{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T04:31:41Z","timestamp":1793939501066,"version":"4.8.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T00:00:00Z","timestamp":1556496000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T00:00:00Z","timestamp":1556496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007044","name":"Macula Vision Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007044","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic central serous chorioretinopathy (cCSC) is a multifactorial eye disease characterized by subretinal fluid accumulation that leads to vision loss. Clinically, cCSC is associated with stress, hypercortisolism and corticosteroid use, and is more frequent in males (80%) than in females (20%). Current genetic studies on cCSC have thus far focussed on common variants, but familial occurrence of cCSC also suggests a role for rare variants in the disease susceptibility. Therefore, in this study, we performed exome sequencing of cCSC patients to elucidate the role of rare (protein-altering) variants in the disease. Exome sequencing was performed on 269 cCSC patients and 1,586 controls. Data were processed according to the Genome-Analysis-Toolkit (GATK) best practices. Principal component analysis was performed to check for genetic ancestry and only unrelated subjects of European descent were retained. Burden, SKAT and SKAT-O tests were performed using 2 different grouping criteria. One group included protein-altering variants only, while the other contained synonymous and splice site variants as well. The gene-based analyses were performed using the SKAT R-package correcting for two principal components using two approaches; (1) on the entire cohort correcting for sex and (2) on males and females separately. Additionally, the gene-based associations of genes at previously reported cCSC loci were investigated. After filtering, the dataset contained 263 cCSC patients (208 males [79%]) and 1352 controls (671 males [50%]) carrying 197,915 protein-altering variants in 16,370 genes and 330,689 exonic variants in 18,173 genes. Analysis stratified by sex identified significant associations with the <jats:italic>PIGZ<\/jats:italic> (P<jats:sub>SKAT<\/jats:sub>\u2009=\u20099.19\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup> &amp; P<jats:sub>SKAT-O<\/jats:sub>\u2009=\u20092.48\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>), <jats:italic>DUOX1<\/jats:italic> (P<jats:sub>SKAT<\/jats:sub>\u2009=\u20091.03\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>), <jats:italic>RSAD1<\/jats:italic> (P<jats:sub>SKAT<\/jats:sub>\u2009=\u20091.92\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup> &amp; P<jats:sub>SKAT-O<\/jats:sub>\u2009=\u20098.57\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>) and <jats:italic>LAMB3<\/jats:italic> (P<jats:sub>Burden<\/jats:sub>\u2009=\u20091.40\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup> &amp; P<jats:sub>SKAT-O<\/jats:sub>\u2009=\u20091.14\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>) genes in female cCSC patients, after correction for multiple testing. The number of rare variant carriers in these genes was significantly higher in the female cCSC cohort compared to female controls (45,5% vs. 18.5%, P\u2009=\u20091.92\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>, OR\u2009=\u20093.67 [95% CI\u2009=\u20092.09\u20136.46]). No significant associations were identified in the entire cohort nor in the male patients. In this exome study on cCSC patients, we have identified <jats:italic>PIGZ<\/jats:italic>, <jats:italic>DUOX1, RSAD1<\/jats:italic> and <jats:italic>LAMB3<\/jats:italic> as potential new candidate genes for cCSC in females. The sex-specific associations identified here suggest a possible interaction between rare genetic factors and sex for cCSC, but replication of these findings in additional cohorts of cCSC patients is necessary.