Mendelian randomisation study of smoking exposure in relation to breast cancer risk
Authors: Park Hanla A. , Neumeyer Sonja , Michailidou Kyriaki , Bolla Manjeet K. , Wang Qin , Dennis Joe , Ahearn Thomas U. , Andrulis Irene L. , Anton-Culver Hoda , Antonenkova Natalia N. , Arndt Volker , Aronson Kristan J. , Augustinsson Annelie , Baten Adinda , Beane Freeman Laura E. , Becher Heiko , Beckmann Matthias W. , Behrens Sabine , Benitez Javier , Bermisheva Marina , Bogdanova Natalia V. , Bojesen Stig E. , Brauch Hiltrud , Brenner Hermann , Brucker Sara Y. , Burwinkel Barbara , Campa Daniele , Canzian Federico , Castelao Jose E. , Chanock Stephen J. , Chenevix-Trench Georgia , Clarke Christine L. ,   NBCS Collaborators, Børresen-Dale Anne-Lise , Grenaker Alnæs Grethe I. , Sahlberg Kristine K. , Ottestad Lars , Kåresen Rolf , Schlichting Ellen , Holmen Marit Muri , Sauer Toril , Haakensen Vilde , Engebråten Olav , Naume Bjørn , Fosså Alexander , Kiserud Cecile E. , Reinertsen Kristin V. , Helland Åslaug , Riis Margit , Geisler Jürgen , Conroy Don M. , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , Devilee Peter , Dörk Thilo , dos-Santos-Silva Isabel , Dwek Miriam , Eccles Diana M. , Eliassen A. Heather , Engel Christoph , Eriksson Mikael , Evans D. Gareth , Fasching Peter A. , Flyger Henrik , Fritschi Lin , García-Closas Montserrat , García-Sáenz José A. , Gaudet Mia M. , Giles Graham G. , Glendon Gord , Goldberg Mark S. , Goldgar David E. , González-Neira Anna , Grip Mervi , Guénel Pascal , Hahnen Eric , Haiman Christopher A. , Håkansson Niclas , Hall Per , Hamann Ute , Han Sileny , Harkness Elaine F. , Hart Steven N. , He Wei , Heemskerk-Gerritsen Bernadette A. M. , Hopper John L. , Hunter David J. ,   ABCTB Investigators, Clarke Christine , Marsh Deborah , Scott Rodney , Baxter Robert , Yip Desmond , Carpenter Jane , Davis Alison , Pathmanathan Nirmala , Simpson Peter , Graham Dinny , Sachchithananthan Mythily ,   kConFab Investigators, Amor David , Andrews Lesley , Antill Yoland , Balleine Rosemary , Beesley Jonathan , Bennett Ian , Bogwitz Michael , Botes Leon , Brennan Meagan , Brown Melissa , Buckley Michael , Burke Jo , Butow Phyllis , Caldon Liz , Campbell Ian , Chauhan Deepa , Chauhan Manisha , Chenevix-Trench Georgia , Christian Alice , Cohen Paul , Colley Alison , Crook Ashley , Cui James , Cummings Margaret , Dawson Sarah-Jane , DeFazio Anna , Delatycki Martin , Dickson Rebecca , Dixon Joanne , Edkins Ted , Edwards Stacey , Farshid Gelareh , Fellows Andrew , Fenton Georgina , Field Michael , Flanagan James , Fong Peter , Forrest Laura , Fox Stephen , French Juliet , Friedlander Michael , Gaff Clara , Gattas Mike , George Peter , Greening Sian , Harris Marion , Hart Stewart , Hayward Nick , Hopper John , Hoskins Cass , Hunt Clare , James Paul , Jenkins Mark , Kidd Alexa , Kirk Judy , Koehler Jessica , Kollias James , Lakhani Sunil , Lawrence Mitchell , Lindeman Geoff , Lipton Lara , Lobb Liz , Mann Graham , Marsh Deborah , McLachlan Sue Anne , Meiser Bettina , Milne Roger , Nightingale Sophie , O’Connell Shona , O’Sullivan Sarah , Ortega David Gallego , Pachter Nick , Patterson Briony , Pearn Amy , Phillips Kelly , Pieper Ellen , Rickard Edwina , Robinson Bridget , Saleh Mona , Salisbury Elizabeth , Saunders Christobel , Saunus Jodi , Scott Rodney , Scott Clare , Sexton Adrienne , Shelling Andrew , Simpson Peter , Southey Melissa , Spurdle Amanda , Taylor Jessica , Taylor Renea , Thorne Heather , Trainer Alison , Tucker Kathy , Visvader Jane , Walker Logan , Williams Rachael , Winship Ingrid , Young Mary Ann , Jager Agnes , Jakubowska Anna , John Esther M. , Jung Audrey , Kaaks Rudolf , Kapoor Pooja Middha , Keeman Renske , Khusnutdinova Elza , Kitahara Cari M. , Koppert Linetta B. , Koutros Stella , Kristensen Vessela N. , Kurian Allison W. , Lacey James , Lambrechts Diether , Le Marchand Loic , Lo Wing-Yee , Lubiński Jan , Mannermaa Arto , Manoochehri Mehdi , Margolin Sara , Martinez Maria Elena , Mavroudis Dimitrios , Meindl Alfons , Menon Usha , Milne Roger L. , Muranen Taru A. , Nevanlinna Heli , Newman William G. , Nordestgaard Børge G. , Offit Kenneth , Olshan Andrew F. , Olsson Håkan , Park-Simon Tjoung-Won , Peterlongo Paolo , Peto Julian , Plaseska-Karanfilska Dijana , Presneau Nadege , Radice Paolo , Rennert Gad , Rennert Hedy S. , Romero Atocha , Saloustros Emmanouil , Sawyer Elinor J. , Schmidt Marjanka K. , Schmutzler Rita K. , Schoemaker Minouk J. , Schwentner Lukas , Scott Christopher , Shah Mitul , Shu Xiao-Ou , Simard Jacques , Smeets Ann , Southey Melissa C. , Spinelli John J. , Stevens Victoria , Swerdlow Anthony J. , Tamimi Rulla M. , Tapper William J. , Taylor Jack A. , Terry Mary Beth , Tomlinson Ian , Troester Melissa A. , Truong Thérèse , Vachon Celine M. , van Veen Elke M. , Vijai Joseph , Wang Sophia , Wendt Camilla , Winqvist Robert , Wolk Alicja , Ziogas Argyrios , Dunning Alison M. , Pharoah Paul D. P. , Easton Douglas F. , Zheng Wei , Kraft Peter , Chang-Claude Jenny 
Published: August 2021

Abstract
Background
Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods
We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results
Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion
Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.