Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect

• Published in: Schizophrenia bulletin Vol. 45; no. 4; pp. 824 - 834
• Main Authors: Ikeda, Masashi, Takahashi, Atsushi, Kamatani, Yoichiro, Momozawa, Yukihide, Saito, Takeo, Kondo, Kenji, Shimasaki, Ayu, Kawase, Kohei, Sakusabe, Takaya, Iwayama, Yoshimi, Toyota, Tomoko, Wakuda, Tomoyasu, Kikuchi, Mitsuru, Kanahara, Nobuhisa, Yamamori, Hidenaga, Yasuda, Yuka, Watanabe, Yuichiro, Hoya, Satoshi, Aleksic, Branko, Kushima, Itaru, Arai, Heii, Takaki, Manabu, Hattori, Kotaro, Kunugi, Hiroshi, Okahisa, Yuko, Ohnuma, Tohru, Ozaki, Norio, Someya, Toshiyuki, Hashimoto, Ryota, Yoshikawa, Takeo, Kubo, Michiaki, Iwata, Nakao
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 18-06-2019
• Subjects: Regular; SLC38A; GWAS; CABP1; SPHKAP; ACADS; polygenic score
• ISSN: 0586-7614; 1745-1701
• DOI: 10.1093/schbul/sby140

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 54479 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.