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 (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.
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Permuth
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Ailith
authors.initials: A
authors.lastname: Pirie
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ann Chen
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Reid
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Monteiro
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Dennis
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Mendoza-Fandino
authors.affiliation: Department of Epidemiology, Director of Genetic Epidemiology Research Institute, UCI School of Medicine, University of California Irvine, Irvine, CA, USA.
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.affiliation: Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.affiliation: Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Bisogna
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Brinton
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver BC, Canada.|Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Brooks-Wilson
authors.affiliation: Department of Obstetrics and Gynecology, John A Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Carney
authors.affiliation: Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Queensland, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Cook
authors.affiliation: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Cramer
authors.affiliation: Department of Laboratory of Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Cybulski
authors.affiliation: Social and Scientific Systems, Inc, Durham, NC, USA.
authors.forename: Aimee A
authors.initials: AA
authors.lastname: D'Aloisio
authors.affiliation: Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NY, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Anne Doherty
authors.affiliation: Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Madalene
authors.initials: M
authors.lastname: Earp
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee- Womens Research Institute & University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Gentry-Maharaj
authors.affiliation: Cancer Prevention and Control, Samuel Oshin Comprehensive Cancer Institute, Cedars- Sinai Medical Center, Los Angeles, CA, USA.|Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Goodman
authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Gronwald
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark and Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Estrid
authors.initials: E
authors.lastname: Hogdall
authors.affiliation: Department of Statistical Science, Duke University, Durham, NC, USA.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Iversen
authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Jakubowska
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Jensen
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina College of Medicine, Charleston, SC, USA.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Kelemen
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Suzanne K
authors.initials: SK
authors.lastname: Kjaer
authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard TH Chan School of Public Health, Boston, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Nhu D
authors.initials: ND
authors.lastname: Le
authors.affiliation: Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Department of Cancer Epidemiology and Prevention, The Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Menon
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee- Womens Research Institute & University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Modugno
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Moysich
authors.affiliation: Department of Gynecologic Oncology, Aichi Cancer Center Central Hospital, Nagoya, Aichi, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: The University of Texas School of Public Health, Houston, TX, USA.
authors.forename: Roberta B
authors.initials: RB
authors.lastname: Ness
authors.affiliation: Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York,NY, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Olson
authors.affiliation: Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York,NY, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Orlow
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.|Department of Epidemology,University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: Celeste L
authors.initials: CL
authors.lastname: Pearce
authors.affiliation: Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Tanja
authors.initials: T
authors.lastname: Pejovic
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Anne Rossing
authors.affiliation: Epidemiology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Xiao-Ou
authors.initials: XO
authors.lastname: Shu
authors.affiliation: Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Honglin
authors.initials: H
authors.lastname: Song
authors.affiliation: Epidemiology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Malaysia.|University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
authors.forename: Soo-Hwang
authors.initials: SH
authors.lastname: Teo
authors.affiliation: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Terry
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Thompson
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Shelley S
authors.initials: SS
authors.lastname: Tworoger
authors.affiliation: Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Webb
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda MD, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.affiliation: Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Winham
authors.affiliation: Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
authors.forename: Yin-Ling
authors.initials: YL
authors.lastname: Woo
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda MD, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Yang
authors.affiliation: Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
authors.forename: Argyrios
authors.initials: A
authors.lastname: Ziogas
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Phelan
authors.affiliation: Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.|Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA, Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.|Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
mesh_terms: D000199:Actins / Q000235:genetics*; D043523:Biotinidase / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D053535:Keratin-13 / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics*
chemical_list: C526913:ACTC1 protein, human; D000199:Actins; C507426:KRT13 protein, human; D053535:Keratin-13; D009363:Neoplasm Proteins; D044103:Receptor, Melanocortin, Type 2; D043523:Biotinidase