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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. [ABSTRACT FROM AUTHOR]

Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73±95% confidence interval (CI) 1.42–5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64±95% CI 1.23–2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27±95% CI 1.07–1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.Molecular Psychiatry (2009) 14, 865–873; doi:10.1038/mp.2008.22; published online 4 March 2008 [ABSTRACT FROM AUTHOR]

The DISC1 gene at 1q42 has generated considerable interest in various psychiatric diseases, since a balanced translocation interrupting the gene was found to cosegregate with schizophrenia and related mental illnesses in a large Scottish pedigree. To date, linkage and association findings to this locus have been replicated in several study samples ascertained for psychotic disorders. However, the biological function of DISC1 in neuronal development would suggest a potential role for this gene also in other, early onset neuropsychiatric disorders. Here we have addressed the allelic diversity of the DISC1, DISC2 and TRAX genes, clustered in 1q42, in Finnish families ascertained for infantile autism (97 families, naffected=138) and Asperger syndrome (29 families, naffected=143). We established association between autism and a DISC1 intragenic microsatellite (D1S2709; P=0.004). In addition, evidence for association to Asperger syndrome was observed with an intragenic single nucleotide polymorphism (SNP) of DISC1 (rs1322784; P=0.0058), as well as with a three-SNP haplotype (P=0.0013) overlapping the HEP3 haplotype, that was previously observed to associate with schizophrenia in Finnish families. The strongest associations were obtained with broad diagnostic categories for both disorders and with affected males only, in agreement with the previous sex-dependent effects reported for DISC1. These results would further support the involvement of DISC1 gene also in the etiopathogenesis of early onset neuropsychiatric disorders.Molecular Psychiatry (2008) 13, 187–196; doi:10.1038/sj.mp.4002031; published online 19 June 2007 [ABSTRACT FROM AUTHOR]

Taken as a whole, psychiatric disorders are considered as complex genetic disorders. There are clear genetic mutations and susceptibility factors to these disorders. However, these form the full spectrum of impact, frequency, and mutation type. With rare large scale chromosomal rearrangements and copy number mutations of high impact at one end, and common single nucleotide variations of minor impact at the other. This multitude of variation type also means that different epidemiological study designs are needed to test the genetic component of these disorders, from familial forms, to common population level studies. This process has been facilitated by advances in genomic analysis, that enable the measuring of genetic variation at a greater depth in a greater number of individuals and has led to a boom in genetic information. This has given us a greater understanding of the genetic aetiology of psychiatric disorders and how they are biologically related to each other. How this information can be translated to the clinics, can now be considered. Genetic testing in psychiatric disorders, is currently possible for certain disorders and mutation types, but is not universally advised. Much still remains to be understood about population level genetic risk factors before they could conceivably be utilised in the clinic. Whereas genetic testing of high impact mutations could be of use to the clinical programs, and are actively tested for in clinics across Europe. [ABSTRACT FROM AUTHOR]

The authors reflect on the genetic findings and relevance of DISC 1 biology to mental illnesses. They cite the contention of editor Patrick Sullivan on the aspects of DISC 1 gene discovery that fall short in criteria and insights into mental disorders such as autism, schizophrenia, and Alzheimer's disease. The author's think that biological DISC 1 pathways are critical to the advancement of psychiatric research.