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 (transdiseases/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 (P best = 4.1 × 10 −10 ), SLC38A3 (P best = 5.7 × 10 −10 ), and CABP1-ACADS (P best = 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 (P best = 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, r g = 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.

Rare genomic variations inherited in multiplex schizophrenia families are suggested to play a role in the genetic etiology of the disease. To identify rare variations with large effects on the risk of developing schizophrenia, we performed whole-exome sequencing (WES) in two affected and one unaffected individual of a multiplex family with 10 affected individuals. We also performed follow-up resequencing of the unc-13 homolog B (Caenorhabditis elegans) (UNC13B) gene, a potential risk gene identified by WES, in the multiplex family and undertook a case-control study to investigate association between UNC13B and schizophrenia. UNC13B coding regions (39 exons) from 15 individuals of the multiplex family and 111 affected offspring for whom parental DNA samples were available were resequenced. Rare missense UNC13B variations identified by resequencing were further tested for association with schizophrenia in two independent case-control populations comprising a total of 1,753 patients and 1,602 controls. A rare missense variation (V1525M) in UNC13B was identified by WES in the multiplex family; this variation was present in five of six affected individuals, but not in eight unaffected individuals or one individual of unknown disease status. Resequencing UNC13B coding regions identified five rare missense variations (T103M, M813T, P1349T, I1362T, and V1525M). In the case-control study, there was no significant association between rare missense UNC13B variations and schizophrenia, although single-variant meta-analysis indicated that M813T was nominally associated with schizophrenia. These results do not support a contribution of rare missense UNC13B variations to the genetic etiology of schizophrenia in the Japanese population. © 2016 Wiley Periodicals, Inc.

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Our meta-analysis did not provide evidence supporting a contribution of CMYA5 rs3828611 and rs4704591 to schizophrenia susceptibility in Asian populations.

Rare variations contribute substantially to autism spectrum disorder (ASD) liability. We recently performed whole-exome sequencing in two families with affected siblings and then carried out a follow-up study and identified ceroid-lipofuscinosis neuronal 8 (epilepsy, progressive with mental retardation) (CLN8) as a potential genetic risk factor for ASD. To further investigate the role of CLN8 in the genetic etiology of ASD, we performed resequencing and association analysis of CLN8 with ASD in a Japanese population. Resequencing the CLN8 coding region in 256 ASD patients identified five rare missense variations: g.1719291G>A (R24H), rs201670636 (F39L), rs116605307 (R97H), rs143701028 (T108M) and rs138581191 (N152S). These variations were genotyped in 568 patients (including the resequenced 256 patients) and 1017 controls. However, no significant association between these variations and ASD was identified. This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population.