DeepPheWAS: an R package for phenotype generation and association analysis for phenome-wide association studies.

SUMMARY: DeepPheWAS is an R package for phenome-wide association studies that creates clinically curated composite phenotypes and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes. AVAILABILITY AND IMPLEMENTATION: The DeepPheWAS R package is freely available under GNU general public licence v3.0 from at https://github.com/Richard-Packer/DeepPheWAS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population.

We have previously reported a replicable association between variants at the PDE4D gene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations underlying these previous findings, we sequenced 1.5 Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals and 79 independent chromosomes), followed by two stages of genotyping across 6668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4570 SNPs across the PDE4D gene, with 380 associated to schizophrenia (p ≤ 0.05). Importantly, two of these variants, rs35278 and rs165940, are located at transcription factor-binding sites, and displayed replicable association in the two-stage enlargement of the familial schizophrenia cohort (combined statistics for rs35278 p = 0.0012; OR = 1.18, 95% CI: 1.06-1.32; and rs165940 p = 0.0016; OR = 1.27, 95% CI: 1.13-1.41). Further analysis using additional cohorts and endophenotypes revealed that rs165940 principally associates within the psychosis (p = 0.025, OR = 1.18, 95% CI: 1.07-1.30) and cognitive domains of major mental illnesses (g-score p = 0.044, ß = -0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, ß = -0.044) and verbal working memory (p = 0.0062, ß = -0.036). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels of PDE4D in the cerebellum (p-value = 0.04; m-value = 0.9), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at the PDE4D locus in the Finnish population, increasing risk broadly to psychotic disorders.

The effect of the DISC1 Ser704Cys polymorphism on striatal dopamine synthesis capacity: an [18F]-DOPA PET study.

Whilst the role of the Disrupted-in-Schizophrenia 1 (DISC1) gene in the aetiology of major mental illnesses is debated, the characterization of its function lends it credibility as a candidate. A key aspect of this functional characterization is the determination of the role of common non-synonymous polymorphisms on normal variation within these functions. The common allele (A) of the DISC1 single-nucleotide polymorphism (SNP) rs821616 encodes a serine (ser) at the Ser704Cys polymorphism, and has been shown to increase the phosphorylation of extracellular signal-regulated protein Kinases 1 and 2 (ERK1/2) that stimulate the phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. We therefore set out to test the hypothesis that human ser (A) homozygotes would show elevated dopamine synthesis capacity compared with cysteine (cys) homozygotes and heterozygotes (TT and AT) for rs821616. [18F]-DOPA positron emission tomography (PET) was used to index striatal dopamine synthesis capacity as the influx rate constant Kicer in healthy volunteers DISC1 rs821616 ser homozygotes (N = 46) and healthy volunteers DISC1 rs821616 cys homozygotes and heterozygotes (N = 56), matched for age, gender, ethnicity and using three scanners. We found DISC1 rs821616 ser homozygotes exhibited a significantly higher striatal Kicer compared with cys homozygotes and heterozygotes (P = 0.012) explaining 6.4% of the variance (partial η2 = 0.064). Our finding is consistent with its previous association with heightened activation of ERK1/2, which stimulates tyrosine hydroxylase activity for dopamine synthesis. This could be a potential mechanism mediating risk for psychosis, lending further credibility to the fact that DISC1 is of functional interest in the aetiology of major mental illness.

Neuropeptide precursor VGF is genetically associated with social anhedonia and underrepresented in the brain of major mental illness: its downregulation by DISC1.

In a large Scottish pedigree, disruption of the gene coding for DISC1 clearly segregates with major depression, schizophrenia and related mental conditions. Thus, study of DISC1 may provide a clue to understand the biology of major mental illness. A neuropeptide precursor VGF has potent antidepressant effects and has been reportedly associated with bipolar disorder. Here we show that DISC1 knockdown leads to a reduction of VGF, in neurons. VGF is also downregulated in the cortices from sporadic cases with major mental disease. A positive correlation of VGF single-nucleotide polymorphisms (SNPs) with social anhedonia was also observed. We now propose that VGF participates in a common pathophysiology of major mental disease.

Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits.

Schizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post-mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n = 4651) corroborated the association of physical and social anhedonia with the CRMP1 locus in a DISC1 (Disrupted-in-schizophrenia 1)-dependent manner. Physical and social anhedonia are heritable traits, present as chronic, negative symptoms of schizophrenia and severe major depression, thus constituting serious vulnerability factors for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role as a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of a disease-associated epitope in post-mortem brains, powered by a genetic association study, is rapidly translated into a potential blood-based diagnostic marker.

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease.

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

The effects of DISC1 risk variants on brain activation in controls, patients with bipolar disorder and patients with schizophrenia.

Three risk variants (rs1538979, rs821577, and rs821633) in the Disrupted-in-Schizophrenia-1 (DISC1) gene have previously been associated with both schizophrenia and bipolar disorder in a recent collaborative analysis of European cohorts. In this study we examined the effects of these risk variants on brain activation during functional magnetic resonance imaging (fMRI) of the Hayling Sentence Completion Task (HSCT) in healthy volunteers (n=33), patients with schizophrenia (n=20) and patients with bipolar disorder (n=36). In the healthy controls the risk associated allele carriers of SNPs rs1538979 and rs821633 demonstrated decreased activation of the cuneus. Moreover, there was an effect of SNP rs1538979 in the pre/postcentral gyrus with decreased activation in healthy controls and increased activation in patients with schizophrenia. In the bipolar group there was decreased activation in the risk carriers of SNP rs821633 in the inferior parietal lobule and left cingulate cortex. Clusters in the precentral gyrus, left middle temporal gyrus and left cerebellum were found to be significant on examining the group × genotype interactions. These findings may provide a better understanding of the neural effects of DISC1 variants and on the pathophysiology of schizophrenia and bipolar disorder.

Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice.

Disrupted-in-schizophrenia 1 (DISC1) was initially discovered through a balanced translocation (1;11)(q42.1;q14.3) that results in loss of the C terminus of the DISC1 protein, a region that is thought to play an important role in brain development. Here, we use an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of a C-terminal portion of DISC1 in mice results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Accordingly, we report that individuals in a discordant twin sample with a DISC1 haplotype, associating with schizophrenia as well as working memory impairments and reduced gray matter density, were more likely to show deficits in sociability than those without the haplotype. Our findings demonstrate that alterations in DISC1 function during brain development contribute to schizophrenia pathogenesis.

Association of AKT1 with verbal learning, verbal memory, and regional cortical gray matter density in twins.

AKT1, encoding the protein kinase B, has been associated with the genetic etiology of schizophrenia and bipolar disorder. However, minuscule data exist on the role of different alleles of AKT1 in measurable quantitative endophenotypes, such as cognitive abilities and neuroanatomical features, showing deviations in schizophrenia and bipolar disorder. We evaluated the contribution of AKT1 to quantitative cognitive traits and 3D high-resolution neuroanatomical images in a Finnish twin sample consisting of 298 twins: 61 pairs with schizophrenia (8 concordant), 31 pairs with bipolar disorder (5 concordant) and 65 control pairs matched for age, sex and demographics. An AKT1 allele defined by the SNP rs1130214 located in the UTR of the gene revealed association with cognitive traits related to verbal learning and memory (P = 0.0005 for a composite index). This association was further fortified by a higher degree of resemblance of verbal memory capacity in pairs sharing the rs1130214 genotype compared to pairs not sharing the genotype. Furthermore, the same allele was also associated with decreased gray matter density in medial and dorsolateral prefrontal cortex (P < 0.05). Our findings support the role of AKT1 in the genetic background of cognitive and anatomical features, known to be affected by psychotic disorders. The established association of the same allelic variant of AKT1 with both cognitive and neuroanatomical aberrations could suggest that AKT1 exerts its effect on verbal learning and memory via neural networks involving prefrontal cortex.

The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland.

