DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

被引:141
作者
Nakata, Kenji [1 ]
Lipska, Barbara K. [1 ]
Hyde, Thomas M. [1 ]
Ye, Tianzhang [1 ]
Newburn, Erin N. [1 ]
Morita, Yukitaka [1 ]
Vakkalanka, Radhakrishna [1 ]
Barenboim, Maxim [1 ]
Sei, Yoshitatsu [1 ]
Weinberger, Daniel R. [1 ]
Kleinman, Joel E. [1 ]
机构
[1] NIMH, Clin Brain Disorders Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA
关键词
alternative splicing; genetic; hippocampus; psychiatric illness; DISORDER SUSCEPTIBILITY LOCUS; MAJOR MENTAL-ILLNESS; BIPOLAR-DISORDER; NEURITE OUTGROWTH; GENE-EXPRESSION; GENOME SCAN; DISRUPTED-IN-SCHIZOPHRENIA-1; DISC1; SCHIZOAFFECTIVE DISORDER; POSITIVE SYMPTOMS; CHROMOSOME; 1Q42;
D O I
10.1073/pnas.0903413106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Disrupted-In-Schizophrenia-1 (DISC1) is a promising susceptibility gene for major mental illness, but the mechanism of the clinical association is unknown. We searched for DISC1 transcripts in adult and fetal human brain and tested whether their expression is altered in patients with schizophrenia and is associated with genetic variation in DISC1. Many alternatively spliced transcripts were identified, including groups lacking exon 3 (Delta 3), exons 7 and 8 (Delta 7 Delta 8), an exon 3 insertion variant (extra short variant-1, Esv1), and intergenic splicing between TSNAX and DISC1. Isoforms Delta 7 Delta 8, Esv1, and Delta 3, which encode truncated DISC1 proteins, were expressed more abundantly during fetal development than during postnatal ages, and their expression was higher in the hippocampus of patients with schizophrenia. Schizophrenia risk-associated polymorphisms [non-synonymous SNPs rs821616 (Cys704Ser) and rs6675281 (Leu607Phe), and rs821597] were associated with the expression of Delta 3 and Delta 7 Delta 8. Moreover, the same allele at rs6675281, which predicted higher expression of these transcripts in the hippocampus, was associated with higher expression of DISC1 Delta 7 Delta 8 in lymphoblasts in an independent sample. Our results implicate a molecular mechanism of genetic risk associated with DISC1 involving specific alterations in gene processing.
引用
收藏
页码:15873 / 15878
页数:6
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