<\/jats:p>","DOI":"10.1038\/s41598-019-43152-3","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T13:52:08Z","timestamp":1556545928000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Exome sequencing in patients with chronic central serous chorioretinopathy"],"prefix":"10.1038","volume":"9","author":[{"given":"Rosa L.","family":"Schellevis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myrte B.","family":"Breukink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1693-9699","authenticated-orcid":false,"given":"Christian","family":"Gilissen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camiel J. F.","family":"Boon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carel B.","family":"Hoyng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiko K.","family":"de Jong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0634-5408","authenticated-orcid":false,"given":"Anneke I.","family":"den Hollander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,4,29]]},"reference":[{"key":"43152_CR1","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.preteyeres.2015.05.003","volume":"48","author":"A Daruich","year":"2015","unstructured":"Daruich, A. et al. Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis. Prog Retin Eye Res 48, 82\u2013118, https:\/\/doi.org\/10.1016\/j.preteyeres.2015.05.003 (2015).","journal-title":"Prog Retin Eye Res"},{"key":"43152_CR2","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.ophtha.2007.02.032","volume":"115","author":"AS Kitzmann","year":"2008","unstructured":"Kitzmann, A. S., Pulido, J. S., Diehl, N. N., Hodge, D. O. & Burke, J. P. The incidence of central serous chorioretinopathy in Olmsted County, Minnesota, 1980\u20132002. Ophthalmology 115, 169\u2013173, https:\/\/doi.org\/10.1016\/j.ophtha.2007.02.032 (2008).","journal-title":"Ophthalmology"},{"key":"43152_CR3","doi-asserted-by":"publisher","unstructured":"van Dijk, E. H. C. et al. Familial Central Serous Chorioretinopathy. Retina, https:\/\/doi.org\/10.1097\/IAE.0000000000001966 (2017).","DOI":"10.1097\/IAE.0000000000001966"},{"key":"43152_CR4","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1159\/000050855","volume":"215","author":"AC Weenink","year":"2001","unstructured":"Weenink, A. C., Borsje, R. A. & Oosterhuis, J. A. Familial chronic central serous chorioretinopathy. Ophthalmologica. Journal international d\u2019ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde 215, 183\u2013187, https:\/\/doi.org\/10.1159\/000050855 (2001).","journal-title":"Ophthalmologica. Journal international d\u2019ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde"},{"key":"43152_CR5","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1016\/j.ophtha.2013.11.020","volume":"121","author":"A Miki","year":"2014","unstructured":"Miki, A. et al. Common variants in the complement factor H gene confer genetic susceptibility to central serous chorioretinopathy. Ophthalmology 121, 1067\u20131072, https:\/\/doi.org\/10.1016\/j.ophtha.2013.11.020 (2014).","journal-title":"Ophthalmology"},{"key":"43152_CR6","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1016\/j.ophtha.2014.09.026","volume":"122","author":"EK de Jong","year":"2015","unstructured":"de Jong, E. K. et al. Chronic central serous chorioretinopathy is associated with genetic variants implicated in age-related macular degeneration. Ophthalmology 122, 562\u2013570, https:\/\/doi.org\/10.1016\/j.ophtha.2014.09.026 (2015).","journal-title":"Ophthalmology"},{"key":"43152_CR7","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1002\/humu.22551","volume":"35","author":"C Schubert","year":"2014","unstructured":"Schubert, C. et al. Cadherin 5 is regulated by corticosteroids and associated with central serous chorioretinopathy. Human mutation 35, 859\u2013867, https:\/\/doi.org\/10.1002\/humu.22551 (2014).","journal-title":"Human mutation"},{"key":"43152_CR8","doi-asserted-by":"publisher","unstructured":"van Dijk, E. H. et al. Association of a Haplotype in the NR3C2 Gene, Encoding the Mineralocorticoid Receptor, With Chronic Central Serous Chorioretinopathy. JAMA ophthalmology, https:\/\/doi.org\/10.1001\/jamaophthalmol.2017.0245 (2017).","DOI":"10.1001\/jamaophthalmol.2017.0245"},{"key":"43152_CR9","doi-asserted-by":"publisher","first-page":"5608","DOI":"10.1167\/iovs.15-17343","volume":"56","author":"MB Breukink","year":"2015","unstructured":"Breukink, M. B. et al. Genomic Copy Number Variations of the Complement Component C4B Gene Are Associated With Chronic Central Serous Chorioretinopathy. Invest Ophthalmol Vis Sci 56, 5608\u20135613, https:\/\/doi.org\/10.1167\/iovs.15-17343 (2015).