Validation of Copy Number Variants Associated with Schizophrenia Risk in an Irish Population and Implications to Clinical Practice

Schizophrenia is a complex disorder affecting 1% of the population and is highly heritable, but the majority of contributing genetic factors has remained elusive. Current risk estimates for clinical practice are primarily determined by family history and associated empirical risk. Copy number variants (CNVs) may hold the key to explaining the missing heritability in schizophrenia research; schizophrenia risk estimates as high as 30% have been found for the most-studied CNV associated with schizophrenia, 22q11. Currently, there are methods to identify CNVs though previously collected data from SNP microarrays that would facilitate these types of studies. To determine if algorithms that call CNVs from microarray data are robust four genomic regions with putative CNVs called by the Wellcome Trust Consortium using Birdseye in Birdsuite with Affymetrix 6.0 array raw SNP intensities, primarily affecting genes CHD1L, COX5B, PAK7, ZFYVE20, were validated using Taqman real-time qPCR assays in 29 samples by research groups at VCU and Dublin. CNVs called from the algorithm were 100% validated at VCU though there were false negatives from the algorithm that were validated. Two samples at loci with putative duplications were not called by the Dublin group, which may be because of differing sensitivities of the Taqman assays to be able to detect a 50% difference in copy number between duplications and diploid controls, or because of another technical or analytical difference between the two sites. Deletion frequency of one common CNV found in the gene ERBB4, was assessed by qPCR in both Irish singleton (ICCSS) and Irish family (IHDSF) samples and compared with Irish control (Trinity Biobank) and North American control populations. The ERBB4 deletion frequency was not significantly different when comparing the Irish controls to the Irish singleton or the Irish family samples though the family samples were different when compared against the North American control population, which suggests population stratification, rather than a true association between ERBB4 and increased schizophrenia risk. Current clinical practice has been improved by knowledge and evaluation of CNV-related disorders that include risk for psychosis and additional phenotypes. Genotyping of individuals with known psychosis has led to improved patient care for non-psychosis-related phenotypes associated with CNVs. Individuals with suspected genomic disorders that are found to have CNVs can be counseled on potential psychosis risk and potential risk to their offspring. Recurrent CNVs may hold promise in future clinical practice in order to individualize risk estimates in the general patient population, and increase the number of individuals able to receive anticipatory treatment to minimize disease severity

An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis

FUNDING Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. ACKNOWLEDGEMENTS The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank Akira Sawa and Koko Ishzuki for advice on the PAK7–DISC1 interaction experiment and Jan Korbel for discussions on mechanism of structural variation.Peer reviewedPublisher PD

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio