Obesity and risk of female reproductive conditions: A Mendelian randomisation study

被引:106
|
作者
Venkatesh, Samvida S. [1 ,2 ]
Ferreira, Teresa [1 ,3 ]
Benonisdottir, Stefania [1 ]
Rahmioglu, Nilufer
Becker, Christian M.
Granne, Ingrid
Zondervan, Krina T.
Holmes, Michael V. [4 ]
Lindgren, Cecilia M. [1 ,2 ,4 ,5 ,6 ]
Wittemans, Laura B. L. [1 ,3 ]
机构
[1] Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England
[2] Univ Oxford, Nuffield Dept Med, Wellcome Ctr Human Genet, Oxford, England
[3] Univ Oxford, Div Med Sci, Nuffield Dept Womens & Reprod Hlth, Oxford, England
[4] Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
[5] Univ Oxford, Med Res Council Populat Hlth Res Unit, Oxford, England
[6] Broad Inst & Harvard, Cambridge, MA USA
基金
英国惠康基金; 英国医学研究理事会;
关键词
BODY-MASS INDEX; POLYCYSTIC-OVARY-SYNDROME; GENOME-WIDE ASSOCIATION; FALSE DISCOVERY RATE; GENETIC-VARIANTS; REFERRAL BIAS; ENDOMETRIOSIS; INFERTILITY; WOMEN; CAUSAL;
D O I
10.1371/journal.pmed.1003679
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders. Methods and findings Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 x 10(-05)), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 x 10(-07)). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy. Conclusions We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.
引用
收藏
页数:30
相关论文
共 50 条
  • [41] Mendelian randomisation study of the relationship between vitamin D and risk of glioma
    Takahashi, Hannah
    Cornish, Alex J.
    Sud, Amit
    Law, Philip J.
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Eckel-Passow, Jeanette E.
    Armstrong, Georgina N.
    Claus, Elizabeth B.
    Il'yasova, Dora
    Schildkraut, Joellen
    Barnholtz-Sloan, Jill S.
    Olson, Sara H.
    Bernstein, Jonine L.
    Lai, Rose K.
    Schoemaker, Minouk J.
    Simon, Matthias
    Hoffmann, Per
    Noethen, Markus M.
    Joeckel, Karl-Heinz
    Chanock, Stephen
    Rajaraman, Preetha
    Johansen, Christoffer
    Jenkins, Robert B.
    Melin, Beatrice S.
    Wrensch, Margaret R.
    Sanson, Marc
    Bondy, Melissa L.
    Turnbull, Clare
    Houlston, Richard S.
    SCIENTIFIC REPORTS, 2018, 8
  • [42] Breast cancer risk factors and their effects on survival: a Mendelian randomisation study
    Maria Escala-Garcia
    Anna Morra
    Sander Canisius
    Jenny Chang-Claude
    Siddhartha Kar
    Wei Zheng
    Stig E. Bojesen
    Doug Easton
    Paul D. P. Pharoah
    Marjanka K. Schmidt
    BMC Medicine, 18
  • [43] Mendelian randomisation study for statin treatment
    Morita, Hiroyuki
    Komuro, Issei
    LANCET, 2015, 385 (9981): : 1945 - 1946
  • [44] Cardiorespiratory fitness, obesity, diabetes and longevity: a two-sample Mendelian randomisation study
    Kjaergaard, A. D.
    Ellervik, C.
    Jessen, N.
    Lessard, S. J.
    DIABETOLOGIA, 2023, 66 (SUPPL 1) : S168 - S168
  • [45] Mendelian randomisation supports causal link between obesity and asthma
    van der Plaat, Diana A.
    THORAX, 2020, 75 (03) : 194 - 195
  • [46] Long-term cost-effectiveness of interventions for obesity: A mendelian randomisation study
    Harrison, Sean
    Dixon, Padraig
    Jones, Hayley E.
    Davies, Alisha R.
    Howe, Laura D.
    Davies, Neil M.
    PLOS MEDICINE, 2021, 18 (08)
  • [47] Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study
    Zhou, Kaiping
    Yang, Huan
    Xie, Zhihao
    Wang, Weiping
    Qu, Zhenzhen
    BMC PHARMACOLOGY & TOXICOLOGY, 2024, 25 (01):
  • [48] Circulating Biomarkers and Risk of Hypertension: A Two-Sample Mendelian Randomisation Study
    Li, Jin
    Yao, Yue-Xian
    Yao, Pei-Sen
    HEART LUNG AND CIRCULATION, 2023, 32 (12): : 1434 - 1442
  • [49] Proton pump inhibitors and the risk of inflammatory bowel disease: a Mendelian randomisation study
    An, Hongjin
    Zhong, Min
    Gan, Huatian
    GUT, 2024, 73 (12)
  • [50] Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer
    Sonja Neumeyer
    Barbara L. Banbury
    Volker Arndt
    Sonja I. Berndt
    Stephane Bezieau
    Stephanie A. Bien
    Dan D. Buchanan
    Katja Butterbach
    Bette J. Caan
    Peter T. Campbell
    Graham Casey
    Andrew T. Chan
    Stephen J. Chanock
    James Y. Dai
    Steven Gallinger
    Edward L. Giovannucci
    Graham G. Giles
    William M. Grady
    Jochen Hampe
    Michael Hoffmeister
    John L. Hopper
    Li Hsu
    Mark A. Jenkins
    Amit Joshi
    Susanna C. Larsson
    Loic Le Marchand
    Annika Lindblom
    Victor Moreno
    Mathieu Lemire
    Li Li
    Yi Lin
    Kenneth Offit
    Polly A. Newcomb
    Paul D. Pharaoh
    John D. Potter
    Lihong Qi
    Gad Rennert
    Clemens Schafmayer
    Robert E. Schoen
    Martha L. Slattery
    Mingyang Song
    Cornelia M. Ulrich
    Aung K. Win
    Emily White
    Alicja Wolk
    Michael O. Woods
    Anna H. Wu
    Stephen B. Gruber
    Hermann Brenner
    Ulrike Peters
    British Journal of Cancer, 2018, 118 : 1639 - 1647