Several putative schizophrenia susceptibility genes have recently been identified. Significant associations between schizophrenia and neuregulin 1 (NRG1) and dysbindin (DTNBP1) were first reported in 2002 and studies in several populations have since independently reported positive associations to these gene regions. Further, both tentative functional and genetic data have implicated the role of AKT1 in the genetic background of this disorder. However, findings have not been consistent in all populations. We investigated the allelic diversity of these three genes NRG1, DTNBP1 and AKT1 in a representative nation-wide study sample of 441 Finnish schizophrenia families consisting of 865 affected individuals, in order to assess their role in one of the largest population-based study samples. DTNBP1 and AKT1 failed to show evidence of association, whereas two SNPs in the 3' region of the NRG1 gene yielded suggestive evidence of association (p=0.012 and p=0.048) in family-based association analyses. Thus, our study does not indicate that AKT1 or DTNBP1 play a role in the etiology of schizophrenia in the Finnish population. Furthermore, results do not support a major role for NRG1, but we cannot completely exclude a minor role of this gene in the Finnish population.

Genome-Wide Association Study of Psychosis Proneness in the Finnish Population.

The current study examined quantitative measures of psychosis proneness in a nonpsychotic population, in order to elucidate their underlying genetic architecture and to observe if there is any commonality to that already detected in the studies of individuals with overt psychotic conditions, such as schizophrenia and bipolar disorder. Heritability, univariate and multivariate genome-wide association (GWAs) tests, including a series of comprehensive gene-based association analyses, were developed in 4269 nonpsychotic persons participating in the Northern Finland Birth Cohort 1966 study with information on the following psychometric measures: Hypomanic Personality, Perceptual Aberration, Physical and Social Anhedonia (also known as Chapman's Schizotypia scales), and Schizoidia scale. Genome-wide genetic data was available for ~9.84 million SNPs. Heritability estimates ranged from 16% to 27%. Phenotypic, genetic and environmental correlations ranged from 0.04-0.43, 0.25-0.73, and 0.12-0.43, respectively. Univariate GWAs tests revealed an intronic SNP (rs12449097) at the TMC7 gene (16p12.3) that significantly associated (P = 3.485 × 10-8) with the hypomanic scale. Bivariate GWAs tests including the hypomanic and physical anhedonia scales suggested a further borderline significant SNP (rs188320715; P-value = 5.261 × 10-8, ~572 kb downstream the ARID1B gene at 6q25.3). Gene-based tests highlighted 20 additional genes of which 5 had previously been associated to schizophrenia and/or bipolar disorder: CSMD1, CCDC141, SLC1A2, CACNA1C, and SNAP25. Altogether the findings explained from 3.7% to 14.1% of the corresponding trait heritability. In conclusion, this study provides preliminary genomic evidence suggesting that qualitatively similar biological factors may underlie different psychosis proneness measures, some of which could further predispose to schizophrenia and bipolar disorder.

The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to microRNA-484.

Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the 'DISC1 network'. Here, we use gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, while prescription medication information has been collected over a 10-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2908 probes (2542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p = 3.0 × 10-8), located on a non-coding exon of NDE1 Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.

Genes and schizophrenia: beyond schizophrenia: the role of DISC1 in major mental illness.

Schizophrenia and related disorders have a major genetic component, but despite much effort and many claims, few genes have been consistently replicated and fewer have biological support. One recent exception is "Disrupted in Schizophrenia 1" (DISC1), which was identified at the breakpoint on chromosome 1 of the balanced translocation (1;11)(q42.1;q14.3) that co-segregated in a large Scottish family with a wide spectrum of major mental illnesses. Since then, genetic analysis has implicated DISC1 in schizophrenia, schizoaffective disorder, bipolar affective disorder, and major depression. Importantly, evidence is emerging from genetic studies for a causal relationship between DISC1 and directly measurable trait variables such as working memory, cognitive aging, and decreased gray matter volume in the prefrontal cortex, abnormalities in hippocampal structure and function, and reduction in the amplitude of the P300 event-related potential. Further, DISC1 binds a number of proteins known to be involved in essential processes of neuronal function, including neuronal migration, neurite outgrowth, cytoskeletal modulation, and signal transduction. Thus, both genetic and functional data provide evidence for a critical role for DISC1 in schizophrenia and related disorders, supporting the neurodevelopmental hypothesis for the molecular pathogenesis of these devastating illnesses.

Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory.

CONTEXT: Chromosome 1q42 is among several genomic regions showing replicated evidence of linkage with schizophrenia, but the specific susceptibility mechanisms underlying this relationship remain to be identified. OBJECTIVE: To examine a series of haplotype blocks of single-nucleotide polymorphic markers from a segment of 1q42 spanning the disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX) genes for association with schizophrenia and several endophenotypic traits thought to be involved in disease pathogenesis. DESIGN: Population-based twin cohort study. SETTING: Finland. PARTICIPANTS: Two hundred thirty-six subjects, consisting of 7 twin pairs concordant for schizophrenia (6 monozygotic [MZ] and 1 dizygotic [DZ]), 52 pairs discordant for schizophrenia (20 MZ and 32 DZ), and 59 demographically balanced normal pairs (28 MZ and 31 DZ), were drawn from a twin cohort consisting of all of the same-sex twins born in Finland from 1940 through 1957. MAIN OUTCOME MEASURES: Psychiatric diagnosis, performance on neurocognitive tests of short- and long-term memory, and gray matter volume measurements taken from high-resolution magnetic resonance images. RESULTS: A common haplotype incorporating 3 single-nucleotide polymorphic markers near the translocation break point of DISC1 (odds ratio, 2.6 [P = .02]) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (odds ratio, 13.0 [P = .001]) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative endophenotypic traits previously observed to covary with schizophrenia and genetic liability to schizophrenia, including impairments in short- and long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a population-based brain atlas method, with a trend toward association with reduced hippocampal volume. CONCLUSIONS: Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission.

An interaction between NDE1 and high birth weight increases schizophrenia susceptibility.

Pre- and perinatal environmental factors have been shown to increase schizophrenia risk particularly when combined with genetic liability. The investigation of specific gene environment interactions in the etiology of psychiatric disorders has gained momentum. We used multivariate GEE regression modeling to investigate the interaction between genes of the DISC1 pathway and birth weight, in relation to schizophrenia susceptibility in a Finnish schizophrenia family cohort. The study sample consisted of 457 subjects with both genotype and birth weight information. Gender and place of birth were adjusted for in the models. We found a significant interaction between birth weight and two NDE1 markers in relation to increased schizophrenia risk: a four SNP haplotype spanning NDE1 (b=1.26, SE=0.5, p=0.012) and one of its constituent SNPs rs4781678 (b=1.33, SE=0.51, p=0.010). Specifically, high birth weight (>4000g) was associated with increased schizophrenia risk among subjects homozygous for the previously identified risk alleles. The study was based on a family study sample with high genetic loading for schizophrenia and thus our findings cannot directly be generalized as representing the general population. Our results suggest that the functions mediated by NDE1 during the early stages of neurodevelopment are susceptible to the additional disruptive effects of pre- and perinatal environmental factors associated with high birth weight, augmenting schizophrenia susceptibility.

Allele-specific regulation of DISC1 expression by miR-135b-5p.

Disrupted-in-schizophrenia-1 (DISC1) gene has been established as a risk factor for various neuropsychiatric phenotypes. Both coding and regulatory variants in DISC1 have been identified and associated with these phenotypes in genetic studies. MicroRNAs (miRNAs) are important regulators of protein coding genes. Since the miRNA-mRNA target recognition mechanism is vulnerable to disruption by DNA polymorphisms, we investigated whether polymorphisms in the DISC1 3'UTR affect binding of miRNAs and lead to allele-specific regulation of DISC1. We identified four predicted polymorphic miRNA target sites in the DISC1 3'UTR, and demonstrated that miR-135b-5p regulates the level of DISC1 mRNA. Moreover, DISC1 regulation by miR-135b-5p is allele specific: miR-135b-5p only binds to the major allele (A) of rs11122396, not to the minor allele (G). Thus, the G allele may be functionally related to the DISC1-associated phenotypes by abolishing regulation by miR-135b-5p, leading to elevated DISC1 levels.

