A welcome change in psychiatric genetics has been the widespread recognition of the essential role of uncompromising statistical rigor and replication. Put simply, the genome is a big place, and it is trivial to find false leads—non-significant but ‘suggestive’ genomic findings that an integrative scientist might find ‘intriguing’.

Indeed, due to advances in sequencing technology, the next few years are certain to see an explosion in observations of unique events in people with schizophrenia and other psychiatric disorders. Some of these will be claimed to be causal. However, the paucity of results from exome sequencing of sizable samples in autism1, 2, 3 and schizophrenia,4, 5 combined with the surprisingly high rates of deleterious exonic variation in apparently normal people,6 indicates that it will be highly challenging to delineate disease-related variants from background noise. For example, even with the improbably optimistic assumption that 1% of schizophrenia cases are caused by fully penetrant mutations in one gene that has no confounding background variation, observing 10 deleterious mutations in 1000 cases and 0 in 1000 controls would not be clearly delineated from the distribution of test statistics across 15–20 000 genes. In reality, locus heterogeneity, incomplete penetrance and realistic background variation will make this task markedly more difficult.

As there is already an influential example of a unique genomic event, it is timely to review the genomics of ‘Disrupted in Schizophrenia 1’ (DISC1), a t(1;11) (q42.1;q14.3) structural variant identified using cytogenetic methods.7, 8 (The chromosomal bands are sometimes different from 1q42.1 and 11q14.3. I determined these bands by mapping the breakpoint sequences in Millar et al.7. to hg19 using UCSC/BLAT.) Over 20 years after the initial report, the status of DISC1 as a risk factor for schizophrenia is unclear and perhaps polarized: some researchers are convinced that it is a proven etiological factor in schizophrenia, and others that it is not. Other groups await empirical data to resolve its role. Indeed, my group has found non-significant but ‘intriguing’ results about DISC1 twice, and both times its potential salience faded with more data.9, 10

The purpose of this editorial is to review the genetic evidence for the involvement of DISC1 in schizophrenia. There are important unanswered questions that need to be resolved for DISC1 to be established as a bona fide genetic risk factor for schizophrenia.

Views on DISC1 in the literature

Some consider DISC1 as a proven risk factor for schizophrenia.11, 12 Examples of statements about DISC1 include: ‘this private mutation has revealed important mechanisms of disease’,13 ‘a key susceptibility gene for schizophrenia is DISC1’,14 ‘a susceptibility gene for schizophrenia’,15 ‘a convincing candidate gene’16 and ‘DISC1, a major susceptibility factor for several mental disorders’.17 Some psychiatric disorders have been termed ‘DISC1opathies’,18 and DISC1 has been referred to as the ‘special gene’.

The DISC1 pedigree

The pedigree was initially reported in 1970, and identified via an 18-year-old male karyotyped in a cytogenetic study of boys sentenced to a youth prison in Scotland.19 The propositus had conduct disorder, and none of his first-degree relatives had a psychotic disorder.

Three cytogenetic abnormalities were reported to segregate in this pedigree: a balanced translocation between chr1 and a group C chromosome (chr6–12), a separate chr1 ‘unusually large secondary constriction’, and a Robertsonian translocation between two group D chromosomes (chr13–15). To my knowledge, the most recent report of the phenotypes in the pedigree was in 2001,20 but the 2001 pedigree is considerably smaller than that in the 1970 report. Diagnoses were established using a structured diagnostic interview by psychiatrists blinded to genotype, and of 29 individuals with t(1;11) (q42.1;q14.3): 11 (37.9%) had no diagnosis, an anxiety disorder, conduct disorder or alcohol dependence; 10 (34.4%) had recurrent major depressive disorder; and 8 (27.6%) had a psychotic disorder (7 schizophrenia and 1 bipolar disorder). Parametric linkage analyses under a dominant model maximized at a logarithm of odds (LOD) score of 7.1 when recurrent major depressive disorder, schizophrenia and bipolar disorder were considered affected. The next largest LOD of 4.5 was for mood disorders (recurrent major depressive disorder and bipolar disorder), and schizophrenia alone had a LOD of 3.6.

