Schizophrenia (SCZ) is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits with heritability estimated at up to 80%1,2. We adopted two analytic approaches to determine the extent to which common genetic variation underlies risk of SCZ using genome-wide association study (GWAS) data from 3,322 European individuals with SCZ and 3,587 controls. First, we implicate the major histocompatibility complex (MHC). Second, we provide molecular genetic evidence for a substantial polygenic component to risk of SCZ involving thousands of common alleles of very small effect. We show that this component also contributes to risk of bipolar disorder (BPD), but not to multiple non-psychiatric diseases.

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn’s disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10−11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10−9), ANK3 (rs10994359, P = 2.5 × 10−8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10−9).

We conducted a combined genome-wide association (GWAS) analysis of 7,481 individuals affected with bipolar disorder and 9,250 control individuals within the Psychiatric Genomewide Association Study Consortium Bipolar Disorder group (PGC-BD). We performed a replication study in which we tested 34 independent SNPs in 4,493 independent bipolar disorder cases and 42,542 independent controls and found strong evidence for replication. In the replication sample, 18 of 34 SNPs had P value < 0.05, and 31 of 34 SNPs had signals with the same direction of effect (P = 3.8 × 10−7). In the combined analysis of all 63,766 subjects (11,974 cases and 51,792 controls), genome-wide significant evidence for association was confirmed for CACNA1C and found for a novel gene ODZ4. In a combined analysis of non-overlapping schizophrenia and bipolar GWAS samples we observed strong evidence for association with SNPs in CACNA1C and in the region of NEK4/ITIH1,3,4. Pathway analysis identified a pathway comprised of subunits of calcium channels enriched in the bipolar disorder association intervals. The strength of the replication data implies that increasing samples sizes in bipolar disorder will confirm many additional loci.

The disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

A number of recent studies have provided new insights into mechanisms that regulate genomic imprinting in the mammalian genome. Regions of allele-specific differential methylation (DMRs) are present in all imprinted genes examined. Differential methylation is erased in germ cells at an early stage of their development, and germ-line-specific methylation imprints in DMRs are reestablished around the time of birth. After fertilization, differential methylation is retained in core DMRs despite genome-wide demethylation and de novo methylation during preimplantation and early postimplantation stages. Direct repeats near CG-rich DMRs may be involved in the establishment and maintenance of allele-specific methylation patterns. Imprinted genes tend to be clustered; one important component of clustering is enhancer competition, whereby promoters of linked imprinted genes compete for access to enhancers. Regional organization and spreading of the epigenotype during development is also important and depends on DMRs and imprinting centers. The mechanism of cis spreading of DNA methylation is not known, but precedent is provided by the Xist RNA, which results in X chromosome inactivation in cis. Reading of the somatic imprints could be carried out by transcription factors that are sensitive to methylation, or by methyl-cytosine-binding proteins that are involved in transcriptional repression through chromatin remodeling.

A quick-start guide in Macromedia Flash format is available at http://www.genetics.med.ed.ac.uk/suspects/help.shtml and Excel spreadsheets detailing the comparative performance of the software are included as Supplementary material.