes revealed by GWASs and their follow-up studies. We then used meta-analysis to combine our results with those of the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). In our newly genotyped samples, there were no significant associations of any of the 12 candidate SNPs with schizophrenia; however, all genome-wide significant results from the schizophrenia PGC analysis were maintained after combination with our new data by meta-analysis. One SNP (rs4765905 in CACNA1C) showed a stronger effect and decreased p-value (5.14e-17) after meta-analysis relative to the original PGC results, with no significant between-study heterogeneity. The findings of this study support the significant results in the PGC, especially for CACNA1C. The sample size in our study was considerably smaller than that in the PGC-SCZ study; thus, the weights carried by our samples in the meta-analysis were small. Therefore, our data could not vastly reduce PGC association signals. However, we considered that the well replicated results from the PGC hold up in our new samples, and may suggest that the top hits from the PGC are generalizable, even to other ancestral groups.

Introduction

Schizophrenia is a severe and common psychiatric disorder with a prevalence of approximately 1% (van Os et al., 2010). Many epidemiological studies have suggested a strong genetic component in the development of schizophrenia (Tsuang and Faraone, 1995, Tsuang, 2000). Its heritability is estimated at approximately 80% (Sullivan et al., 2003), and its mode of inheritance is multifactorial (Tsuang and Faraone, 1995).

Genome-wide association studies (GWASs) have been often performed to detect causal or risk-conferring genes for common and complex diseases in recent years (Manolio, 2010). For schizophrenia, several GWASs have been also published to date (O'Donovan et al., 2008, Sullivan et al., 2008, International Schizophrenia Consortium, 2009, Shi et al., 2009, Shi et al., 2011, Stefansson et al., 2009, Yue et al., 2011). Moreover, several of these GWASs have been followed-up by the Psychiatric Genomics Consortium (PGC) using additional large samples. To date, the PGC have reported three mega-analyses for the follow-up in schizophrenia (The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (SCZ-GWASC), 2011; Ripke et al., 2013, Schizophrenia Working Group of the Psychiatric Genomics Consortium (SCZ-PGC), 2014). A recent Schizophrenia PGC study conducted a mega-analysis using 36,989 cases and 113,075 controls. As a result, 128 significant genetic loci for schizophrenia were found (SCZ-PGC, 2014).

After GWAS, follow-up studies are essential to confirm the GWAS findings and extend them (for example, into samples of other ancestries). Thus, here we followed up top GWAS results by typing those variants in our own independent schizophrenia samples. We tested selected variants (see Supplementary Information, SNP collection methods) both independent of and in meta-analysis with the current schizophrenia PGC data.

Section snippets

Newly genotyped samples

Five-hundred thirty-six affected families (comprising 1633 members including 698 individuals with schizophrenia) were genotyped in this study. This sample consisted of 162 Chinese (Ch), 42 Japanese (Jp) and 332 Taiwanese (Tw) families.

The Ch and Jp families were recruited through Peking University (Beijing, China) and Nihon University Hospital along with five affiliated hospitals (Tokyo, Japan), respectively. After the purpose and procedures of the project were fully explained, written informed

SNP selection

Based on our criteria, the following 13 SNPs were chosen for follow-up: rs9295938 (MUC21), rs16977195 (AGBL1), rs2162361 (RNLS), rs2241785 (DOCK3) and rs2652007 (BICD1) from the seven original GWASs; rs2239547 (ITIH4), rs10503253 (CSMD1), rs2021722 (TRIM26), rs7914558 (CNNM2), rs11191580 (NT5C2) and rs4765905 (CACNA1C) from the 2011 PGC; and rs6703335 (SDCCAG8) and rs11819869 (AMBRA1) from the two GWAS follow-up papers (Supplementary Table 1). Genotyping of SNPs was successful except for

Discussion

In this study, we successfully analyzed 12 SNPs in some of the most important genes revealed by GWASs and their follow-up studies using 536 newly genotyped schizophrenia families. For the 12 SNPs, meta-analysis of the latest schizophrenia PGC data and our data was also performed. There were no significant associations of any SNPs with schizophrenia in our sample alone; however, although our data showed negative results, all genome-wide significant results observed in the current PGC dataset

Conflict of interest

All authors declare that they have no conflicts of interest.

Contributors

All authors designed the study; and Drs. Faraone SV and Tsuang MT supervised the study. Dr. Takahashi S and his genetic analyzing staff genotyped the DNA samples. Drs. Takahashi S, Glatt SJ and Faraone SV undertook the statistical analyses. All authors contributed to write the manuscript.

Funding body agreements and policies

This research was supported in part by grants from the Scientific Research on Priority Areas (C) of the Japanese Ministry of Education, Science, Sports and Culture of Japan, 23591683 (S. T.) and by grants from the U.S. National Institute of Mental Health, the Gerber Foundation, the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain and Behavior Research Foundation (S.J.G.).

Acknowledgments

The authors appreciate genotyping staffs of Department of Psychiatry, Nihon University, School of Medicine. The authors also appreciate staffs of the NIMH Repository and Genomics Resource, and the Rutgers University, RUCDR infinite Biologics. Moreover, the authors appreciate Dr. Yong-hua Han and Dr. Pan Chao that were main staffs collecting the DNA samples in Institute of Mental Health, Peking University. Finally, the authors appreciate published data on the PGC web site.

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