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"43152_CR10","doi-asserted-by":"publisher","unstructured":"Schellevis, R. L. et al. Role of the Complement System in Chronic Central Serous Chorioretinopathy: A Genome-Wide Association Study. JAMA Ophthalmol, https:\/\/doi.org\/10.1001\/jamaophthalmol.2018.3190 (2018).","DOI":"10.1001\/jamaophthalmol.2018.3190"},{"key":"43152_CR11","doi-asserted-by":"publisher","first-page":"6261","DOI":"10.1073\/pnas.1802212115","volume":"115","author":"Y Hosoda","year":"2018","unstructured":"Hosoda, Y. et al. CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy. Proc Natl Acad Sci USA 115, 6261\u20136266, https:\/\/doi.org\/10.1073\/pnas.1802212115 (2018).","journal-title":"Proc Natl Acad Sci USA"},{"key":"43152_CR12","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1038\/nn.4352","volume":"19","author":"SH Lelieveld","year":"2016","unstructured":"Lelieveld, S. H. et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci 19, 1194\u20131196, https:\/\/doi.org\/10.1038\/nn.4352 (2016).","journal-title":"Nat Neurosci"},{"key":"43152_CR13","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome research 20, 1297\u20131303, https:\/\/doi.org\/10.1101\/gr.107524.110 (2010).","journal-title":"Genome research"},{"key":"43152_CR14","doi-asserted-by":"publisher","first-page":"2867","DOI":"10.1093\/bioinformatics\/btq559","volume":"26","author":"A Manichaikul","year":"2010","unstructured":"Manichaikul, A. et al. Robust relationship inference in genome-wide association studies. Bioinformatics 26, 2867\u20132873, https:\/\/doi.org\/10.1093\/bioinformatics\/btq559 (2010).","journal-title":"Bioinformatics"},{"key":"43152_CR15","doi-asserted-by":"publisher","first-page":"2843","DOI":"10.1093\/bioinformatics\/btu356","volume":"30","author":"H Li","year":"2014","unstructured":"Li, H. Toward better understanding of artifacts in variant calling from high-coverage samples. Bioinformatics 30, 2843\u20132851, https:\/\/doi.org\/10.1093\/bioinformatics\/btu356 (2014).","journal-title":"Bioinformatics"},{"key":"43152_CR16","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/gim.2013.73","volume":"15","author":"RC Green","year":"2013","unstructured":"Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine: official journal of the American College of Medical Genetics 15, 565\u2013574, https:\/\/doi.org\/10.1038\/gim.2013.73 (2013).","journal-title":"Genetics in medicine: official journal of the American College of Medical Genetics"},{"key":"43152_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/biostatistics\/kxv033","volume":"17","author":"S Lee","year":"2016","unstructured":"Lee, S., Fuchsberger, C., Kim, S. & Scott, L. An efficient resampling method for calibrating single and gene-based rare variant association analysis in case-control studies. Biostatistics 17, 1\u201315, https:\/\/doi.org\/10.1093\/biostatistics\/kxv033 (2016).","journal-title":"Biostatistics"},{"key":"43152_CR18","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.ajhg.2012.06.007","volume":"91","author":"S Lee","year":"2012","unstructured":"Lee, S. et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. American journal of human genetics 91, 224\u2013237, https:\/\/doi.org\/10.1016\/j.ajhg.2012.06.007 (2012).","journal-title":"American journal of human genetics"},{"key":"43152_CR19","doi-asserted-by":"publisher","first-page":"27","DOI":"10.2307\/2336755","volume":"80","author":"D Firth","year":"1993","unstructured":"Firth, D. Bias Reduction of Maximum-Likelihood-Estimates. Biometrika 80, 27\u201338, https:\/\/doi.org\/10.2307\/2336755 (1993).","journal-title":"Biometrika"},{"key":"43152_CR20","unstructured":"Sinnwell, J. P. & Schaid D. J. haplo.stats: statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous; R package version 1.7.7, https:\/\/CRAN.R-project.org\/package=haplo.stats."