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

被引：98

作者：

Ikeda, Masashi ^{[1
]}

Takahashi, Atsushi ^{[2
,3
]}

Kamatanim, Yoichiro ^{[2
,4
]}

Momozawa, Yukihide ^{[5
]}

Saito, Takeo ^{[1
]}

Kondo, Kenji ^{[1
]}

Shimasaki, Ayu ^{[1
]}

Kawase, Kohei ^{[1
]}

Sakusabe, Takaya ^{[6
]}

Iwayama, Yoshimi ^{[7
]}

Toyota, Tomoko ^{[7
]}

Wakudas, Tomoyasu ^{[8
]}

Kikuchi, Mitsuru ^{[9
]}

Kanahara, Nobuhisa ^{[10
]}

Yamamori, Hidenaga ^{[11
]}

Yasuda, Yuka ^{[11
]}

Watanabe, Yuichiro ^{[12
]}

Hoya, Satoshi ^{[12
]}

Aleksic, Branko ^{[13
]}

Kushima, Itaru ^{[13
]}

Arai, Heii ^{[14
]}

Takaki, Manabu ^{[15
]}

Hattori, Kotaro ^{[16
]}

Kurrugi, Hiroshi ^{[15
]}

Okahisa, Yuko ^{[15
]}

Ohnuma, Tohru ^{[14
]}

Ozaki, Norio ^{[13
]}

Someya, Toshiyuki ^{[12
]}

Hashimotovs, Ryota ^{[17
,18
]}

Yoshikawa, Takeo ^{[7
]}

Kubo, Michiaki ^{[19
]}

Iwata, Nakao ^{[1
]}

机构：

[1] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 4701192, Japan

[2] RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan

[3] Natl Cerebral & Cardiovasc Ctr, Dept Genom Med, Res Inst, Osaka, Japan

[4] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan

[5] RIKEN, Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan

[6] Fujita Hlth Univ, Sch Hlth Sci, Fac Clin Engn, Toyoake, Aichi, Japan

[7] RIKEN, Ctr Brain Sci, Lab Mol Psychiat, Wako, Saitama, Japan

[8] Hamamatsu Univ Sch Med, Dept Psychiat, Hamamatsu, Shizuoka, Japan

[9] Kanazawa Univ, Res Ctr Child Mental Dev, Kanazawa, Ishikawa, Japan

[10] Chiba Univ, Grad Sch Med, Dept Psychiat, Chiba, Japan

[11] Osaka Univ, Grad Sch Med, Dept Psychiat, Suita, Osaka, Japan

[12] Niigata Univ, Grad Sch Med & Dent Sci, Dept Psychiat, Niigata, Japan

[13] Nagoya Univ, Grad Sch Med, Dept Psychiat, Nagoya, Aichi, Japan

[14] Juntendo Univ, Fac Med, Dept Psychiat, Tokyo, Japan

[15] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neuropsychiat, Okayama, Japan

[16] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mental Disorder Res, Tokyo, Japan

[17] Natl Ctr Neurol & Psychiat, Natl Inst Mental Hlth, Dept Pathol Mental Dis, Tokyo, Japan

[18] Osaka Univ, Suita, Osaka, Japan

[19] RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan

来源：

SCHIZOPHRENIA BULLETIN | 2019年 / 45卷 / 04期

基金：

日本学术振兴会;

关键词：

polygenic score; SLC38A; SPHKAP; CABP1; ACADS; GWAS; IDENTIFIES; 2; RISK LOCI; POLYGENICITY; INDIVIDUALS; GLUTAMATE; PROTEIN;

D O I：

10.1093/schbul/sby140

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

Genome-wide association studies (GWASs) have identified >1(M) 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 WAS' 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 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (P-best = 4.1 x 10(-10)), SLC38A3 (P-best = 5.7 x 10(-10)), and CABP1-ACADS (P-best = 9.8 x 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 x 10(-11)) and between SCZ and BD in the JPN population (P similar to 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 rho = 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, rho = 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.

引用

页码：824 / 834

页数：11

共 33 条

[11] Transport of L-Glutamine, L-Alanine, L-Arginine and L-Histidine by the Neuron-Specific Slc38a8 (SNAT8) in CNS [J].

Hagglund, Maria G. A. ;

Hellsten, Sofie V. ;

Bagchi, Sonchita ;

Philippot, Gaetan ;

Lofqvist, Erik ;

Nilsson, Victor C. O. ;

Almkvist, Ingrid ;

Karlsson, Edvin ;

Sreedharan, Smitha ;

Tafreshiha, Atieh ;

Fredriksson, Robert .

JOURNAL OF MOLECULAR BIOLOGY, 2015, 427 (06) :1495-1512

[12] Random-Effects Model Aimed at Discovering Associations in Meta-Analysis of Genome-wide Association Studies [J].

Han, Buhm ;

Eskin, Eleazar .

AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 88 (05) :586-598

[13] Glutamate and dopamine in schizophrenia: An update for the 21st century [J].

Howes, Oliver ;

McCutcheon, Rob ;

Stone, James .

JOURNAL OF PSYCHOPHARMACOLOGY, 2015, 29 (02) :97-115

[14] The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies [J].

Hu, Wei ;

MacDonald, Matthew L. ;

Elswick, Daniel E. ;

Sweet, Robert A. .

