Skip to main content
Journal cover image

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

Publication ,  Journal Article
Permuth, JB; Pirie, A; Ann Chen, Y; Lin, H-Y; Reid, BM; Chen, Z; Monteiro, A; Dennis, J; Mendoza-Fandino, G; AOCS Study Group, ; Bandera, EV ...
Published in: Hum Mol Genet
August 15, 2016

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 -  7). One of the most significant signals (Pall histologies = 1.01 × 10 -  13;Pserous = 3.54 × 10 -  14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 -  5 > P≥5.0 ×10 -  7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 -  5; PSKAT-o = 9.23 × 10 -  4) and KRT13 (PAML = 1.67 × 10 -  4; PSKAT-o = 1.07 × 10 -  5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

August 15, 2016

Volume

25

Issue

16

Start / End Page

3600 / 3612

Location

England

Related Subject Headings

  • Receptor, Melanocortin, Type 2
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Neoplasms, Glandular and Epithelial
  • Neoplasm Proteins
  • Keratin-13
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetics & Heredity
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Permuth, J. B., Pirie, A., Ann Chen, Y., Lin, H.-Y., Reid, B. M., Chen, Z., … Ovarian Cancer Association Consortium, . (2016). Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk. Hum Mol Genet, 25(16), 3600–3612. https://doi.org/10.1093/hmg/ddw196
Permuth, Jennifer B., Ailith Pirie, Y. Ann Chen, Hui-Yi Lin, Brett M. Reid, Zhihua Chen, Alvaro Monteiro, et al. “Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.Hum Mol Genet 25, no. 16 (August 15, 2016): 3600–3612. https://doi.org/10.1093/hmg/ddw196.
Permuth JB, Pirie A, Ann Chen Y, Lin H-Y, Reid BM, Chen Z, et al. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk. Hum Mol Genet. 2016 Aug 15;25(16):3600–12.
Permuth, Jennifer B., et al. “Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.Hum Mol Genet, vol. 25, no. 16, Aug. 2016, pp. 3600–12. Pubmed, doi:10.1093/hmg/ddw196.
Permuth JB, Pirie A, Ann Chen Y, Lin H-Y, Reid BM, Chen Z, Monteiro A, Dennis J, Mendoza-Fandino G, AOCS Study Group, Australian Cancer Study (Ovarian Cancer), Anton-Culver H, Bandera EV, Bisogna M, Brinton L, Brooks-Wilson A, Carney ME, Chenevix-Trench G, Cook LS, Cramer DW, Cunningham JM, Cybulski C, D’Aloisio AA, Anne Doherty J, Earp M, Edwards RP, Fridley BL, Gayther SA, Gentry-Maharaj A, Goodman MT, Gronwald J, Hogdall E, Iversen ES, Jakubowska A, Jensen A, Karlan BY, Kelemen LE, Kjaer SK, Kraft P, Le ND, Levine DA, Lissowska J, Lubinski J, Matsuo K, Menon U, Modugno R, Moysich KB, Nakanishi T, Ness RB, Olson S, Orlow I, Pearce CL, Pejovic T, Poole EM, Ramus SJ, Anne Rossing M, Sandler DP, Shu X-O, Song H, Taylor JA, Teo S-H, Terry KL, Thompson PJ, Tworoger SS, Webb PM, Wentzensen N, Wilkens LR, Winham S, Woo Y-L, Wu AH, Yang H, Zheng W, Ziogas A, Phelan CM, Schildkraut JM, Berchuck A, Goode EL, Pharoah PDP, Sellers TA, Ovarian Cancer Association Consortium. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk. Hum Mol Genet. 2016 Aug 15;25(16):3600–3612.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

August 15, 2016

Volume

25

Issue

16

Start / End Page

3600 / 3612

Location

England

Related Subject Headings

  • Receptor, Melanocortin, Type 2
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Neoplasms, Glandular and Epithelial
  • Neoplasm Proteins
  • Keratin-13
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetics & Heredity