708 common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits

Thomson, P. A., Parla, J. S., McRae, A. F., Kramer, M., Ramakrushnan, K., Yao, J., Soares, D. C., McCarthy, S., Morris, S. W., Cardone, L., Cass, S., Ghiban, E., Hennah, W., Evans, K. L., Rebolini, D., Millar, J. K., Harris, S. E., Starr, J. M., MacIntyre, J., Generation Scotland, McIntosh, A. M., Watson, J. D., Deary, I. J., Visscher, P. M., Blackwood, D. H., McCombie, W. R. and Porteous, D. J. (2013) 708 common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits. Molecular Psychiatry, Advance online publication 6: 1-8. doi:10.1038/mp.2013.68

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Author Thomson, P. A.
Parla, J. S.
McRae, A. F.
Kramer, M.
Ramakrushnan, K.
Yao, J.
Soares, D. C.
McCarthy, S.
Morris, S. W.
Cardone, L.
Cass, S.
Ghiban, E.
Hennah, W.
Evans, K. L.
Rebolini, D.
Millar, J. K.
Harris, S. E.
Starr, J. M.
MacIntyre, J.
Generation Scotland
McIntosh, A. M.
Watson, J. D.
Deary, I. J.
Visscher, P. M.
Blackwood, D. H.
McCombie, W. R.
Porteous, D. J.
Total Author Count Override 27
Title 708 common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits
Formatted title
708 common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits
Journal name Molecular Psychiatry   Check publisher's open access policy
ISSN 1359-4184
1476-5578
Publication date 2013-06-04
Year available 2013
Sub-type Article (original research)
DOI 10.1038/mp.2013.68
Open Access Status DOI
Volume Advance online publication
Issue 6
Start page 1
End page 8
Total pages 8
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2014
Language eng
Formatted abstract
A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10−5, OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.
Keyword DISC1
Recurrent major depressive disorder
Sequencing
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes http://www.nature.com/mp/journal/vaop/ncurrent/pdf/mp201368a.pdf

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2014 Collection
UQ Diamantina Institute Publications
 
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Created: Fri, 14 Mar 2014, 13:38:53 EST by Kylie Hengst on behalf of UQ Diamantina Institute