Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Gabriel Cuellar-Partida, Yi Lu, Suzanne C. Dixon, Ovarian Cancer Study Australian Ovarian Cancer Study, Peter A. Fasching, Alexander Hein, Stefanie Burghaus, Matthias W. Beckmann, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Adriaan Vanderstichele, Jennifer Anne Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Shan Wang-Gohrke, Marc T. Goodman, Natalia Bogdanova, Thilo Dörk & 89 others Matthias Dürst, Peter Hillemanns, Ingo B. Runnebaum, Natalia Antonenkova, Ralf Butzow, Arto Leminen, Heli Nevanlinna, Liisa M. Pelttari, Robert P. Edwards, Joseph L. Kelley, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Rikki Cannioto, Estrid Høgdall, Claus Høgdall, Allan Jensen, Graham G. Giles, Fiona Bruinsma, Susanne K. Kjaer, Michelle A T Hildebrandt, Dong Liang, Karen H. Lu, Xifeng Wu, Maria Bisogna, Fanny Dao, Douglas A. Levine, Daniel W. Cramer, Kathryn L. Terry, Shelley S. Tworoger, Meir Stampfer, Stacey Missmer, Line Bjorge, Helga B. Salvesen, Reidun K. Kopperud, Katharina Bischof, Katja K H Aben, Lambertus A. Kiemeney, Leon F A G Massuger, Angela Brooks-Wilson, Sara H. Olson, Valerie McGuire, Joseph H. Rothstein, Weiva Sieh, Alice S. Whittemore, Linda S. Cook, Nhu D. Le, C. Blake Gilks, Jacek Gronwald, Anna Jakubowska, Jan Lubiński, Tomasz Kluz, Honglin Song, Jonathan P. Tyrer, Nicolas Wentzensen, Louise Brinton, Britton Trabert, Jolanta Lissowska, John R. McLaughlin, Steven A. Narod, Catherine Phelan, Hoda Anton-Culver, Argyrios Ziogas, Diana Eccles, Ian Campbell, Simon A. Gayther, Aleksandra Gentry-Maharaj, Usha Menon, Susan J. Ramus, Anna H. Wu, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Agnieszka Timorek, Lukasz Szafron, Julie M. Cunningham, Brooke L. Fridley, Stacey J. Winham, Elisa V. Bandera, Elizabeth M. Poole, Terry Morgan, Ellen L. Goode, Joellen M. Schildkraut, Celeste L. Pearce, Andrew Berchuck, Paul D P Pharoah, Penelope M. Webb, Georgia Chenevix-Trench, Harvey A. Risch, Stuart MacGregor

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (hg2 = 8.8 ± 1.1 %), endometrioid (hg2 = 3.2 ± 1.6 %), clear cell (hg2 = 6.7 ± 3.3 %) and all EOC (hg2 = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Original languageEnglish (US)
Pages (from-to)741-756
Number of pages16
JournalHuman Genetics
Volume135
Issue number7
DOIs
StatePublished - Jul 1 2016

Fingerprint

Obesity
Chromosomes
Menarche
Ovarian Neoplasms
Single Nucleotide Polymorphism
Smoking
Ovarian epithelial cancer
Carcinoma
Neoplasms
Therapeutics
Genetic Background

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics
  • Genetics(clinical)

Cite this

Cuellar-Partida, G., Lu, Y., Dixon, S. C., Australian Ovarian Cancer Study, O. C. S., Fasching, P. A., Hein, A., ... MacGregor, S. (2016). Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. Human Genetics, 135(7), 741-756. https://doi.org/10.1007/s00439-016-1663-9

