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., Ramakrishnan, 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, D. J., McIntosh, A. M., Watson, J. D., Deary, I. J., Visscher, P. M., Blackwood, D. H., McCombie, W. R., Porteous, D. J. (2014) 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: Analysis for association with psychiatric disorder and cognitive traits. Molecular Psychiatry, 19 (6). pp. 668-675. ISSN 14765578

URL: http://www.ncbi.nlm.nih.gov/pubmed/23732877
DOI: 10.1038/mp.2013.68

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. © 2014 Macmillan Publishers Limited.

Item Type: Paper
Uncontrolled Keywords: DISC1 recurrent major depressive disorder sequencing
Subjects: diseases & disorders > mental disorders > schizophrenia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
Investigative techniques and equipment > assays > next generation sequencing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > single nucleotide polymorphism
Investigative techniques and equipment > whole exome sequencing
Investigative techniques and equipment > assays > whole exome sequencing

Investigative techniques and equipment > assays > whole genome sequencing
CSHL Authors:
Communities: CSHL labs > McCombie lab
Stanley Institute for Cognitive Genomics
Depositing User: Matt Covey
Date Deposited: 13 Jun 2014 14:54
Last Modified: 06 Nov 2015 20:05
PMCID: PMC4031635
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30303

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