708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits

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.

Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci

“…This novel locus may interact directly with DISC1 , a possible schizophrenia 37,38 and OD 2,31 risk gene whose protein product has a role in cognitive function. 39 Additionally, we added to the already considerable evidence for association of variants in the ADH alcohol-metabolizing enzyme genes to AD. Further studies are needed to confirm these associations and to elucidate the functional relationships of the several novel risk loci we identified to AD.…”

The link between long noncoding RNAs and depression

“…A t(1;11) translocation revealed genomewide significant linkage for schizophrenia, rMDD and together with BD (Thomson et al, 2014). DISC1, translin-associated factor X (TSNAX) and D-amino acid oxidase activator (DAOA) were supposed to play a role as DISC1-TSNAX variants in MDD susceptibility (Arias et al, 2014).…”

“…Up to 2012, more than 350 million people suffer from depression all over the world, patients suffering from major depressive disorder (MDD) will get a 12-month prevalence of 6.6% and a lifetime prevalence of 16.2%, and women are twice susceptible compared to men (Thomson et al, 2014). Compared to unipolar depression patients, bipolar patients are much more likely to present to clinicians, while unipolar depression is more prevalent than bipolar disorder (Hirschfeld, 2014).…”

Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid schizophrenia

“…Moreover, it might significantly contribute to cell cycle abnormalities as well as to deficits in oligodendroglial cell differentiation and maturation found in schizophrenia. of evidence has accumulated pointing toward disruptedin-schizophrenia 1 (DISC1) as a candidate gene that influences risk of schizophrenia and other mental disorders (overview in [25]). DISC1 codes for a major protein of about 100 kDa and various, yet incompletely characterized isoforms generated by alternative splicing [26].…”

“…Many studies have demonstrated that DISC1 plays important roles during neurodevelopment, including neuronal proliferation, neurite outgrowth, neuronal migration, and synapse formation, all implicated in the pathophysiology of schizophrenia (reviewed in [27]). Furthermore, genetic variants of DISC1 were shown to be associated with the hippocampal volume [28], cortical thickness [29], and prefrontal-associated cognition [25]. DISC1 protein is predominantly localized in neurons ( [30] and many others), but there is also evidence for a wide extra-neuronal expression (i.e., in cultured astrocytes, OLs, microglia, and radial progenitor cells, [1,23,[31][32][33]).…”