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. / Cuellar-Partida, Gabriel; Lu, Yi; Dixon, Suzanne C.; Australian Ovarian Cancer Study, Ovarian Cancer Study; Fasching, Peter A.; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias W.; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan; Doherty, Jennifer Anne; Rossing, Mary Anne; Chang-Claude, Jenny; Rudolph, Anja; Wang-Gohrke, Shan; Goodman, Marc T.; Bogdanova, Natalia; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B.; Antonenkova, Natalia; Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.; Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary; Moysich, Kirsten B.; Ness, Roberta B.; Cannioto, Rikki; Høgdall, Estrid; Høgdall, Claus; Jensen, Allan; Giles, Graham G.; Bruinsma, Fiona; Kjaer, Susanne K.; Hildebrandt, Michelle A T; Liang, Dong; Lu, Karen H.; Wu, Xifeng; Bisogna, Maria; Dao, Fanny; Levine, Douglas A.; Cramer, Daniel W.; Terry, Kathryn L.; Tworoger, Shelley S.; Stampfer, Meir; Missmer, Stacey; Bjorge, Line; Salvesen, Helga B.; Kopperud, Reidun K.; Bischof, Katharina; Aben, Katja K H; Kiemeney, Lambertus A.; Massuger, Leon F A G; Brooks-Wilson, Angela; Olson, Sara H.; McGuire, Valerie; Rothstein, Joseph H.; Sieh, Weiva; Whittemore, Alice S.; Cook, Linda S.; Le, Nhu D.; Blake Gilks, C.; Gronwald, Jacek; Jakubowska, Anna; Lubiński, Jan; Kluz, Tomasz; Song, Honglin; Tyrer, Jonathan P.; Wentzensen, Nicolas; Brinton, Louise; Trabert, Britton; Lissowska, Jolanta; McLaughlin, John R.; Narod, Steven A.; Phelan, Catherine; Anton-Culver, Hoda; Ziogas, Argyrios; Eccles, Diana; Campbell, Ian; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J.; Wu, Anna H.; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Timorek, Agnieszka; Szafron, Lukasz; Cunningham, Julie M.; Fridley, Brooke L.; Winham, Stacey J.; Bandera, Elisa V.; Poole, Elizabeth M.; Morgan, Terry; Goode, Ellen L.; Schildkraut, Joellen M.; Pearce, Celeste L.; Berchuck, Andrew; Pharoah, Paul D P; Webb, Penelope M.; Chenevix-Trench, Georgia; Risch, Harvey A.; MacGregor, Stuart.

In: Human Genetics, Vol. 135, No. 7, 01.07.2016, p. 741-756.

