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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.

Reference:
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 examining common and rare DISC1 variants. The authors report no significant apparent association with schizophrenia, although potential associations with depression and cognition merit examination and replication.

The main value of the paper is that it is the most extensive effort thus far examining DISC1 variants in schizophrenia and, in agreement with many of the more recent studies, no robust linkage to schizophrenia is reported.

View all comments by Bryan Roth

Comments on Related News


Related News: New Details About DISC1’s Role in Cellular Compartments Emerge

Comment by:  Verian Bader
Submitted 1 June 2012
Posted 1 June 2012

A couple of recently published papers have provided insights into the cell physiology of DISC1. Although DISC1 is one of the most extensively studied susceptibility genes for psychiatric illness, the promoter of DISC1 has not been characterized so far. In a systematic approach based on luciferase reporter genes, Walker et al. (Walker et al., 2012) describe a repressive and an enhancing promoter region upstream of the transcription start. The DISC1 promoter is negatively regulated by FOXP2; hence, affected FOXP2 mutation carriers might show a higher DISC1 expression. Therefore, it would be interesting to know if these FOXP2 mutation carriers also display a higher level of insoluble DISC1, since increased expression leads to an increase of insoluble DISC1 (Leliveld et al., 2008). As a result, and possibly through aggregation, DISC1 loses its ability to bind to specific interaction partners, thereby disrupting some cellular pathways (Atkin et al., 2012) and potentially leading to other gain-of-function effects. In this context, Malavasi et al. (Malavasi et al., 2012) report in detail on the control of DISC1 over the transcriptional activity of ATF4. ATF4 itself acts as a key protein in emotional learning and memory via its ability to repress CREB activity. The authors provide intriguing results on how full-length DISC1 protein and its non-synonymous polymorphisms 37W and 607F differentially inhibit ATF4 activity by distinct mechanisms. Both genetic variants—the rare, putatively causal substitution 37W and the common variant 607F—exclude the protein from the nucleus, thereby reducing ATF4 inhibition.

Eykelenboom et al. (Eykelenboom et al., 2012) also report on an abnormal subcellular distribution of mutated DISC1 by elegantly expanding the concept of DISC1 translocation-derived fusion proteins proposed previously (Zhou et al., 2008; Zhou et al., 2010). This is the first paper to confirm the existence of three different transcripts from the translocated DISC1 gene, potentially giving rise to DISC1 proteins adding 1, 60 or 69 amino acids to the N-terminus (1-597). Upon biophysical characterization, the two larger proteins termed CP60 and CP69 exhibit a higher helical amount and larger protein assemblies. When the recombinant fusion proteins were expressed in cells, they mediated abnormal mitochondrial localization and altered mitochondrial membrane potential.

The last two publications show that altered DISC1 protein structure, ranging from single amino acid changes to large, chimeric fusion proteins, can culminate in changes of the protein cellular distribution, oligomerization status, and abnormal cellular function. Increasing evidence suggests that defined DISC1 protein species have particular local functions within the neuron or glia cells, and that at least a part of the DISC1-mediated pathology is dependent on abnormal cellular distribution of the protein.

References:

Atkin TA, Brandon NJ, Kittler JT. Disrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport. Hum Mol Genet . 2012 May 1 ; 21(9):2017-28. Abstract

Eykelenboom JE, Briggs GJ, Bradshaw NJ, Soares DC, Ogawa F, Christie S, Malavasi EL, Makedonopoulou P, Mackie S, Malloy MP, Wear MA, Blackburn EA, Bramham J, McIntosh AM, Blackwood DH, Muir WJ, Porteous DJ, Millar JK. A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins. Hum Mol Genet . 2012 May 16. Abstract

Leliveld SR, Bader V, Hendriks P, Prikulis I, Sajnani G, Requena JR, Korth C. Insolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J Neurosci . 2008 Apr 9 ; 28(15):3839-45. Abstract

Malavasi EL, Ogawa F, Porteous DJ, Millar JK. DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription. Hum Mol Genet . 2012 Jun 15 ; 21(12):2779-92. Abstract

Walker RM, Hill AE, Newman AC, Hamilton G, Torrance HS, Anderson SM, Ogawa F, Derizioti P, Nicod J, Vernes SC, Fisher SE, Thomson PA, Porteous DJ, Evans KL. The DISC1 promoter: characterization and regulation by FOXP2. Hum Mol Genet . 2012 Apr 4. Abstract

Zhou X, Geyer MA, Kelsoe JR. Does disrupted-in-schizophrenia (DISC1) generate fusion transcripts? Mol Psychiatry . 2008 Apr ; 13(4):361-3. Abstract

Zhou X, Chen Q, Schaukowitch K, Kelsoe JR, Geyer MA. Insoluble DISC1-Boymaw fusion proteins generated by DISC1 translocation. Mol Psychiatry . 2010 Jul 1 ; 15(7):669-72. Abstract

View all comments by Verian Bader