Shucheng Si1,2,3, Jiqing Li1,2,3, Marlvin Anemey Tewara4, Hongkai Li1,2,3, Xinhui Liu1,2,3, Yunxia Li1, Xiaolu Chen1, Congcong Liu1, Tonghui Yuan1, Wenchao Li1, Bojie Wang1, Fuzhong Xue5,6,7. 1. Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012, Jinan, P.R. China. 2. Institute for Medical Dataology, Shandong University, 250002, Jinan, P.R. China. 3. National Institute of Health Data Science of China, 250002, Jinan, P.R. China. 4. The Bamenda Center for Health Promotion and Research (Former Tuberculosis Reference Lab Bamenda), P.O Box 586, Bamenda, Cameroon. 5. Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012, Jinan, P.R. China. xuefzh@sdu.edu.cn. 6. Institute for Medical Dataology, Shandong University, 250002, Jinan, P.R. China. xuefzh@sdu.edu.cn. 7. National Institute of Health Data Science of China, 250002, Jinan, P.R. China. xuefzh@sdu.edu.cn.
Abstract
BACKGROUND: Genetic correlations, causalities and pathways between large-scale complex exposures and ovarian and breast cancers need systematic exploration. METHODS: Mendelian randomisation (MR) and genetic correlation (GC) were used to identify causal biomarkers from 95 cancer-related exposures for risk of breast cancer [BC: oestrogen receptor-positive (ER + BC) and oestrogen receptor-negative (ER - BC) subtypes] and ovarian cancer [OC: high-grade serous (HGSOC), low-grade serous, invasive mucinous (IMOC), endometrioid (EOC) and clear cell (CCOC) subtypes]. RESULTS: Of 31 identified robust risk factors, 16 were new causal biomarkers for BC and OC. Body mass index (BMI), body fat mass (BFM), comparative body size at age 10 (CBS-10), waist circumference (WC) and education attainment were shared risk factors for overall BC and OC. Childhood obesity, BMI, CBS-10, WC, schizophrenia and age at menopause were significantly associated with ER + BC and ER - BC. Omega-6:omega-3 fatty acids, body fat-free mass and basal metabolic rate were positively associated with CCOC and EOC; BFM, linoleic acid, omega-6 fatty acids, CBS-10 and birth weight were significantly associated with IMOC; and body fat percentage, BFM and adiponectin were significantly associated with HGSOC. Both GC and MR identified 13 shared factors. Factors were stratified into five priority levels, and visual causal networks were constructed for future interventions. CONCLUSIONS: With analysis of large-scale exposures for breast and ovarian cancers, causalities, genetic correlations, shared or specific factors, risk factor priority and causal pathways and networks were identified.
BACKGROUND: Genetic correlations, causalities and pathways between large-scale complex exposures and ovarian and breast cancers need systematic exploration. METHODS: Mendelian randomisation (MR) and genetic correlation (GC) were used to identify causal biomarkers from 95 cancer-related exposures for risk of breast cancer [BC: oestrogen receptor-positive (ER + BC) and oestrogen receptor-negative (ER - BC) subtypes] and ovarian cancer [OC: high-grade serous (HGSOC), low-grade serous, invasive mucinous (IMOC), endometrioid (EOC) and clear cell (CCOC) subtypes]. RESULTS: Of 31 identified robust risk factors, 16 were new causal biomarkers for BC and OC. Body mass index (BMI), body fat mass (BFM), comparative body size at age 10 (CBS-10), waist circumference (WC) and education attainment were shared risk factors for overall BC and OC. Childhood obesity, BMI, CBS-10, WC, schizophrenia and age at menopause were significantly associated with ER + BC and ER - BC. Omega-6:omega-3 fatty acids, body fat-free mass and basal metabolic rate were positively associated with CCOC and EOC; BFM, linoleic acid, omega-6 fatty acids, CBS-10 and birth weight were significantly associated with IMOC; and body fat percentage, BFM and adiponectin were significantly associated with HGSOC. Both GC and MR identified 13 shared factors. Factors were stratified into five priority levels, and visual causal networks were constructed for future interventions. CONCLUSIONS: With analysis of large-scale exposures for breast and ovarian cancers, causalities, genetic correlations, shared or specific factors, risk factor priority and causal pathways and networks were identified.
