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DISC1 Sequencing Suggests Many Rare Variants Still Unknown

14 June 2013. The most complete look at the genetic variation of the disrupted in schizophrenia (DISC1) locus to date is provided by a study published online June 4 in Molecular Psychiatry. Led by W. Richard McCombie of New York’s Cold Spring Harbor Laboratory and David Porteous of the University of Edinburgh, U.K., researchers sequenced DISC1 in more than 1,500 people, with and without mental illness, finding that the majority of variants had not been previously described. The study also reports a new association between a DISC1 variant and recurrent major depression.

The scaffolding protein DISC1 has received much attention in relation to psychiatric disorders after a chromosomal translocation that disrupts the gene was found to be associated with schizophrenia, major depression, and other mental disorders in a large Scottish family. Although several small genetic studies have implicated single nucleotide polymorphisms (SNPs) in DISC1 with risk for schizophrenia, bipolar disorder, or major depression, these results have not been supported in meta-analyses or large-scale genomewide association studies.

However, because of the strong association with mental illness and the fact that DISC1 plays a role in neurodevelopment, neuronal migration, and signaling (see SRF related news story and SRF news story)—processes that are thought to be disrupted in mental illnesses—the gene remains of interest in psychiatry. The current study examined the nature and frequency of DISC1 variation and its effect on risk for schizophrenia, bipolar disorder, and major depression.

Cataloguing SNPs
First authors Pippa Thomson, Jennifer Parla, and Allan McRae sequenced 528 kb of the DISC1 locus in a total of 1,542 Scottish individuals (240 with schizophrenia, 221 with bipolar disorder, 192 with recurrent major depression, and 889 controls). Of the 2,718 SNPs identified, 708 had a minor allele frequency above 1 percent, indicating that they were common alleles, while the majority (2,010) were rare. In addition, only 36 of the SNPs were located within the coding regions of exons, whereas 489 mapped to regulatory regions and 177 were in non-coding exons.

Only 38 percent of these SNPs were reported in the European subset of the 1000 Genomes Project, and thus the majority are novel. When the researchers combined both datasets (yielding some 2,500 genomes in which DISC1 has been sequenced) in order to estimate the effective pool of DISC1 variants, they identified 905 common and 2,305 rare variants. However, Thomson and colleagues estimate that the number of rare variants is actually much higher, indicating that at least 40 percent remain undiscovered and will occur with such low frequencies as to be "private."

The current study identified 12 of the 17 rare coding SNPs that have previously been reported for DISC1. In addition, Thomson and colleagues identified eight more non-synonymous SNPs (five of which have not been seen in previous sequencing studies), for a total of 20 DISC1 SNPs that lead to changes in the amino acid sequence of the protein. Using applied prediction algorithms, the researchers identified five that are likely to be deleterious.

DISC1 and disease
Consistent with other recent findings, none of the DISC1 SNPs was associated with any of the psychiatric diagnoses, individually or combined, at genomewide levels of significance. There was no significant locus-wide association of variants with either schizophrenia or bipolar disorder, although intronic SNP rs16856199 was associated with recurrent major depression. In the four risk allele carriers with additional family members available for study, rs16856199 segregated with the illness in all four families.

Thomson and colleagues followed up on this finding in three additional depression samples—two with recurrent and one with single-episode major depression. Although no significant association was observed with the three replication cohorts individually or combined, when the three recurrent major depression cohorts (the original plus the two replication sets) were examined together, a significant association with rs16856199 was found. In addition, subjects referred from primary care were significantly associated with the risk SNP, while those from the population-based samples were not. Moreover, the risk allele for rs16856199 did not segregate with recurrent major depression in 10 families of carriers drawn from the population-based sample. Taken together, the authors write, these data suggest that rs16856199 is more strongly associated with individuals with a more severe illness course.

Overall, the current study suggests that there is a high level of sequence variation in DISC1 that has yet to be discovered and, according to the authors, is “likely to generalize to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.”—Allison A. Curley.

Thomson PA, Parla JS, McRae AF, Kramer M, Ramakrishnan K, Yao J, Soares DC, McCarthy S, Morris SW, Cardone L, Cass S, Ghiban E, Hennah W, Evans KL, Rebolini D, Millar JK, Harris SE, Starr JM, Macintyre DJ, , McIntosh AM, Watson JD, Deary IJ, Visscher PM, Blackwood DH, McCombie WR, Porteous DJ. 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits. Mol Psychiatry . 2013 Jun 4. Abstract

Comments on News and Primary Papers
Primary Papers: 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits.

Comment by:  Bryan Roth, SRF Advisor
Submitted 8 June 2013 Posted 10 June 2013
  I recommend this paper

This is an important, albeit somewhat negative, study...  Read more

View all comments by Bryan Roth
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