Top

Journal of Assisted Reproduction and Genetics

Published in:

01-01-2017 | Genetics

Copy number variation analysis reveals additional variants contributing to endometriosis development

Authors: Fernanda Mafra, Diego Mazzotti, Renata Pellegrino, Bianca Bianco, Caio Parente Barbosa, Hakon Hakonarson, Denise Christofolini

Published in: Journal of Assisted Reproduction and Genetics | Issue 1/2017

Abstract

Purpose

Endometriosis is a gynecological disease influenced by multiple genetic and environmental factors. The aim of the current study was to use SNP-array technology to identify genomic aberrations that may possibly contribute to the development of endometriosis.

Methods

We performed an SNP-array genotyping of pooled DNA samples from both patients (n = 100) and controls (n = 50). Copy number variation (CNV) calling and association analyses were performed using PennCNV software. MLPA and TaqMan Copy-Number assays were used for validation of CNVs discovered.

Results

We detected 49 CNV loci that were present in patients with endometriosis and absent in the control group. After validation procedures, we confirmed six CNV loci in the subtelomeric regions, including 1p36.33, 16p13.3, 19p13.3, and 20p13, representing gains, while 17q25.3 and 20q13.33 showed losses. Among the intrachromosomal regions, our results revealed duplication at 19q13.1 within the FCGBP gene (p = 0.007).

Conclusions

We identified CNVs previously associated with endometriosis, together with six suggestive novel loci possibly involved in this disease. The intergenic locus on chromosome 19q13.1 shows strong association with endometriosis and is under further functional investigation.

Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79.CrossRefPubMed

Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–99.CrossRefPubMed

Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. 2008;1127:106–15.CrossRefPubMedPubMedCentral

de Oliveira R et al. Causes of endometriosis and prevalent infertility in patients undergoing laparoscopy without achieving pregnancy. 2015. Minerva Ginecol.

Bischoff F, Simpson JL. Genetic basis of endometriosis. Ann N Y Acad Sci. 2004;1034:284–99.CrossRefPubMed

Stefansson H et al. Genetic factors contribute to the risk of developing endometriosis. Hum Reprod. 2002;17(3):555–9.CrossRefPubMed

Bouquet De Joliniere J et al. Endometriosis: a new cellular and molecular genetic approach for understanding the pathogenesis and evolutivity. Front Surg. 2014;1:16.PubMedPubMedCentral

Kobayashi H et al. Understanding the role of epigenomic, genomic and genetic alterations in the development of endometriosis (review). Mol Med Rep. 2014;9(5):1483–505.PubMed

Spielman RS, Ewens WJ. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet. 1996;59(5):983–9.PubMedPubMedCentral

10.

Montgomery GW et al. The search for genes contributing to endometriosis risk. Hum Reprod Update. 2008;14(5):447–57.CrossRefPubMedPubMedCentral

11.

Zhang F et al. Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009;10:451–81.CrossRefPubMedPubMedCentral

12.

Treloar SA et al. Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. Am J Hum Genet. 2005;77(3):365–76.CrossRefPubMedPubMedCentral

13.

Yang W et al. High-resolution array-comparative genomic hybridization profiling reveals 20q13.33 alterations associated with ovarian endometriosis. Gynecol Endocrinol. 2013;29(6):603–7.CrossRefPubMed

14.

Chettier R, Ward K, Albertsen HM. Endometriosis is associated with rare copy number variants. PLoS One. 2014;9(8), e103968.CrossRefPubMedPubMedCentral

15.

Welter D et al. The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42(Database issue):D1001–6.CrossRefPubMed

16.

ASRM. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–21.CrossRef

17.

Lahiri DK, Nurnberger Jr JI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19(19):5444.CrossRefPubMedPubMedCentral

18.

Docherty SJ et al. Applicability of DNA pools on 500 K SNP microarrays for cost-effective initial screens in genomewide association studies. BMC Genomics. 2007;8:214.CrossRefPubMedPubMedCentral

19.

Macgregor S et al. Highly cost-efficient genome-wide association studies using DNA pools and dense SNP arrays. Nucleic Acids Res. 2008;36(6), e35.CrossRefPubMedPubMedCentral

20.

Ho DW, Yap MK, Yip SP. UPDG: utilities package for data analysis of pooled DNA GWAS. BMC Genet. 2012;13:1.CrossRefPubMedPubMedCentral

21.

Purcell S et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.CrossRefPubMedPubMedCentral

22.

Wang K et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 2007;17(11):1665–74.CrossRefPubMedPubMedCentral

23.

Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26(6):841–2.CrossRefPubMedPubMedCentral

24.

Glessner JT, Li J, Hakonarson H. ParseCNV integrative copy number variation association software with quality tracking. Nucleic Acids Res. 2013;41(5), e64.CrossRefPubMedPubMedCentral

25.

MacDonald JR et al. The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2014;42(Database issue):D986–92.CrossRefPubMed

26.

Kent WJ et al. The human genome browser at UCSC. Genome Res. 2002;12(6):996–1006.CrossRefPubMedPubMedCentral

27.

Abraham R et al. A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling. BMC Med Genomics. 2008;1:44.CrossRefPubMedPubMedCentral

28.

Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest. 2008;118(5):1590–605.CrossRefPubMedPubMedCentral

29.

Meaburn E et al. Genotyping DNA pools on microarrays: tackling the QTL problem of large samples and large numbers of SNPs. BMC Genomics. 2005;6:52.CrossRefPubMedPubMedCentral

30.

Lin CH et al. Genome-wide copy number analysis using copy number inferring tool (CNIT) and DNA pooling. Hum Mutat. 2008;29(8):1055–62.CrossRefPubMed

31.

