Sex specific associations in genome wide association analysis of renal cell carcinoma

Ruhina S Laskar (1) , David C. Muller (2) , Peng Li , Mitchell J Machiela (3) , Yuanqing Ye (4) , Valerie Gaborieau (1) , Matthieu Foll (1) , Jonathan N Hofmann (3) , Leandro Colli (3) , Joshua N Sampson (3) , Zhaoming Wang (5) , Delphine Bacq-Daian (6) , Anne Boland (7, 8) , Behnoush Abedi-Ardekani (9) , Geoffroy Durand (9) , Florence Le Calvez-Kelm (9) , Nivonirina Robinot (1) , Helene Blanche (10) , Egor Prokhortchouk (11) , Konstantin G Skryabin (11, 12) , Laurie Burdett (3) , Meredith Yeager (3) , Sanja Radojevic-Skodric (13) , Slavisa Savic , Lenka Foretova (14) , Ivana Holcatova (15) , Vladimir Janout (16) , Dana Mates (17) , Stefan Rascu (18) , Anush Mukeria (19) , David Zaridze (20, 21) , Vladimir Bencko (22) , Cezary Cybulski (23) , Eleonora Fabianova (24) , Viorel Jinga (18) , Jolanta Lissowska (25) , Jan Lubinski (23) , Marie Navratilova (14) , Peter Rudnai (26) , Beata Świątkowska (27) , Simone Benhamou (28, 29) , Geraldine Cancel-Tassin (30, 31) , Olivier Cussenot (31, 30) , Antonia Trichopoulou (32) , Elio Riboli (2) , Kim Overvad (33) , Salvatore Panico (34) , Borje Ljungberg , Raviprakash T Sitaram , Graham G Giles , Roger L Milne , Gianluca Severi (35) , Fiona Bruinsma , Tony Fletcher , Kvetoslava Koppova , Susanna C Larsson , Alicja Wolk , Rosamonde E Banks , Peter J Selby , Douglas F Easton , Paul Pharoah , Gabriella Andreotti , Laura E Beane Freeman , Stella Koutros , Demetrius Albanes , Satu Männistö , Stephanie Weinstein , Peter E Clark , Todd L Edwards , Loren Lipworth , Hallie Carol , Matthew L Freedman , Mark M Pomerantz , Eunyoung Cho , Peter Kraft , Mark A Preston , Kathryn M Wilson , J. Michael Gaziano , Howard D Sesso , Amanda Black , Neal D Freedman , Wen-Yi Huang , John G Anema , Richard J Kahnoski , Brian R Lane , Sabrina L Noyes , David Petillo , Bin Tean Teh , Ulrike Peters , Emily White , Garnet L Anderson , Lisa Johnson , Juhua Luo , Wong-Ho Chow , Lee E Moore , Toni K Choueiri , Christopher Wood , Mattias Johansson (1) , James D Mckay (1) , Kevin M Brown , Nathaniel Rothman , Mark G Lathrop , Jean-Francois Deleuze (6, 36) , Xifeng Wu , Paul Brennan (1) , Stephen J Chanock , Mark P Purdue , Ghislaine Scelo (1)

1 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
2 Imperial College London
3 NCI-NIH - National Cancer Institute [Bethesda]
4 The University of Texas M.D. Anderson Cancer Center [Houston]
5 St Jude Children's Research Hospital
6 CNRGH - Centre National de Recherche en Génomique Humaine
7 CNG - Centre National de Génotypage
8 JACOB - Institut de Biologie François JACOB
9 CIRC - Centre international de Recherche sur le Cancer
10 Fondation Jean Dausset CEPH
11 RAS - Russian Academy of Sciences [Moscow]
12 NRC KI - National Research Center "Kurchatov Institute"
13 School of Medecine [Belgrade]
14 MMCI - Masaryk Memorial Cancer Institute
15 Medicine Charles University and General Faculty Hospital in Prague
16 Department of Optics [Univ Palacký]
17 INSP - National Institute of Public Health [Romania]
18 UMPCD - University of Medicine and Pharmacy “Carol Davila” Bucharest
19 N.N. Blokhin Russian Cancer Research Center
20 N.N. Blokhin National Medical Research Center of Oncology
21 Russian Cancer Research Centre
22 Institute of Hygiene and Epidemiology
23 Department of Genetics and Pathology
24 RAPH - Regional Authority of Public Health [Slovaquia]
25 The M Sklodowska-Curie Cancer Center and Institute of Oncology
26 National center for public health [Hungary]
27 MUL - Medical University of Łódź
28 U946 - Variabilité Génétique et Maladies Humaines
29 UMR 8200 - Stabilité Génétique et Oncogenèse
30 CHU Tenon [AP-HP]
31 SU - Sorbonne Université
32 Hellenic Health Foundation, Athens, Greece
33 Aarhus University [Aarhus]
34 Department of Clinical and Experimental Medicine
35 CESP - INSERM U1018 - Equipe 7 - Sexualité et soins (Genre, Sexualité, Santé)
36 CEPH - Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris]

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10−8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90–1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10−8 compared with ORfemale = 0.93 [95% CI = 0.82–1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

Domaines: Sciences du Vivant [q-bio]; Génétique humaine

Ruhina S Laskar, David C. Muller, Peng Li, Mitchell J Machiela, Yuanqing Ye, et al.. Sex specific associations in genome wide association analysis of renal cell carcinoma. European Journal of Human Genetics, 2019, 27 (10), pp.1589-1598. ⟨10.1038/s41431-019-0455-9⟩. ⟨cea-04449401⟩