These reports do not answer multiple questions of interest to the research community (Table 1). First, it is possible that t(1;11) (q42.1;q14.3) status is based on laboratory assessments done over 40 years ago. This should give any researcher pause, particularly if the key linkage analyses in Blackwood et al.20 are based on the Jacobs et al.19 structural variant assignments. Second, I could find no published explanation or analysis of why the researchers focused on one of the three structural variants reported to segregate in this pedigree. Third, critically, sensitivity analyses were not reported (that is, systematically changing diagnoses within the pedigree and re-evaluating linkage evidence). The importance of these analyses was amply illustrated by the old-order Amish linkage studies in the late 1980s, where a LOD of 4.9 faded to non-significance with a few changes in the pedigree.21 It is possible that the reported LOD scores are fragile and sensitive to changes in diagnostic status.

Table 1 Unanswered questions about DISC1
Full size table

Fourth, the logical connections of t(1;11) (q42.1;q14.3) with schizophrenia are not compelling. The propositus and his immediate relatives have conduct disorder. The linkage analyses are more consonant with a mood disorder phenotype. The high prevalence of recurrent MDD is disconcerting given the predominant role of environmental risk factors in its etiology.22, 23 Of greatest concern is that mental retardation, autism spectrum disorders and epilepsy have not been reported to segregate with t(1;11) (q42.1;q14.3) in this pedigree. This is atypical for rare structural variants of strong effect that tend to increase the risk for multiple neuropsychiatric disorders.24

DISC1 proponents have argued that the lack of a uniform connection to a single psychiatric phenotype is expected and consistent with genetic risk factors having pleomorphic effects. Empirical data have suggested that pleomorphic effects are indeed the case;25 however, this does not appear to be a cleanly falsifiable argument in this pedigree. Indeed, if this argument were true, the authors make the case that ‘disrupted in schizophrenia’ is a misnomer.

The focus on the Chr1 translocation region

The t(1;11) (q42.1;q14.3) structural variant was identified as disrupting a novel gene that was given the name DISC1.7 Although this was a standard medical genetics approach, there are additional unanswered questions. First, the chr11 side of the breakpoint disrupts a predicted long intergenic non-coding RNA (lincRNA, ENST00000562245.1 or RP11-660M18.2). Such RNA molecules are expressed and do not code for protein, but can have important regulatory roles. Second, as noted above, t(1;11) (q42.1;q14.3) is one of the three structural variants reported in this pedigree, and other structural variants could be relevant. Third, the members of this pedigree share considerable amounts of the genome identical-by-descent; have the relevance of other genetic variants been excluded? Is a gene-disrupting translocation in DISC1 merely a red herring for causal variation elsewhere in the genome? For example, some translocations are not copy number neutral, causal genetic variation in the vicinity of the breakpoints could be ‘hitchhiking’ due to limited recombination within the pedigree, and the disease status could result from an entirely distinctive mechanism from what has been stated.

Finally, causal environmental effects can also cluster in extended pedigrees. The high prevalences of conduct disorder and recurrent MDD in this pedigree are notable. As these can emerge from the ‘matrix of disadvantage’, it is possible that non-genetic effects have an etiological role in this pedigree.

