Novel hypothesis for pathophysiology of schizophrenia based on its genetic architectures

• Project/Area Number: 16H05378
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Fujita Health University
• Principal Investigator: Iwata Nakao 藤田医科大学, 医学部, 教授 (60312112)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2018: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
• Keywords: 精神科遺伝学 / 精神医学 / ゲノム / 遺伝学 / 精神科 / 精神神経科学

Outline of Final Research Achievements

Genetic architecture of schizophrenia remains largely unknown, although Genome-wide association study (GWAS) has contributed for detecting pathophysiology of complex disorders. One of the reasons is that most studies are conducted based on “separate analysis” between common polymorphism (single nucleotide polymorphism: SNP) and rare variant (copy number variant: CNV), so far. In this study, we conducted a joint analysis merging SNP (and polygenic risk score calculated by whole-genome SNP effect) and CNV. Here, we detected the possible “genuine” CNVs were enriched in the lower PRS which had lower risk for schizophrenia based on polygenic model. Further study will be required to obtain conclusive results, however, such hybrid analysis will be essential for schizophrenia.

Academic Significance and Societal Importance of the Research Achievements

CNVを始めとする稀な変異のリスクを統計的に証明することは検出力の観点から極めて困難である。そのため、リスクとなりうるCNVの重み付けをつけることは、膨大なCNVの機能を解明していく上で、一定の優先順位を与えることとなり、極めて有用な情報を与えうる。すなわち、本方法論を用いれば、統計的には有意でなくとも、ポリジェニックスコアの低い患者は、リスクとなりうる稀でかつ効果の大きい変異を持つ可能性があり、その変異自体の機能解析を実施する指針を与えうる。

Research Products

• [Journal Article] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population. (2019)
  • Author(s): Suzuki K, Akiyama M, Ishigaki K, Kanai M, Hosoe J, Shojima N, Hozawa A, Kadota A, Kuriki K, Naito M, Tanno K, Ishigaki Y, et al.
  • Journal Title: Nat Genet. Volume: 51 Issue: 3 Pages: 379-386
  • DOI: 10.1038/s41588-018-0332-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases (2018)
  • Author(s): Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Kubo M, Okada Y, Kamatani Y
  • Journal Title: Nat Genet Volume: 50 Issue: 3 Pages: 390-400
  • DOI: 10.1038/s41588-018-0047-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect (2018)
  • Author(s): 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,Kushima I,Arai H,Takaki M,Hattori K,Kunugi H,Okahisa Y,Ohnuma T,Ozaki N,Someya T,Hashimoto R,Yoshikawa T,Kubo M,Iwata N
  • Journal Title: Schizophrenia Bulletin Volume: 印刷中 Issue: 4 Pages: 824-834
  • DOI: 10.1093/schbul/sby140
  • Peer Reviewed / Open Access
• [Journal Article] Re-evaluating classical body type theories: genetic correlation between psychiatric disorders and body mass index (2018)
  • Author(s): Ikeda Masashi、Tanaka Satoshi、Saito Takeo、Ozaki Norio、Kamatani Yoichiro、Iwata Nakao
  • Journal Title: Psychological Medicine Volume: in press Issue: 10 Pages: 1-4
  • DOI: 10.1017/s0033291718000685
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association studies of bipolar disorder: A systematic review of recent findings and their clinical implications (2017)
  • Author(s): Ikeda Masashi、Saito Takeo、Kondo Kenji、Iwata Nakao
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 72 Issue: 2 Pages: 52-63
  • DOI: 10.1111/pcn.12611
  • Peer Reviewed / Open Access
• [Journal Article] Transethnic Replication Study to Assess the Association Between Clozapine-Induced Agranulocytosis/Granulocytopenia and Genes at 12p12.2 in a Japanese Population (2017)
  • Author(s): Saito T, Ikeda M, Hashimoto R, Iwata N; Members of the Clozapine Pharmacogenomics Consortium of Japan
  • Journal Title: Biol Psychiatry Volume: in press Issue: 1 Pages: e9-e10
  • DOI: 10.1016/j.biopsych.2016.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder. (2017)
  • Author(s): Ikeda M, Shimasaki A, Takahashi A,et al.
  • Journal Title: Mol Psychiatry Volume: in press Issue: 3 Pages: 1-9
  • DOI: 10.1038/mp.2016.259
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Risk factors and clinical characteristics of the depressive state induced by pegylated interferon therapy in patients with hepatitis C virus infection: A prospective study. (2016)
  • Author(s): 3.Kawase K, Kondo K, Saito T, Shimasaki A, Takahashi A, Kamatani Y, Kawabe N, Hashimoto S, Ikeda M, Kubo M, Yoshioka K, Iwata N
  • Journal Title: Psychiatry Clin Neurosci Volume: 70(11) Issue: 11 Pages: 489-97
  • DOI: 10.1111/pcn.12424
  • Peer Reviewed / Acknowledgement Compliant