YEAR IN NEUROLOGY AND PSYCHIATRY, 2015, 1338 :38-57

[15] Identification of 15 genetic loci associated with risk of major depression in individuals of European descent [J].

Hyde, Craig L. ;

Nagle, Michael W. ;

Tian, Chao ;

Chen, Xing ;

Paciga, Sara A. ;

Wendland, Jens R. ;

Tung, Joyce Y. ;

Hinds, David A. ;

Perlis, Roy H. ;

Winslow, Ashley R. .

NATURE GENETICS, 2016, 48 (09) :1031-+

[16] A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder [J].

Ikeda, M. ;

Takahashi, A. ;

Kamatani, Y. ;

Okahisa, Y. ;

Kunugi, H. ;

Mori, N. ;

Sasaki, T. ;

Ohmori, T. ;

Okamoto, Y. ;

Kawasaki, H. ;

Shimodera, S. ;

Kato, T. ;

Yoneda, H. ;

Yoshimura, R. ;

Iyo, M. ;

Matsuda, K. ;

Akiyama, M. ;

Ashikawa, K. ;

Kashiwase, K. ;

Tokunaga, K. ;

Kondo, K. ;

Saito, T. ;

Shimasaki, A. ;

Kawase, K. ;

Kitajima, T. ;

Matsuo, K. ;

Itokawa, M. ;

Someya, T. ;

Inada, T. ;

Hashimoto, R. ;

Inoue, T. ;

Akiyama, K. ;

Tanii, H. ;

Arai, H. ;

Kanba, S. ;

Ozaki, N. ;

Kusumi, I. ;

Yoshikawa, T. ;

Kubo, M. ;

Iwata, N. .

MOLECULAR PSYCHIATRY, 2018, 23 (03) :639-647

[17] Genome-Wide Association Study of Schizophrenia in a Japanese Population [J].

Ikeda, Masashi ;

Aleksic, Branko ;

Kinoshita, Yoko ;

Okochi, Tomo ;

Kawashima, Kunihiro ;

Kushima, Itaru ;

Ito, Yoshihito ;

Nakamura, Yukako ;

Kishi, Taro ;

Okumura, Takenori ;

Fukuo, Yasuhisa ;

Williams, Hywel J. ;

Hamshere, Marian L. ;

Ivanov, Dobril ;

Inada, Toshiya ;

Suzuki, Michio ;

Hashimoto, Ryota ;

Ujike, Hiroshi ;

Takeda, Masatoshi ;

Craddock, Nick ;

Kaibuchi, Kozo ;

Owen, Michael J. ;

Ozaki, Norio ;

O'Donovan, Michael C. ;

Iwata, Nakao .

BIOLOGICAL PSYCHIATRY, 2011, 69 (05) :472-478

[18] Sphingosine Kinase Interacting Protein is an A-Kinase Anchoring Protein Specific for Type I cAMP-Dependent Protein Kinase [J].

Kovanich, Duangnapa ;

van der Heyden, Marcel A. G. ;

Aye, Thin Thin ;

van Veen, Toon A. B. ;

Heck, Albert J. R. ;

Scholten, Arjen .

CHEMBIOCHEM, 2010, 11 (07) :963-971

[19] Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs [J].

Lee, S. Hong ;

Ripke, Stephan ;

Neale, Benjamin M. ;

Faraone, Stephen V. ;

Purcell, Shaun M. ;

Perlis, Roy H. ;

Mowry, Bryan J. ;

Thapar, Anita ;

Goddard, Michael E. ;

Witte, John S. ;

Absher, Devin ;

Agartz, Ingrid ;

Akil, Huda ;

Amin, Farooq ;

Andreassen, Ole A. ;

Anjorin, Adebayo ;

Anney, Richard ;

Anttila, Verneri ;

Arking, Dan E. ;

Asherson, Philip ;

Azevedo, Maria H. ;

Backlund, Lena ;

Badner, Judith A. ;

Bailey, Anthony J. ;

Banaschewski, Tobias ;

Barchas, Jack D. ;

Barnes, Michael R. ;

Barrett, Thomas B. ;

Bass, Nicholas ;

Battaglia, Agatino ;

Bauer, Michael ;

Bayes, Monica ;

Bellivier, Frank ;

Bergen, Sarah E. ;

Berrettini, Wade ;

Betancur, Catalina ;

Bettecken, Thomas ;

Biederman, Joseph ;

Binder, Elisabeth B. ;

Black, Donald W. ;

Blackwood, Douglas H. R. ;

Bloss, Cinnamon S. ;

Boehnke, Michael ;

Boomsma, Dorret I. ;

Breen, Gerome ;

Breuer, Rene ;

Bruggeman, Richard ;

Cormican, Paul ;

Buccola, Nancy G. ;

Buitelaar, Jan K. .

NATURE GENETICS, 2013, 45 (09) :984-+

[20] MaCH: Using Sequence and Genotype Data to Estimate Haplotypes and Unobserved Genotypes [J].

Li, Yun ;

Willer, Cristen J. ;

Ding, Jun ;

Scheet, Paul ;

Abecasis, Goncalo R. .

GENETIC EPIDEMIOLOGY, 2010, 34 (08) :816-834

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