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 Kushima; Heii Arai; Manabu Takaki; Kotaro Hattori; Hiroshi Kunugi; Yuko Okahisa; Tohru Ohnuma; Norio Ozaki; Toshiyuki Someya; Ryota Hashimoto; Takeo Yoshikawa; Michiaki Kubo; Nakao Iwata

doi:10.1093/schbul/sby140

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

Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.

Authors

Masashi Ikeda¹, Atsushi Takahashi^{2

3}, Yoichiro Kamatani^{2

4}, Yukihide Momozawa⁵, Takeo Saito¹, Kenji Kondo¹, Ayu Shimasaki¹, Kohei Kawase¹, Takaya Sakusabe⁶, Yoshimi Iwayama⁷, Tomoko Toyota⁷, Tomoyasu Wakuda⁸, Mitsuru Kikuchi⁹, Nobuhisa Kanahara¹⁰, Hidenaga Yamamori¹¹, Yuka Yasuda¹¹, Yuichiro Watanabe¹², Satoshi Hoya¹², Branko Aleksic¹³, Itaru Kushima¹³, Heii Arai¹⁴, Manabu Takaki¹⁵, Kotaro Hattori¹⁶, Hiroshi Kunugi¹⁶, Yuko Okahisa¹⁵, Tohru Ohnuma¹⁴, Norio Ozaki¹³, Toshiyuki Someya¹², Ryota Hashimoto^{17

18}, Takeo Yoshikawa⁷, Michiaki Kubo¹⁹, Nakao Iwata¹

Affiliations

¹ Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
² Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³ Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁴ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁵ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁶ Faculty of Clinical Engineering, Fujita Health University, School of Health Sciences, Toyoake, Japan.
⁷ Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan.
⁸ Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁹ Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan.
¹⁰ Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
¹¹ Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.
¹² Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
¹³ Department of Psychiatry, Nagoya University, Graduate School of Medicine, Nagoya, Japan.
¹⁴ Depearmtnt of Psychaitry, Juntendo University, Faculty of Medicine, Tokyo, Japan.
¹⁵ Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
¹⁶ Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁷ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁸ Osaka University, Suita, Japan.
¹⁹ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

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 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.

Keywords: ACADS; CABP1; SLC38A; SPHKAP; GWAS; polygenic score.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Asia, Eastern
Bipolar Disorder / genetics*
Datasets as Topic
Depressive Disorder, Major / genetics*
Europe
Female
Genetic Loci
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study*
Humans
Japan
Male
Middle Aged
Schizophrenia / genetics*