Genetic findings in other samples

To the best of my knowledge, t(1;11) (q42.1;q14.3) is private to this Scottish pedigree and has never been reported elsewhere. I am aware of no copy number variants in the DISC1 region that are significantly more common in cases with schizophrenia, bipolar disorder or autism in comparison to controls.24

Genome-wide linkage meta-analyses for schizophrenia and bipolar disorder do not provide support for DISC1 or for the chr11 side of the translocation.26, 27

For common genetic variation, candidate gene studies have reported genetic associations with various psychiatric disorders in DISC1. However, these small studies are known to have issues with quality control. The largest and most comprehensive studies show no common single-nucleotide polymorphism (SNP) association signal in the DISC1 region. The PGC (Psychiatric Genomics Consortium) schizophrenia GWAS (genome-wide association study) mega-analysis (9394 cases and 12 462 controls) had a minimum P=0.02 in DISC1, a level of significance about 1 million times larger than that required for genome-wide significance.28 A separate meta-analysis of DISC1 variants from 10 candidate gene studies and 3 GWAS (11 626 schizophrenia cases and 15 237 controls) found no significant associations even at a liberal gene-wise significance level.29 Similarly, a yet larger GWAS shows no DISC1 evidence (Sullivan, submitted). There are also no notable findings on the chr11 side of the translocation.

Some papers have hypothesized that the effects of DISC1 are pleomorphic in the sense of predisposing to multiple psychiatric disorders. The PGC cross-disorders group has conducted an integrated GWAS mega-analysis of 61 220 subjects, including cases with schizophrenia, bipolar disorder, MDD, autism and attention deficit-hyperactivity disorder.25 This analysis directly and systematically evaluated the pleomorphic effects of common genetic variation in DISC1, effectively testing whether any common SNP was associated with more than one disorder. There were no notable associations in the DISC1 region (minimum P=0.02, a million times larger than that required for genome-wide significance).

There are few published resequencing studies of DISC1, and larger and more comprehensive studies are in progress. To date, the largest published study of rare exonic variation was negative (discovery in 727 schizophrenia cases and 733 controls, replication in 2191 cases and 2659 controls).10 Some smaller studies have claimed association although replication efforts were absent or negative. The strong assertion that 2% of the attributable risk for schizophrenia was due to rare DISC1 variants30 has not been replicated.

The genetic evidence for DISC1 is not strong

Confident associations in human genetics require evidence of statistical association beyond chance and replication in multiple independent samples.31 Moreover, we have come to expect exceptional quality control and vigorous efforts to understand the impact of many different types of bias. In my view, the central goal of psychiatric genetics is now the identification of high-confidence associations and not the potential confusion engendered by lists of ‘intriguing’ findings.

The published genetic evidence for an association of DISC1 with schizophrenia does not meet a high standard. The genetic evidence is limited solely to cytogenetic abnormalities within a single pedigree. There is no independent line of genetic evidence (for example, structural variation in other pedigrees, evidence for increased exonic deleterious mutations in cases, or common variant associations). The apparent absence of autism, mental retardation and epilepsy, and the presence of recurrent MDD and conduct disorder in this pedigree is perplexing and atypical.

It is certainly possible that the outstanding questions in Table 1 are readily addressed or have already been answered via analyses, of which I am unaware. However, one cannot escape the conclusion that the genetic findings for DISC1 do not now meet community standards in human genetics. DISC1 stands apart: the genetic evidence in support of other rare variants of strong effect have increased in the past decade, whereas the genetic evidence for DISC1 has not.24

What about biology? DISC1 proponents argue that its fascinating roles in the development and function of the brain trump the genetic findings. This argument is not accepted in mainstream human genetics: biology does not have a role in establishing a genetic association (but only later in understanding its role). Invoking biology to cover up deficiencies in the genetic evidence is a slippery slope. Most genes have a direct or indirect role in central nervous system biology and any integrative scientist worth his or her salt could make an ‘intriguing’ case for a large fraction of human genes. To connect DISC1 to any psychiatric disorder requires iron-clad genetic associations, which are currently lacking.

Names are powerful things, and, at present, one could reasonably posit that ‘disrupted in schizophrenia’ is a misnomer and prone to misinterpretation. The official HUGO gene name unmistakably but incorrectly implies a highly certain role in the etiology of schizophrenia. Unless the genetic evidence improves in the near future, wouldn’t it be be scientifically responsible to change the name of DISC1 to a more neutral descriptor?