Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect

Masashi Ikeda, Atsushi Takahashi, Yoichiro Kamatani, Yukihide Momozawa, Takeo Saito, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Takaya Sakusabe, Yoshimi Iwayama, Tomoko Toyota, Tomoyasu Wakuda, Mitsuru Kikuchi, Nobuhisa Kanahara, Hidenaga Yamamori, Yuka Yasuda, Yuichiro Watanabe, Satoshi Hoya, Branko Aleksic, Itaru KushimaHeii Arai, Manabu Takaki, Kotaro Hattori, Hiroshi Kunugi, Yuko Okahisa, Tohru Ohnuma, Norio Ozaki, Toshiyuki Someya, Ryota Hashimoto, Takeo Yoshikawa, Michiaki Kubo, Nakao Iwata

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15 Citations (Scopus)

Abstract

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54 479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10−10), SLC38A3 (Pbest = 5.7 × 10−10), and CABP1-ACADS (Pbest = 9.8 × 10−9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10−11) and between SCZ and BD in the JPN population (P ~ 10−40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/ lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ “risk” effect is shared with other psychiatric disorders even across populations.

Original languageEnglish
Pages (from-to)824-834
Number of pages11
JournalSchizophrenia Bulletin
Volume45
Issue number4
DOIs
Publication statusPublished - 2019

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health

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    Ikeda, M., Takahashi, A., Kamatani, Y., Momozawa, Y., Saito, T., Kondo, K., Shimasaki, A., Kawase, K., Sakusabe, T., Iwayama, Y., Toyota, T., Wakuda, T., Kikuchi, M., Kanahara, N., Yamamori, H., Yasuda, Y., Watanabe, Y., Hoya, S., Aleksic, B., ... Iwata, N. (2019). Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect. Schizophrenia Bulletin, 45(4), 824-834. https://doi.org/10.1093/schbul/sby140