Research output: Contribution to journalArticle

Cuellar-Partida, G, Lu, Y, Dixon, SC, Australian Ovarian Cancer Study, OCS, Fasching, PA, Hein, A, Burghaus, S, Beckmann, MW, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Vanderstichele, A, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Wang-Gohrke, S, Goodman, MT, Bogdanova, N, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, Antonenkova, N, Butzow, R, Leminen, A, Nevanlinna, H, Pelttari, LM, Edwards, RP, Kelley, JL, Modugno, F, Moysich, KB, Ness, RB, Cannioto, R, Høgdall, E, Høgdall, C, Jensen, A, Giles, GG, Bruinsma, F, Kjaer, SK, Hildebrandt, MAT, Liang, D, Lu, KH, Wu, X, Bisogna, M, Dao, F, Levine, DA, Cramer, DW, Terry, KL, Tworoger, SS, Stampfer, M, Missmer, S, Bjorge, L, Salvesen, HB, Kopperud, RK, Bischof, K, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Brooks-Wilson, A, Olson, SH, McGuire, V, Rothstein, JH, Sieh, W, Whittemore, AS, Cook, LS, Le, ND, Blake Gilks, C, Gronwald, J, Jakubowska, A, Lubiński, J, Kluz, T, Song, H, Tyrer, JP, Wentzensen, N, Brinton, L, Trabert, B, Lissowska, J, McLaughlin, JR, Narod, SA, Phelan, C, Anton-Culver, H, Ziogas, A, Eccles, D, Campbell, I, Gayther, SA, Gentry-Maharaj, A, Menon, U, Ramus, SJ, Wu, AH, Dansonka-Mieszkowska, A, Kupryjanczyk, J, Timorek, A, Szafron, L, Cunningham, JM, Fridley, BL, Winham, SJ, Bandera, EV, Poole, EM, Morgan, T, Goode, EL, Schildkraut, JM, Pearce, CL, Berchuck, A, Pharoah, PDP, Webb, PM, Chenevix-Trench, G, Risch, HA & MacGregor, S 2016, 'Assessing the genetic architecture of epithelial ovarian cancer histological subtypes', Human Genetics, vol. 135, no. 7, pp. 741-756. https://doi.org/10.1007/s00439-016-1663-9
Cuellar-Partida G, Lu Y, Dixon SC, Australian Ovarian Cancer Study OCS, Fasching PA, Hein A et al. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. Human Genetics. 2016 Jul 1;135(7):741-756. https://doi.org/10.1007/s00439-016-1663-9
Cuellar-Partida, Gabriel ; Lu, Yi ; Dixon, Suzanne C. ; Australian Ovarian Cancer Study, Ovarian Cancer Study ; Fasching, Peter A. ; Hein, Alexander ; Burghaus, Stefanie ; Beckmann, Matthias W. ; Lambrechts, Diether ; Van Nieuwenhuysen, Els ; Vergote, Ignace ; Vanderstichele, Adriaan ; Doherty, Jennifer Anne ; Rossing, Mary Anne ; Chang-Claude, Jenny ; Rudolph, Anja ; Wang-Gohrke, Shan ; Goodman, Marc T. ; Bogdanova, Natalia ; Dörk, Thilo ; Dürst, Matthias ; Hillemanns, Peter ; Runnebaum, Ingo B. ; Antonenkova, Natalia ; Butzow, Ralf ; Leminen, Arto ; Nevanlinna, Heli ; Pelttari, Liisa M. ; Edwards, Robert P. ; Kelley, Joseph L. ; Modugno, Francesmary ; Moysich, Kirsten B. ; Ness, Roberta B. ; Cannioto, Rikki ; Høgdall, Estrid ; Høgdall, Claus ; Jensen, Allan ; Giles, Graham G. ; Bruinsma, Fiona ; Kjaer, Susanne K. ; Hildebrandt, Michelle A T ; Liang, Dong ; Lu, Karen H. ; Wu, Xifeng ; Bisogna, Maria ; Dao, Fanny ; Levine, Douglas A. ; Cramer, Daniel W. ; Terry, Kathryn L. ; Tworoger, Shelley S. ; Stampfer, Meir ; Missmer, Stacey ; Bjorge, Line ; Salvesen, Helga B. ; Kopperud, Reidun K. ; Bischof, Katharina ; Aben, Katja K H ; Kiemeney, Lambertus A. ; Massuger, Leon F A G ; Brooks-Wilson, Angela ; Olson, Sara H. ; McGuire, Valerie ; Rothstein, Joseph H. ; Sieh, Weiva ; Whittemore, Alice S. ; Cook, Linda S. ; Le, Nhu D. ; Blake Gilks, C. ; Gronwald, Jacek ; Jakubowska, Anna ; Lubiński, Jan ; Kluz, Tomasz ; Song, Honglin ; Tyrer, Jonathan P. ; Wentzensen, Nicolas ; Brinton, Louise ; Trabert, Britton ; Lissowska, Jolanta ; McLaughlin, John R. ; Narod, Steven A. ; Phelan, Catherine ; Anton-Culver, Hoda ; Ziogas, Argyrios ; Eccles, Diana ; Campbell, Ian ; Gayther, Simon A. ; Gentry-Maharaj, Aleksandra ; Menon, Usha ; Ramus, Susan J. ; Wu, Anna H. ; Dansonka-Mieszkowska, Agnieszka ; Kupryjanczyk, Jolanta ; Timorek, Agnieszka ; Szafron, Lukasz ; Cunningham, Julie M. ; Fridley, Brooke L. ; Winham, Stacey J. ; Bandera, Elisa V. ; Poole, Elizabeth M. ; Morgan, Terry ; Goode, Ellen L. ; Schildkraut, Joellen M. ; Pearce, Celeste L. ; Berchuck, Andrew ; Pharoah, Paul D P ; Webb, Penelope M. ; Chenevix-Trench, Georgia ; Risch, Harvey A. ; MacGregor, Stuart. / Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. In: Human Genetics. 2016 ; Vol. 135, No. 7. pp. 741-756.
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abstract = "Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (hg2 = 8.8 ± 1.1 {\%}), endometrioid (hg2 = 3.2 ± 1.6 {\%}), clear cell (hg2 = 6.7 ± 3.3 {\%}) and all EOC (hg2 = 5.6 ± 0.6 {\%}). Known associated loci contributed approximately 40 {\%} of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.",
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T1 - Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

AU - Cuellar-Partida, Gabriel

AU - Lu, Yi

AU - Dixon, Suzanne C.

