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

Jennifer B Permuth; Ailith Pirie; Y Ann Chen; Hui-Yi Lin; Brett M Reid; Zhihua Chen; Alvaro Monteiro; Joe Dennis; Gustavo Mendoza-Fandino; Hoda Anton-Culver; Elisa V Bandera; Maria Bisogna; Louise Brinton; Angela Brooks-Wilson; Michael E Carney; Georgia Chenevix-Trench; Linda S Cook; Daniel W Cramer; Julie M Cunningham; Cezary Cybulski; Aimee A D'Aloisio; Jennifer Anne Doherty; Madalene Earp; Robert P Edwards; Brooke L Fridley; Simon A Gayther; Aleksandra Gentry-Maharaj; Marc T Goodman; Jacek Gronwald; Estrid Vilma Solyom Høgdall; Edwin S Iversen; Anna Jakubowska; Allan Jensen; Beth Y Karlan; Linda E Kelemen; Susanne Krüger Kjær; Peter Kraft; Nhu D Le; Douglas A Levine; Jolanta Lissowska; Jan Lubinski; Keitaro Matsuo; Usha Menon; Rosemary Modugno; Kirsten B Moysich; Toru Nakanishi; Roberta B Ness; Sara Olson; Irene Orlow; Celeste L Pearce; AOCS Study Group

doi:10.1093/hmg/ddw196

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

Jennifer B Permuth, Ailith Pirie, Y Ann Chen, Hui-Yi Lin, Brett M Reid, Zhihua Chen, Alvaro Monteiro, Joe Dennis, Gustavo Mendoza-Fandino, Hoda Anton-Culver, Elisa V Bandera, Maria Bisogna, Louise Brinton, Angela Brooks-Wilson, Michael E Carney, Georgia Chenevix-Trench, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary CybulskiAimee A D'Aloisio, Jennifer Anne Doherty, Madalene Earp, Robert P Edwards, Brooke L Fridley, Simon A Gayther, Aleksandra Gentry-Maharaj, Marc T Goodman, Jacek Gronwald, Estrid Vilma Solyom Høgdall, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Beth Y Karlan, Linda E Kelemen, Susanne Krüger Kjær, Peter Kraft, Nhu D Le, Douglas A Levine, Jolanta Lissowska, Jan Lubinski, Keitaro Matsuo, Usha Menon, Rosemary Modugno, Kirsten B Moysich, Toru Nakanishi, Roberta B Ness, Sara Olson, Irene Orlow, Celeste L Pearce, AOCS Study Group

Department of Pathology

18 Citations (Scopus)

Abstract

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 (r(2 )=( )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.

Original language	English
Journal	Human Molecular Genetics
Volume	25
Issue number	16
Pages (from-to)	3600-3612
Number of pages	13
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddw196
Publication status	Published - 15 Aug 2016

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10.1093/hmg/ddw196

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Permuth, J. B., Pirie, A., Ann Chen, Y., Lin, H.-Y., Reid, B. M., Chen, Z., Monteiro, A., Dennis, J., Mendoza-Fandino, G., Anton-Culver, H., Bandera, E. V., Bisogna, M., Brinton, L., Brooks-Wilson, A., Carney, M. E., Chenevix-Trench, G., Cook, L. S., Cramer, D. W., Cunningham, J. M., ... AOCS Study Group (2016). 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

Permuth, JB, Pirie, A, Ann Chen, Y, Lin, H-Y, Reid, BM, Chen, Z, Monteiro, A, Dennis, J, Mendoza-Fandino, G, 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, Høgdall, EVS, Iversen, ES, Jakubowska, A, Jensen, A, Karlan, BY, Kelemen, LE, Kjær, 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 & AOCS Study Group 2016, '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

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

abstract = "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 (r(2 )=( )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.",

author = "Permuth, \{Jennifer B\} and Ailith Pirie and \{Ann Chen\}, Y and Hui-Yi Lin 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 \{Anne Doherty\}, Jennifer 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 H{\o}gdall, \{Estrid Vilma Solyom\} and Iversen, \{Edwin S\} and Anna Jakubowska and Allan Jensen and Karlan, \{Beth Y\} and Kelemen, \{Linda E\} and Kj{\ae}r, \{Susanne Kr{\"u}ger\} 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 Pearce, \{Celeste L\} and \{AOCS Study Group\}",

year = "2016",

month = aug,

day = "15",

doi = "10.1093/hmg/ddw196",

language = "English",

volume = "25",

pages = "3600--3612",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

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TY - JOUR

T1 - Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk

AU - Permuth, Jennifer B

AU - Pirie, Ailith

AU - Ann Chen, Y

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 - Anne Doherty, Jennifer

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 - Høgdall, Estrid Vilma Solyom

AU - Iversen, Edwin S

AU - Jakubowska, Anna

AU - Jensen, Allan

AU - Karlan, Beth Y

AU - Kelemen, Linda E

AU - Kjær, Susanne Krüger

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 - Pearce, Celeste L

AU - AOCS Study Group

PY - 2016/8/15

Y1 - 2016/8/15

N2 - 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 (r(2 )=( )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.

AB - 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 (r(2 )=( )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.

UR - https://www.scopus.com/pages/publications/85014320352

U2 - 10.1093/hmg/ddw196

DO - 10.1093/hmg/ddw196

M3 - Journal article

C2 - 27378695

SN - 0964-6906

VL - 25

SP - 3600

EP - 3612

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -

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

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