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      Endometriosis Is Associated with Rare Copy Number Variants

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          Endometriosis is a complex gynecological condition that affects 6–10% of women in their reproductive years and is defined by the presence of endometrial glands and stroma outside the uterus. Twin, family, and genome-wide association (GWA) studies have confirmed a genetic role, yet only a small part of the genetic risk can be explained by SNP variation. Copy number variants (CNVs) account for a greater portion of human genetic variation than SNPs and include more recent mutations of large effect. CNVs, likely to be prominent in conditions with decreased reproductive fitness, have not previously been examined as a genetic contributor to endometriosis. Here we employ a high-density genotyping microarray in a genome-wide survey of CNVs in a case-control population that includes 2,126 surgically confirmed endometriosis cases and 17,974 population controls of European ancestry. We apply stringent quality filters to reduce the false positive rate common to many CNV-detection algorithms from 77.7% to 7.3% without noticeable reduction in the true positive rate. We detected no differences in the CNV landscape between cases and controls on the global level which showed an average of 1.92 CNVs per individual with an average size of 142.3 kb. On the local level we identify 22 CNV-regions at the nominal significance threshold (P<0.05), which is greater than the 8.15 CNV-regions expected based on permutation analysis (P<0.001). Three CNV's passed a genome-wide P-value threshold of 9.3×10 −4; a deletion at SGCZ on 8p22 (P = 7.3×10 −4, OR = 8.5, Cl = 2.3–31.7), a deletion in MALRD1 on 10p12.31 (P = 5.6×10 −4, OR = 14.1, Cl = 2.7–90.9), and a deletion at 11q14.1 (P = 5.7×10 −4, OR = 33.8, Cl = 3.3–1651). Two SNPs within the 22 CNVRs show significant genotypic association with endometriosis after adjusting for multiple testing; rs758316 in DPP6 on 7q36.2 (P = 0.0045) and rs4837864 in ASTN2 on 9q33.1 (P = 0.0002). Together, the CNV-loci are detected in 6.9% of affected women compared to 2.1% in the general population.

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          Large recurrent microdeletions associated with schizophrenia.

          Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
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            Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls

            Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to play an important role in genetic susceptibility to common disease. To address this we undertook a large direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed ~19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated ~50% of all common CNVs larger than 500bp. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell-lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease, IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis, and type 1 diabetes, and TSPAN8 for type 2 diabetes, though in each case the locus had previously been identified in SNP-based studies, reflecting our observation that the majority of common CNVs which are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs which can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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              Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

              More than a thousand disease susceptibility loci have been identified via genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings generally remain to be defined. We utilize pooled next-generation sequencing to study 56 genes in regions associated to Crohn’s Disease in 350 cases and 350 controls. Follow up genotyping of 70 rare and low-frequency protein-altering variants (MAF ~ .001-.05) in nine independent case-control series (16054 CD patients, 12153 UC patients, 17575 healthy controls) identifies four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association to a novel, protective splice variant in CARD9 (p < 1e-16, OR ~ 0.29), as well as additional associations to coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by providing novel, rare, and likely functional variants that will empower functional experiments and predictive models.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1 August 2014
                : 9
                : 8
                : e103968
                [1]Juneau Biosciences, LLC, Salt Lake City, Utah, United States of America
                University of Newcastle, Australia
                Author notes

                Competing Interests: The authors have the following interests, Rakesh Chettier, Kenneth Ward and Hans M. Albertsen are employed by Juneau Biosciences LLC, the funder of this study. All authors have direct financial interest in Juneau Biosciences. A US provisional patent application has been filed by Juneau Biosciences that include the results and inventions reported in the manuscript. Title: Method of Treating Endometriosis Using Genetic Markers. Serial No.: 61/953,673 Filing date: March 14, 2014. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE's policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: RC KW HA. Performed the experiments: RC HA. Analyzed the data: RC HA. Contributed reagents/materials/analysis tools: KW. Contributed to the writing of the manuscript: RC KW HA.

                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 9 May 2014
                : 9 July 2014
                Page count
                Pages: 11
                This study was funded by Juneau Biosciences, LLC. The funder provided support in the form of salaries for authors RC, KW and HA, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Research Article
                Biology and Life Sciences
                Genetic Loci
                Human Genetics
                Population Genetics
                Medicine and Health Sciences
                Clinical Genetics
                Genetic Diseases
                Genetic Testing
                Personalized Medicine
                Women's Health
                Obstetrics and Gynecology
                Custom metadata
                The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. Due to ethical and legal restrictions individual data pertaining to signal intensity, genotypes and CNVs is available for review upon request from Dr. Kenneth Ward.



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