AU - Australian Ovarian Cancer Study, Ovarian Cancer Study

AU - Fasching, Peter A.

AU - Hein, Alexander

AU - Burghaus, Stefanie

AU - Beckmann, Matthias W.

AU - Lambrechts, Diether

AU - Van Nieuwenhuysen, Els

AU - Vergote, Ignace

AU - Vanderstichele, Adriaan

AU - Doherty, Jennifer Anne

AU - Rossing, Mary Anne

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Wang-Gohrke, Shan

AU - Goodman, Marc T.

AU - Bogdanova, Natalia

AU - Dörk, Thilo

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Runnebaum, Ingo B.

AU - Antonenkova, Natalia

AU - Butzow, Ralf

AU - Leminen, Arto

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M.

AU - Edwards, Robert P.

AU - Kelley, Joseph L.

AU - Modugno, Francesmary

AU - Moysich, Kirsten B.

AU - Ness, Roberta B.

AU - Cannioto, Rikki

AU - Høgdall, Estrid

AU - Høgdall, Claus

AU - Jensen, Allan

AU - Giles, Graham G.

AU - Bruinsma, Fiona

AU - Kjaer, Susanne K.

AU - Hildebrandt, Michelle A T

AU - Liang, Dong

AU - Lu, Karen H.

AU - Wu, Xifeng

AU - Bisogna, Maria

AU - Dao, Fanny

AU - Levine, Douglas A.

AU - Cramer, Daniel W.

AU - Terry, Kathryn L.

AU - Tworoger, Shelley S.

AU - Stampfer, Meir

AU - Missmer, Stacey

AU - Bjorge, Line

AU - Salvesen, Helga B.

AU - Kopperud, Reidun K.

AU - Bischof, Katharina

AU - Aben, Katja K H

AU - Kiemeney, Lambertus A.

AU - Massuger, Leon F A G

AU - Brooks-Wilson, Angela

AU - Olson, Sara H.

AU - McGuire, Valerie

AU - Rothstein, Joseph H.

AU - Sieh, Weiva

AU - Whittemore, Alice S.

AU - Cook, Linda S.

AU - Le, Nhu D.

AU - Blake Gilks, C.

AU - Gronwald, Jacek

AU - Jakubowska, Anna

AU - Lubiński, Jan

AU - Kluz, Tomasz

AU - Song, Honglin

AU - Tyrer, Jonathan P.

AU - Wentzensen, Nicolas

AU - Brinton, Louise

AU - Trabert, Britton

AU - Lissowska, Jolanta

AU - McLaughlin, John R.

AU - Narod, Steven A.

AU - Phelan, Catherine

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Eccles, Diana

AU - Campbell, Ian

AU - Gayther, Simon A.

AU - Gentry-Maharaj, Aleksandra

AU - Menon, Usha

AU - Ramus, Susan J.

AU - Wu, Anna H.

AU - Dansonka-Mieszkowska, Agnieszka

AU - Kupryjanczyk, Jolanta

AU - Timorek, Agnieszka

AU - Szafron, Lukasz

AU - Cunningham, Julie M.

AU - Fridley, Brooke L.

AU - Winham, Stacey J.

AU - Bandera, Elisa V.

AU - Poole, Elizabeth M.

AU - Morgan, Terry

AU - Goode, Ellen L.

AU - Schildkraut, Joellen M.

AU - Pearce, Celeste L.

AU - Berchuck, Andrew

AU - Pharoah, Paul D P

AU - Webb, Penelope M.

AU - Chenevix-Trench, Georgia

AU - Risch, Harvey A.

AU - MacGregor, Stuart

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (hg2 = 8.8 ± 1.1 %), endometrioid (hg2 = 3.2 ± 1.6 %), clear cell (hg2 = 6.7 ± 3.3 %) and all EOC (hg2 = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

AB - Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (hg2 = 8.8 ± 1.1 %), endometrioid (hg2 = 3.2 ± 1.6 %), clear cell (hg2 = 6.7 ± 3.3 %) and all EOC (hg2 = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

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