Bosse Y et al. Identification of susceptibility genes for complex diseases using pooling-based genome-wide association scans. Hum Genet. 2009;125(3):305–18.CrossRefPubMed

32.

Kim SY, Kim JH, Chung YJ. Effect of combining multiple CNV defining algorithms on the reliability of CNV calls from SNP genotyping data. Genomics Inform. 2012;10(3):194–9.CrossRefPubMedPubMedCentral

33.

Ota VK et al. Candidate genes for schizophrenia in a mixed Brazilian population using pooled DNA. Psychiatry Res. 2013;208(2):201–2.CrossRefPubMed

34.

Albertsen HM et al. Genome-wide association study link novel loci to endometriosis. PLoS One. 2013;8(3), e58257.CrossRefPubMedPubMedCentral

35.

Nyholt DR et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat Genet. 2012;44(12):1355–9.CrossRefPubMedPubMedCentral

36.

Uno S et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet. 2010;42(8):707–10.CrossRefPubMed

37.

Boyer A et al. WNT4 is required for normal ovarian follicle development and female fertility. FASEB J. 2010;24(8):3010–25.CrossRefPubMedPubMedCentral

38.

Vainio S et al. Female development in mammals is regulated by Wnt-4 signalling. Nature. 1999;397(6718):405–9.CrossRefPubMed

39.

Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 2004;303(5663):1483–7.CrossRefPubMedPubMedCentral

40.

Veiga-Castelli LC et al. Genomic alterations detected by comparative genomic hybridization in ovarian endometriomas. Braz J Med Biol Res. 2010;43(8):799–805.CrossRefPubMed

41.

Meola J et al. Differentially expressed genes in eutopic and ectopic endometrium of women with endometriosis. Fertil Steril. 2010;93(6):1750–73.CrossRefPubMed

42.

Torok I et al. Down-regulation of RpS21, a putative translation initiation factor interacting with P40, produces viable minute imagos and larval lethality with overgrown hematopoietic organs and imaginal discs. Mol Cell Biol. 1999;19(3):2308–21.CrossRefPubMedPubMedCentral

43.

Thienpont B et al. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J Med Genet. 2010;47(3):155–61.CrossRefPubMed

44.

Weiss LA et al. A genome-wide linkage and association scan reveals novel loci for autism. Nature. 2009;461(7265):802–8.CrossRefPubMedPubMedCentral

45.

Xiong L et al. NT5E and FcGBP as key regulators of TGF-1-induced epithelial-mesenchymal transition (EMT) are associated with tumor progression and survival of patients with gallbladder cancer. Cell Tissue Res. 2014;355(2):365–74.CrossRefPubMed

46.

Gazi MH et al. Downregulation of IgG Fc binding protein (Fc gammaBP) in prostate cancer. Cancer Biol Ther. 2008;7(1):70–5.CrossRefPubMed

47.

O’Donovan N et al. Differential expression of IgG Fc binding protein (FcgammaBP) in human normal thyroid tissue, thyroid adenomas and thyroid carcinomas. J Endocrinol. 2002;174(3):517–24.CrossRefPubMed

48.

Zhou C et al. Screening of genes related to lung cancer caused by smoking with RNA-Seq. Eur Rev Med Pharmacol Sci. 2014;18(1):117–25.PubMed

49.

Zhu H et al. Screening for differentially expressed genes between left- and right-sided colon carcinoma by microarray analysis. Oncol Lett. 2013;6(2):353–8.PubMedPubMedCentral

50.

Choi CH et al. Identification of differentially expressed genes according to chemosensitivity in advanced ovarian serous adenocarcinomas: expression of GRIA2 predicts better survival. Br J Cancer. 2012;107(1):91–9.CrossRefPubMedPubMedCentral

51.

Kobayashi K et al. Detection of Fcgamma binding protein antigen in human sera and its relation with autoimmune diseases. Immunol Lett. 2001;79(3):229–35.CrossRefPubMed

52.

Cordeiro Q et al. A review of psychiatric genetics research in the Brazilian population. Rev Bras Psiquiatr. 2009;31(2):154–62.CrossRefPubMed

53.

Giolo SR et al. Brazilian urban population genetic structure reveals a high degree of admixture. Eur J Hum Genet. 2012;20(1):111–6.CrossRefPubMed

54.

Yamaguchi-Kabata Y et al. Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am J Hum Genet. 2008;83(4):445–56.CrossRefPubMedPubMedCentral

Title: Copy number variation analysis reveals additional variants contributing to endometriosis development
Authors: Fernanda Mafra
Diego Mazzotti
Renata Pellegrino
Bianca Bianco
Caio Parente Barbosa
Hakon Hakonarson
Denise Christofolini
Publication date: 01-01-2017
Publisher: Springer US
Published in: Journal of Assisted Reproduction and Genetics / Issue 1/2017
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-016-0822-1

At a glance: The STEP trials

Springer Medicine

Copy number variation analysis reveals additional variants contributing to endometriosis development

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

Differences in pregnancy outcomes in donor egg frozen embryo transfer (FET) cycles following preimplantation genetic screening (PGS): a single center retrospective study

Personalizing reproductive medicine—a biological or technocratic imperative?

Single nucleotide polymorphisms in the TGF-β1 gene are associated with polycystic ovary syndrome susceptibility and characteristics: a study in Korean women

Genetic association between PAX2 and mullerian duct anomalies in Han Chinese females

Optimal embryo transfer strategy in poor response may include freeze-all

Improving IVF: is there a limit to our ability to manipulate human biology?