TY - JOUR
T1 - Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk
AU - behalf of the Ovarian Cancer Association Consortium
AU - AOCS study group
AU - Australian Cancer Study (Ovarian Cancer)
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 - Pearce, Celeste L.
N1 - Publisher Copyright:
© The Author 2016. Published by Oxford University Press. All rights reserved.
PY - 2016/8/15
Y1 - 2016/8/15
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.
UR - https://www.scopus.com/pages/publications/85014320352
U2 - 10.1093/hmg/ddw196
DO - 10.1093/hmg/ddw196
M3 - Article
C2 - 27378695
AN - SCOPUS:85014320352
SN - 0964-6906
VL - 25
SP - 3600
EP - 3612
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 16
ER -