Authors: Farhad Islami; Ann Goding Sauer; Kimberly D Miller; Rebecca L Siegel; Stacey A Fedewa; Eric J Jacobs; Marjorie L McCullough; Alpa V Patel; Jiemin Ma; Isabelle Soerjomataram; W Dana Flanders; Otis W Brawley; Susan M Gapstur; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2017-11-21 Impact factor: 508.702
Authors: Louise F Wilson; Annika Antonsson; Adele C Green; Susan J Jordan; Bradley J Kendall; Christina M Nagle; Rachel E Neale; Catherine M Olsen; Penelope M Webb; David C Whiteman Journal: Int J Cancer Date: 2017-10-26 Impact factor: 7.396
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Authors: James Yarmolinsky; Caroline L Relton; Artitaya Lophatananon; Kenneth Muir; Usha Menon; Aleksandra Gentry-Maharaj; Axel Walther; Jie Zheng; Peter Fasching; Wei Zheng; Woo Yin Ling; Sue K Park; Byoung-Gie Kim; Ji-Yeob Choi; Boyoung Park; George Davey Smith; Richard M Martin; Sarah J Lewis Journal: PLoS Med Date: 2019-08-07 Impact factor: 11.069
Authors: Brandon Nick Sern Ooi; Huiwen Loh; Peh Joo Ho; Roger L Milne; Graham Giles; Chi Gao; Peter Kraft; Esther M John; Anthony Swerdlow; Hermann Brenner; Anna H Wu; Christopher Haiman; D Gareth Evans; Wei Zheng; Peter A Fasching; Jose Esteban Castelao; Ava Kwong; Xia Shen; Kamila Czene; Per Hall; Alison Dunning; Douglas Easton; Mikael Hartman; Jingmei Li Journal: Int J Epidemiol Date: 2019-06-01 Impact factor: 7.196
Authors: Alisa K Manning; Marie-France Hivert; Robert A Scott; Jonna L Grimsby; Nabila Bouatia-Naji; Han Chen; Denis Rybin; Ching-Ti Liu; Lawrence F Bielak; Inga Prokopenko; Najaf Amin; Daniel Barnes; Gemma Cadby; Jouke-Jan Hottenga; Erik Ingelsson; Anne U Jackson; Toby Johnson; Stavroula Kanoni; Claes Ladenvall; Vasiliki Lagou; Jari Lahti; Cecile Lecoeur; Yongmei Liu; Maria Teresa Martinez-Larrad; May E Montasser; Pau Navarro; John R B Perry; Laura J Rasmussen-Torvik; Perttu Salo; Naveed Sattar; Dmitry Shungin; Rona J Strawbridge; Toshiko Tanaka; Cornelia M van Duijn; Ping An; Mariza de Andrade; Jeanette S Andrews; Thor Aspelund; Mustafa Atalay; Yurii Aulchenko; Beverley Balkau; Stefania Bandinelli; Jacques S Beckmann; John P Beilby; Claire Bellis; Richard N Bergman; John Blangero; Mladen Boban; Michael Boehnke; Eric Boerwinkle; Lori L Bonnycastle; Dorret I Boomsma; Ingrid B Borecki; Yvonne Böttcher; Claude Bouchard; Eric Brunner; Danijela Budimir; Harry Campbell; Olga Carlson; Peter S Chines; Robert Clarke; Francis S Collins; Arturo Corbatón-Anchuelo; David Couper; Ulf de Faire; George V Dedoussis; Panos Deloukas; Maria Dimitriou; Josephine M Egan; Gudny Eiriksdottir; Michael R Erdos; Johan G Eriksson; Elodie Eury; Luigi Ferrucci; Ian Ford; Nita G Forouhi; Caroline S Fox; Maria Grazia Franzosi; Paul W Franks; Timothy M Frayling; Philippe Froguel; Pilar Galan; Eco de Geus; Bruna Gigante; Nicole L Glazer; Anuj Goel; Leif Groop; Vilmundur Gudnason; Göran Hallmans; Anders Hamsten; Ola Hansson; Tamara B Harris; Caroline Hayward; Simon Heath; Serge Hercberg; Andrew A Hicks; Aroon Hingorani; Albert Hofman; Jennie Hui; Joseph Hung; Marjo-Riitta Jarvelin; Min A Jhun; Paul C D Johnson; J Wouter Jukema; Antti Jula; W H Kao; Jaakko Kaprio; Sharon L R Kardia; Sirkka Keinanen-Kiukaanniemi; Mika Kivimaki; Ivana Kolcic; Peter Kovacs; Meena Kumari; Johanna Kuusisto; Kirsten Ohm Kyvik; Markku Laakso; Timo Lakka; Lars Lannfelt; G Mark Lathrop; Lenore J Launer; Karin Leander; Guo Li; Lars Lind; Jaana Lindstrom; Stéphane Lobbens; Ruth J F Loos; Jian'an Luan; Valeriya Lyssenko; Reedik Mägi; Patrik K E Magnusson; Michael Marmot; Pierre Meneton; Karen L Mohlke; Vincent Mooser; Mario A Morken; Iva Miljkovic; Narisu Narisu; Jeff O'Connell; Ken K Ong; Ben A Oostra; Lyle J Palmer; Aarno Palotie; James S Pankow; John F Peden; Nancy L Pedersen; Marina Pehlic; Leena Peltonen; Brenda Penninx; Marijana Pericic; Markus Perola; Louis Perusse; Patricia A Peyser; Ozren Polasek; Peter P Pramstaller; Michael A Province; Katri Räikkönen; Rainer Rauramaa; Emil Rehnberg; Ken Rice; Jerome I Rotter; Igor Rudan; Aimo Ruokonen; Timo Saaristo; Maria Sabater-Lleal; Veikko Salomaa; David B Savage; Richa Saxena; Peter Schwarz; Udo Seedorf; Bengt Sennblad; Manuel Serrano-Rios; Alan R Shuldiner; Eric J G Sijbrands; David S Siscovick; Johannes H Smit; Kerrin S Small; Nicholas L Smith; Albert Vernon Smith; Alena Stančáková; Kathleen Stirrups; Michael Stumvoll; Yan V Sun; Amy J Swift; Anke Tönjes; Jaakko Tuomilehto; Stella Trompet; Andre G Uitterlinden; Matti Uusitupa; Max Vikström; Veronique Vitart; Marie-Claude Vohl; Benjamin F Voight; Peter Vollenweider; Gerard Waeber; Dawn M Waterworth; Hugh Watkins; Eleanor Wheeler; Elisabeth Widen; Sarah H Wild; Sara M Willems; Gonneke Willemsen; James F Wilson; Jacqueline C M Witteman; Alan F Wright; Hanieh Yaghootkar; Diana Zelenika; Tatijana Zemunik; Lina Zgaga; Nicholas J Wareham; Mark I McCarthy; Ines Barroso; Richard M Watanabe; Jose C Florez; Josée Dupuis; James B Meigs; Claudia Langenberg Journal: Nat Genet Date: 2012-05-13 Impact factor: 38.330