統合失調症の分子遺伝学

Molecular genetics of schizophrenia

　統合失調症の分子遺伝学的研究は1980年代より活発に行われており，試行錯誤を重ねた末，2000年に入り連鎖解析，染色体異常に基づいた位置的候補遺伝子法，遺伝子発現解析に基づいた候補遺伝子法により関連遺伝子の検出が続出し，成果が現れ始めている。これにより，統合失調症の分子病態に対しても新しい展開がみられている。しかし，これまでの発見では，統合失調症の脆弱性の遺伝的要因の一部しか説明できず，さらに関連遺伝子の同定や遺伝子・環境相互作用などの評価法の開発が必要で，大きな課題が残っている。

　An overview of current progress and future directions in the molecular genetics of schizophrenia is presented. Positional candidate approach based on linkage analysis and chromosome abnormalities prompted to identify novel genes involved in the susceptibility to schizophrenia. Although difficulties in obtaining clear replicated linkages have led to the skepticism that such approaches would ever be successful, there is now real progress. Several promising linkages regions have emerged and evidence implicating individual genes within some of the linked regions has been reported. The evidence indicates NRG1 located in 8p12, DTNBP1 located in 6p22.3, and DAOA located in 13q33.2 as susceptibility loci at least in some populations, though work remains to understand precisely how genetic variation at each locus confers susceptibility and protection. The study of chromosomal abnormalities in schizophrenia has also added to the evidence for susceptibility loci at 22q11 and 1q42. Evidence implicating DISC1 in 1q42 and PRODH in 22q11 has been reported. Other supportive evidence is waited. High-throughput microarray platforms capable of analyzing the all gene-expression give us the potential to identify candidate genes on the basis of dysregulation in tissues, though their limitations are particularly apparent when they are applied to the analysis of human brain. ATK1 and RGS4 appeared as candidate genes by gene-expression studies in autopsy material. The evidence for these genes is promising but not yet persuasive. While replications are still the top priority, the respective contributions of each gene, relationships with various aspects of the phenotype and the possibility of epistatic interactions between genes will all need investigation. The ability of genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and it is now poised to deliver crucial insights into the nature of schizophrenia. A greater understanding of the genetic mechanisms and the application of pharmacogenetics would lead to improvements in therapeutic interventions.