},{"key":"43152_CR21","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/nrg3051","volume":"12","author":"ZE Sauna","year":"2011","unstructured":"Sauna, Z. E. & Kimchi-Sarfaty, C. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet 12, 683\u2013691, https:\/\/doi.org\/10.1038\/nrg3051 (2011).","journal-title":"Nat Rev Genet"},{"key":"43152_CR22","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1038\/nrg2167","volume":"8","author":"H Ellegren","year":"2007","unstructured":"Ellegren, H. & Parsch, J. The evolution of sex-biased genes and sex-biased gene expression. Nat Rev Genet 8, 689\u2013698, https:\/\/doi.org\/10.1038\/nrg2167 (2007).","journal-title":"Nat Rev Genet"},{"key":"43152_CR23","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1038\/nrg2415","volume":"9","author":"C Ober","year":"2008","unstructured":"Ober, C., Loisel, D. A. & Gilad, Y. Sex-specific genetic architecture of human disease. Nat Rev Genet 9, 911\u2013922, https:\/\/doi.org\/10.1038\/nrg2415 (2008).","journal-title":"Nat Rev Genet"},{"key":"43152_CR24","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1002\/art.40484","volume":"70","author":"AJW Haasnoot","year":"2018","unstructured":"Haasnoot, A. J. W. et al. Identification of an Amino Acid Motif in HLA-DRbeta1 That Distinguishes Uveitis in Patients With Juvenile Idiopathic Arthritis. Arthritis Rheumatol 70, 1155\u20131165, https:\/\/doi.org\/10.1002\/art.40484 (2018).","journal-title":"Arthritis Rheumatol"},{"key":"43152_CR25","doi-asserted-by":"publisher","first-page":"e28","DOI":"10.1371\/journal.pgen.0040028","volume":"4","author":"S Shifman","year":"2008","unstructured":"Shifman, S. et al. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet 4, e28, https:\/\/doi.org\/10.1371\/journal.pgen.0040028 (2008).","journal-title":"PLoS Genet"},{"key":"43152_CR26","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1097\/IAE.0000000000000837","volume":"36","author":"B Liu","year":"2016","unstructured":"Liu, B., Deng, T. & Zhang, J. Risk Factors for Central Serous Chorioretinopathy: A Systematic Review and Meta-Analysis. Retina 36, 9\u201319, https:\/\/doi.org\/10.1097\/IAE.0000000000000837 (2016).","journal-title":"Retina"},{"key":"43152_CR27","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1016\/j.fertnstert.2010.01.068","volume":"94","author":"Y Zhao","year":"2010","unstructured":"Zhao, Y. et al. The impact of luteal phase support on gene expression of extracellular matrix protein and adhesion molecules in the human endometrium during the window of implantation following controlled ovarian stimulation with a GnRH antagonist protocol. Fertil Steril 94, 2264\u20132271, https:\/\/doi.org\/10.1016\/j.fertnstert.2010.01.068 (2010).","journal-title":"Fertil Steril"},{"key":"43152_CR28","doi-asserted-by":"publisher","first-page":"28835","DOI":"10.1074\/jbc.M114.583450","volume":"289","author":"E Ko","year":"2014","unstructured":"Ko, E. et al. Testosterone stimulates Duox1 activity through GPRC6A in skin keratinocytes. J Biol Chem 289, 28835\u201328845, https:\/\/doi.org\/10.1074\/jbc.M114.583450 (2014).","journal-title":"J Biol Chem"},{"key":"43152_CR29","doi-asserted-by":"publisher","unstructured":"Bryan, J. M. et al. Identifying core biological processes distinguishing human eye tissues with precise systems-level gene expression analyses and weighted correlation networks. Human Molecular Genetics, ddy239, https:\/\/doi.org\/10.1093\/hmg\/ddy239 (2018).","DOI":"10.1093\/hmg\/ddy239"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43152-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43152-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43152-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T09:01:06Z","timestamp":1671267666000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43152-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,29]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["43152"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-43152-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,29]]},"assertion":[{"value":"12 October 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 April 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"6598"}}