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

AOCS study group, Australian Cancer Study (Ovarian Cancer), behalf of the Ovarian Cancer Association Consortium

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Rare and low frequency variants are not well covered inmost 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 themost significant signals (Pall histologies=1.01×10-13;Pserous=3.54×10-14) occurred at 3q25.31 for rs62273959, amissense variantmapping 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 raremissense 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). Genesmost 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 thatmay 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.

Original languageEnglish (US)
Pages (from-to)3600-3612
Number of pages13
JournalHuman Molecular Genetics
Volume25
Issue number16
DOIs
StatePublished - 2015

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Exome
Linkage Disequilibrium
Protein Transport
Gene Frequency
Ovarian Neoplasms
Epidemiology
Ovarian epithelial cancer
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

AOCS study group, Australian Cancer Study (Ovarian Cancer), & behalf of the Ovarian Cancer Association Consortium (2015). Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk. Human Molecular Genetics, 25(16), 3600-3612. https://doi.org/10.1093/hmg/ddw196

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk. / AOCS study group; Australian Cancer Study (Ovarian Cancer); behalf of the Ovarian Cancer Association Consortium.

In: Human Molecular Genetics, Vol. 25, No. 16, 2015, p. 3600-3612.

Research output: Contribution to journalArticle

AOCS study group, Australian Cancer Study (Ovarian Cancer) & behalf of the Ovarian Cancer Association Consortium 2015, 'Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk', Human Molecular Genetics, vol. 25, no. 16, pp. 3600-3612. https://doi.org/10.1093/hmg/ddw196
AOCS study group, Australian Cancer Study (Ovarian Cancer), behalf of the Ovarian Cancer Association Consortium. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk. Human Molecular Genetics. 2015;25(16):3600-3612. https://doi.org/10.1093/hmg/ddw196
AOCS study group ; Australian Cancer Study (Ovarian Cancer) ; behalf of the Ovarian Cancer Association Consortium. / Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk. In: Human Molecular Genetics. 2015 ; Vol. 25, No. 16. pp. 3600-3612.
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abstract = "Rare and low frequency variants are not well covered inmost 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 themost significant signals (Pall histologies=1.01×10-13;Pserous=3.54×10-14) occurred at 3q25.31 for rs62273959, amissense variantmapping 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 raremissense 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). Genesmost 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 thatmay 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.",
author = "{AOCS study group} and {Australian Cancer Study (Ovarian Cancer)} and {behalf of the Ovarian Cancer Association Consortium} and Permuth, {Jennifer B.} and Ailith Pirie and Chen, {Y. Ann} and Lin, {Hui Yi} and Reid, {Brett M.} and Zhihua Chen and Alvaro Monteiro and Joe Dennis and Gustavo Mendoza-Fandino and Hoda Anton-Culver and Bandera, {Elisa V.} and Maria Bisogna and Louise Brinton and Angela Brooks-Wilson and Carney, {Michael E.} and Georgia Chenevix-Trench and Cook, {Linda S.} and Cramer, {Daniel W.} and Cunningham, {Julie M.} and Cezary Cybulski and D'Aloisio, {Aimee A.} and Doherty, {Jennifer Anne} and Madalene Earp and Edwards, {Robert P.} and Fridley, {Brooke L.} and Gayther, {Simon A.} and Aleksandra Gentry-Maharaj and Goodman, {Marc T.} and Jacek Gronwald and Estrid Hogdall and Iversen, {Edwin S.} and Anna Jakubowska and Allan Jensen and Karlan, {Beth Y.} and Kelemen, {Linda E.} and Kjaer, {Suzanne K.} and Peter Kraft and Le, {Nhu D.} and Levine, {Douglas A.} and Jolanta Lissowska and Jan Lubinski and Keitaro Matsuo and Usha Menon and Rosemary Modugno and Moysich, {Kirsten B.} and Toru Nakanishi and Ness, {Roberta B.} and Sara Olson and Irene Orlow and Tanja Pejovic",
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T1 - Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk

AU - AOCS study group

AU - Australian Cancer Study (Ovarian Cancer)

AU - behalf of the Ovarian Cancer Association Consortium

AU - Permuth, Jennifer B.

AU - Pirie, Ailith

AU - Chen, Y. Ann

AU - Lin, Hui Yi

AU - Reid, Brett M.

AU - Chen, Zhihua

AU - Monteiro, Alvaro

AU - Dennis, Joe

AU - Mendoza-Fandino, Gustavo

AU - Anton-Culver, Hoda

AU - Bandera, Elisa V.

AU - Bisogna, Maria

AU - Brinton, Louise

AU - Brooks-Wilson, Angela

AU - Carney, Michael E.

AU - Chenevix-Trench, Georgia

AU - Cook, Linda S.

AU - Cramer, Daniel W.

AU - Cunningham, Julie M.

AU - Cybulski, Cezary

AU - D'Aloisio, Aimee A.

AU - Doherty, Jennifer Anne

AU - Earp, Madalene

AU - Edwards, Robert P.

AU - Fridley, Brooke L.

AU - Gayther, Simon A.

AU - Gentry-Maharaj, Aleksandra

AU - Goodman, Marc T.

AU - Gronwald, Jacek

AU - Hogdall, Estrid

AU - Iversen, Edwin S.

AU - Jakubowska, Anna

AU - Jensen, Allan

AU - Karlan, Beth Y.

AU - Kelemen, Linda E.

AU - Kjaer, Suzanne K.

AU - Kraft, Peter

AU - Le, Nhu D.

AU - Levine, Douglas A.

AU - Lissowska, Jolanta

AU - Lubinski, Jan

AU - Matsuo, Keitaro

AU - Menon, Usha

AU - Modugno, Rosemary

AU - Moysich, Kirsten B.

AU - Nakanishi, Toru

AU - Ness, Roberta B.

AU - Olson, Sara

AU - Orlow, Irene

AU - Pejovic, Tanja

PY - 2015

Y1 - 2015

N2 - Rare and low frequency variants are not well covered inmost 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 themost significant signals (Pall histologies=1.01×10-13;Pserous=3.54×10-14) occurred at 3q25.31 for rs62273959, amissense variantmapping 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 raremissense 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). Genesmost 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 thatmay 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.

AB - Rare and low frequency variants are not well covered inmost 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 themost significant signals (Pall histologies=1.01×10-13;Pserous=3.54×10-14) occurred at 3q25.31 for rs62273959, amissense variantmapping 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 raremissense 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). Genesmost 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 thatmay 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.

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