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