Dataset Information

The Ovarian Cancer Association Consortium OncoArray genome-wide association study

ABSTRACT: A custom Illumina genotyping array, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis as described in PMID:27697780.The array was used to genotype ovarian cancer cases and controls from multiple studies participating in the Ovarian Cancer Association Consortium, of which 54,747 passes QC.An initial principal components analysis was carried out using a method described in PMID:27697780 to assign subject to intercontinental ancestry groups: “European”, “African”, “Asian” and "Other". Within ancestry principal components analysis was carried using a set of ~33k unlinked markers. Subsequent analyses were adjusted for the ancestry specific PCs: 9 Eur, 10 Asian, 1 African and 6 Mixed. These PCs are included in the imputed dataset phenotypes file

PROVIDER: EGAS00001002305 | EGA |

REPOSITORIES: EGA

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Publications

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers.

Amos Christopher I CI Dennis Joe J Wang Zhaoming Z Byun Jinyoung J Schumacher Fredrick R FR Gayther Simon A SA Casey Graham G Hunter David J DJ Sellers Thomas A TA Gruber Stephen B SB Dunning Alison M AM Michailidou Kyriaki K Fachal Laura L Doheny Kimberly K Spurdle Amanda B AB Li Yafang Y Xiao Xiangjun X Romm Jane J Pugh Elizabeth E Coetzee Gerhard A GA Hazelett Dennis J DJ Bojesen Stig E SE Caga-Anan Charlisse C Haiman Christopher A CA Kamal Ahsan A Luccarini Craig C Tessier Daniel D Vincent Daniel D Bacot François F Van Den Berg David J DJ Nelson Stefanie S Demetriades Stephen S Goldgar David E DE Couch Fergus J FJ Forman Judith L JL Giles Graham G GG Conti David V DV Bickeböller Heike H Risch Angela A Waldenberger Melanie M Brüske-Hohlfeld Irene I Hicks Belynda D BD Ling Hua H McGuffog Lesley L Lee Andrew A Kuchenbaecker Karoline K Soucy Penny P Manz Judith J Cunningham Julie M JM Butterbach Katja K Kote-Jarai Zsofia Z Kraft Peter P FitzGerald Liesel L Lindström Sara S Adams Marcia M McKay James D JD Phelan Catherine M CM Benlloch Sara S Kelemen Linda E LE Brennan Paul P Riggan Marjorie M O'Mara Tracy A TA Shen Hongbing H Shi Yongyong Y Thompson Deborah J DJ Goodman Marc T MT Nielsen Sune F SF Berchuck Andrew A Laboissiere Sylvie S Schmit Stephanie L SL Shelford Tameka T Edlund Christopher K CK Taylor Jack A JA Field John K JK Park Sue K SK Offit Kenneth K Thomassen Mads M Schmutzler Rita R Ottini Laura L Hung Rayjean J RJ Marchini Jonathan J Amin Al Olama Ali A Peters Ulrike U Eeles Rosalind A RA Seldin Michael F MF Gillanders Elizabeth E Seminara Daniela D Antoniou Antonis C AC Pharoah Paul D P PD Chenevix-Trench Georgia G Chanock Stephen J SJ Simard Jacques J Easton Douglas F DF

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20161003 1

<h4>Background</h4>Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic m ...[more]

PMID: 27697780

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Project description:Background: Mortality from preeclampsia (PE) and PE-associated morbidities are 3-to 5-fold higher in persons of African ancestry than in those of Asian and European ancestries. The placenta is central to the etiology of PE. However, how and to what extent the placenta contributes to worse PE outcomes in persons of African ancestry is yet to be fully elucidated. Objective: We aimed to identify molecular pathways that are unique or enriched in placentas of parturient persons of African ancestry with PE with severe features (sPE) compared to those of Asian and European ancestry with sPE. Study design: Bulk RNA sequencing was performed on 50 placentas from parturient persons with sPE of African (n=9), Asian (n=18) and European (n=23) ancestries and 73 normotensive controls of African (n=9), Asian (n=15) and European (n=49) ancestries. Results: Metabolism, hormone regulation and hypoxia/angiogenesis genes, previously described to be upregulated in PE, including: LEP, PAPPA2, INHA, FSTL3, FLT1, PHYHIP and ENG, were upregulated in sPE across ancestries, with high expression of FSTL3 being additionally associated with intrauterine growth restriction (p<.0001). Notably, LEP, FLT1 and PHYHIP were more highly upregulated in sPE placentas from parturient persons of African versus Asian ancestry. Genes associated with allograft rejection and adaptive immune response were selectively upregulated in placentas from African ancestry parturitions and not in those of Asian and European ancestries. Among the allograft rejection/adaptive immune response genes, IL3RA was of particular interest because the patient with the highest placental IL3RA level, a woman of African ancestry with IL3RA levels 4.5-fold above the average for African ancestry parturitions with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients of Asian and European ancestries with the highest IL3RA levels for their ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placental IL3RA levels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p=.0005). Conclusions: African ancestry parturitions are associated with higher placental upregulation of metabolism (LEP) and hypoxia/angiogenesis (FLT1) genes, and selective upregulation of allograft rejection/adaptive immune response genes, including IL3RA. High placental expression of IL3RA may predict worse maternal cardiovascular outcomes, including peripartum cardiomyopathy. Studies evaluating placental IL3RA levels in peripartum cardiomyopathy cohorts are therefore warranted, as are broader studies evaluating placental factors in maternal cardiovascular outcomes postpartum.

Dataset Information

The Ovarian Cancer Association Consortium OncoArray genome-wide association study

Publications

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers.

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