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.

We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372 193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P = 1.66 Â 10 À7 ) and tetraspanin-8 (TSPAN8; P = 6.11 Â 10 À7 ). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P = 2.04 Â 10 À8 , TSPAN8; P = 7.57 Â 10 À7 and EGFR; P = 8.36 Â 10 À8 ). For replication, we genotyped 304 SNPs in family-based NIMH samples (n = 409 trios) and University of Edinburgh case-control samples (n = 365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.

Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n ¼ 3518; control, n ¼ 4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (410 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects. Keywords: schizophrenia; copy number variation; mosaic; SNP microarrays INTRODUCTION Schizophrenia (SCZ) is a highly heritable, debilitating psychiatric disorder characterized by psychosis and cognitive deficits, and has a lifetime prevalence of B0.5-0.7%. 1,2 Recent studies into the genetic architecture of this disease have implicated both common singlenucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). [3][4][5] In particular, recent studies of rare CNVs in SCZ have identified both individuals with single events of high penetrance and abundant events across the genome. Specifically, CNVs 4500 kb at 22q11-13, 15q11, 15q13, 3q29, 7q36.3 and 1q21 have been linked to SCZ in B1% of cases. 3,[6][7][8][9] In addition, it has been shown that individuals with SCZ are more likely to carry large, rare CNVs than individuals without the disorder. This 'burden' has also been shown to be significant in singleton CNVs -those CNVs observed only once in a particular sample.Recent reports suggest that somatic structural changes in the nuclear genome are not uncommon and can be identified using SNP genotyping arrays, 10-12 at least when using DNA from white blood cells. These studies have detected a mosaicism rate from 0.23 to 2% and mosaicism has been observed in 7 to 95% of lymphocytes based on probe intensity measures. No disease study has yet revealed a difference between cases and controls on this measure.

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