NDE1 and NDEL1: twin neurodevelopmental proteins with similar 'nature' but different 'nurture'.

Nuclear distribution element 1 (NDE1, also known as NudE) and NDE-like 1 (NDEL1, also known as Nudel) are paralogous proteins essential for mitosis and neurodevelopment that have been implicated in psychiatric and neurodevelopmental disorders. The two proteins possess high sequence similarity and have been shown to physically interact with one another. Numerous lines of experimental evidence in vivo and in cell culture have demonstrated that these proteins share common functions, although instances of differing functions between the two have recently emerged. We review the key aspects of NDE1 and NDEL1 in terms of recent advances in structure elucidation and cellular function, with an emphasis on their differing mechanisms of post-translational modification. Based on a review of the literature and bioinformatics assessment, we advance the concept that the twin proteins NDE1 and NDEL1, while sharing a similar 'nature' in terms of their structure and basic functions, appear to be different in their 'nurture', the manner in which they are regulated both in terms of expression and of post-translational modification within the cell. These differences are likely to be of significant importance in understanding the specific roles of NDE1 and NDEL1 in neurodevelopment and disease.

Deletion of TOP3ß, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders.

Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3ß revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3ß to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome. Our results indicate a previously unknown role for TOP3ß in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.

DISC1 conditioned GWAS for psychosis proneness in a large Finnish birth cohort.

BACKGROUND: Genetic evidence implicates the DISC1 gene in the etiology of a number of mental illnesses. Previously, we have reported association between DISC1 and measures of psychosis proneness, the Revised Social Anhedonia Scale (RSAS) and Revised Physical Anhedonia Scale (RPAS), in the Northern Finland Birth Cohort 1966 (NFBC66). As part of the studies of this Finnish birth cohort genome-wide association analysis has recently been performed. METHODOLOGY: In the present study, we re-analyzed the genome-wide association data with regard to these two measures of psychosis proneness, conditioning on our previous DISC1 observation. From the original NFBC66 sample (N = 12 058), 4 561 individuals provided phenotype and genotype data. No markers were significant at the genome-wide level. However, several genes with biological relevance to mental illnesses were highlighted through loci displaying suggestive evidence for association (≥3 SNP with P<10E-4). These included the protein coding genes, CXCL3, KIAA1128, LCT, MED13L, TMCO7, TTN, and the micro RNA MIR620. CONCLUSIONS: By conditioning a previous genome-wide association study on DISC1, we have been able to identify eight genes as associating to psychosis proneness. Further, these molecules predominantly link to the DISC1 pathway, strengthening the evidence for the role of this gene network in the etiology of mental illness. The use of quantitative measures of psychosis proneness in a large population cohort will make these findings, once verified; more generalized to a broad selection of disorders related to psychoses and psychosis proneness.

The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes.

BACKGROUND: Genetic and biological evidence supports a role for DISC1 across a spectrum of major mental illnesses, including schizophrenia and bipolar disorder. There is evidence for genetic interplay between variants in DISC1 and in biologically interacting loci in psychiatric illness. DISC1 also associates with normal variance in behavioral and brain imaging phenotypes. METHODOLOGY: Here, we analyze public domain datasets and demonstrate correlations between variants in the DISC1 pathway genes and levels of gene expression. Genetic variants of DISC1, NDE1, PDE4B and PDE4D regulate the expression of cytoskeletal, synaptogenic, neurodevelopmental and sensory perception proteins. Interestingly, these regulated genes include existing targets for drug development in depression and psychosis. CONCLUSIONS: Our systematic analysis provides further evidence for the relevance of the DISC1 pathway to major mental illness, identifies additional potential targets for therapeutic intervention and establishes a general strategy to mine public datasets for insights into disease pathways.