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Frontiers in Biology

Front Biol    2013, Vol. 8 Issue (1) : 1-31     https://doi.org/10.1007/s11515-012-1254-7
REVIEW
DISC1 genetics, biology and psychiatric illness
Pippa A. THOMSON1, Elise L.V. MALAVASI1, Ellen GRüNEWALD1,2, Dinesh C. SOARES1, Malgorzata BORKOWSKA3, J. Kirsty MILLAR1()
1. The Centre for Molecular Medicine at the Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; 2. Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK; 3. Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK
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Abstract

Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points toward DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain.

Keywords DISC1      schizophrenia      depression      genetics      neural pathways     
Corresponding Author(s): MILLAR J. Kirsty,Email:kirsty.millar@igmm.ed.ac.uk   
Issue Date: 01 February 2013
 Cite this article:   
Pippa A. THOMSON,Ellen GRüNEWALD,Dinesh C. SOARES, et al. DISC1 genetics, biology and psychiatric illness[J]. Front Biol, 2013, 8(1): 1-31.
 URL:  
http://journal.hep.com.cn/fib/EN/10.1007/s11515-012-1254-7
http://journal.hep.com.cn/fib/EN/Y2013/V8/I1/1
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Pippa A. THOMSON
Ellen GRüNEWALD
Dinesh C. SOARES
Malgorzata BORKOWSKA
J. Kirsty MILLAR
Elise L.V. MALAVASI
Fig.1  DISC1 in neurodevelopment, brain functioning and psychiatric illness. DISC1 is a scaffold protein with many functional partners associated with brain development and disease. : The DISC1 protein network was modified from String DB (http://string-db.org/). The t(1;11) Scottish pedigree was modified, with permission, from Blackwood et al. () . A fragment of the gene structure, SNPs and linkage disequilibrium blocks was generated using the UCSC genome browser (http://genome.ucsc.edu/). : Examples of neurocognitive tests in which individuals carrying variants at the locus show altered performance; differences in brain activation by DISC1 L607F genotype as measured by functional MRI (with thanks to Andrew McIntosh); the P300 event related potential, which is elicited in decision making, and shows reduced amplitude and latency in DISC1 translocation carriers. : DISC1 is a multi-compartmentalised protein, present at the nucleus, centrosome, mitochondria, microtubules and synapse; DISC1 has roles in neurodevelopment and plasticity, in proliferation, migration and integration of neurons; neural stem cells are a promise in research and treatment of psychiatric and neurodegenerative disorders; GFP-labeled neural stem cells transplanted into the mouse brain can give rise to cells resembling normal hippocampal neurons (Image by Yirui Sun, Wellcome Images).
GenePresent in SZgeneNumber of studiesResultsMeta-analysis significant SNPs
BoldItalicY45 studies31 positive/9 negative/ 3 trendrs3737597, rs999710
AKT1Y17 studies9 positive/7 negative/1 trendrs3803300
ATF4Y1 studyNegative
ATF5Y1 studyNegative
BBS1
BBS4
CCDC141 (encodes
CCDC88A (encodes KIAA1212/Girdin)
CITY1 studyPositive
DIXDC1
FEZ1Y5 studiesNegative
GRB2
GSK3βY8 studies1 positive/6 negative/1 trend
KALRN(encodes KAL-7)
NDE1Y4 studiesnegative
NDEL1Y7 studies4 positive/3 negative
PAFAH1B1 (encodes LIS1)Y5 studies1 positive/4 negative
PCM1Y7 studies6 positive/1 negative
PCNTY3 studies1 positive/1 negative/1 trend
PDE4A
PDE4BY12 studies9 positive/3 negativers910694
PDE4C
PDE4DY2 studiesPositive
SLC12A2 (encodes NKCC1)
TNIK
YWHAE(encodes 14-3-3?)Y5 studies2 positive/3 negative
Tab.1  Evidence of association to schizophrenia from candidate gene studies for selected DISC1 interactors
TraitSNPContextGenep-value
Neuroanatomyrs12042938IntronBoldItalic4.00E-36
Alzheimer’s disease12044355IntronDISC19.00E-06
Schizophrenia2088885IntronTNIK6.00E-06
Neurotic disorders702543IntronPDE4D2.00E-06
Mental competency295973IntronPDE4D7.61E-07
Mental competency295973IntronPDE4D7.61E-07
Neuroblastoma9892996IntergenicSLC25A19/GRB22.23E-07
Neuroblastoma16967789IntronGRB21.10E-06
Tab.2  Evidence of association between DISC1 interactors and brain-related traits
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