Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases (original) (raw)

• Vasan, R. S. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 113, 2335–2362 (2006).
  Article PubMed Google Scholar
• Ebrahim, S. & Davey Smith, G. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Hum. Genet. 123, 15–33 (2008).
  Article PubMed Google Scholar
• Smith, G. D. & Ebrahim, S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol. 32, 1–22 (2003).
  Article PubMed Google Scholar
• Evans, D. M. & Smith, G. D. Mendelian randomization: new applications in the coming age of hypothesis-free causality. Annu. Rev. Genomics Hum. Genet. 16, 327–350 (2015).
  Article PubMed CAS Google Scholar
• Burgess, S., Bowden, J., Fall, T., Ingelsson, E. & Thompson, S. G. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology 28, 30–42 (2017).
  Article PubMed Google Scholar
• Burgess, S. et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur. J. Epidemiol. 30, 543–552 (2015).
  Article PubMed PubMed Central Google Scholar
• Solovieff, N., Cotsapas, C., Lee, P. H., Purcell, S. M. & Smoller, J. W. Pleiotropy in complex traits: challenges and strategies. Nat. Rev. Genet. 14, 483–495 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Sivakumaran, S. et al. Abundant pleiotropy in human complex diseases and traits. Am. J. Hum. Genet. 89, 607–618 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Gratten, J. & Visscher, P. M. Genetic pleiotropy in complex traits and diseases: implications for genomic medicine. Genome Med. 8, 78 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Parkes, M., Cortes, A., van Heel, D. A. & Brown, M. A. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14, 661–673 (2013).
  Article PubMed CAS Google Scholar
• Pickrell, J. K. et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48, 709–717 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Grassmann, F. et al. Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits. Genome Med. 9, 29 (2017).
  Article PubMed PubMed Central CAS Google Scholar
• Webb, T. R. et al. Systematic evaluation of pleiotropy identifies 6 further loci associated with coronary artery disease. J. Am. Coll. Cardiol. 69, 823–836 (2017).
  Article PubMed PubMed Central CAS Google Scholar
• Pickrell, J. Fulfilling the promise of Mendelian randomization. bioRxiv https://doi.org/10.1101/018150 (2015).
• Smith, G. D. Mendelian randomization: a premature burial? bioRxiv https://doi.org/10.1101/021386 (2015).
• Greco, M. F. D., Minelli, C., Sheehan, N. A. & Thompson, J. R. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat. Med. 34, 2926–2940 (2015).
  Article Google Scholar
• Bowden, J. et al. A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Statist. Med. https://doi.org/10.1002/sim.7221 (2017).
• Bowden, J. et al. Improving the accuracy of two-sample summary data Mendelian randomization: moving beyond the NOME assumption. bioRxiv https://doi.org/10.1101/159442 (2017).
• Bowden, J., Smith, G. D. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512–525 (2015).
  Article PubMed PubMed Central Google Scholar
• Bowden, J. et al. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. Int. J. Epidemiol. 45, 1961–1974 (2016).
  Article PubMed PubMed Central Google Scholar
• Do, R. et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45, 1345–1352 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Burgess, S. & Thompson, S. G. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am. J. Epidemiol. 181, 251–260 (2015).
  Article PubMed PubMed Central Google Scholar
• Corbin, L. J. et al. Body mass index as a modifiable risk factor for type 2 diabetes: refining and understanding causal estimates using Mendelian randomisation. Diabetes 65, 3002–3007 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Fox, J. & Long, J. S. Modern Methods of Data Analysis (Sage Publications, Thousand Oaks, CA, USA, 1990).
• Bowden, J., Davey Smith, G., Haycock, P. C. & Burgess, S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40, 304–314 (2016).
  Article PubMed PubMed Central Google Scholar
• Hartwig, F. P., Davey Smith, G. & Bowden, J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int. J. Epidemiol. https://doi.org/10.1093/ije/dyx102.
• MacArthur, J. et al. The new NHGRI-EBI catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res. 45, D896–D901 (2017).
  Article PubMed CAS Google Scholar
• Cohen, J. C., Boerwinkle, E., Mosley, T. H. & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).
  Article PubMed CAS Google Scholar
• Warren, H. R. et al. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat. Genet. 49, 403–415 (2017).
  Article PubMed PubMed Central CAS Google Scholar
• Ehret, G. B. et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat. Genet. 48, 1171–1184 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Liu, C. et al. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat. Genet. 48, 1162–1170 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Holmes, M. V. et al. Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis. Am. J. Hum. Genet. 94, 198–208 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Lyngdoh, T. et al. Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach. PLoS One 7, e39321 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Hemani, G. et al. Automating Mendelian randomization through machine learning to construct a putative causal map of the human phenome. bioRxiv https://doi.org/10.1101/173682 (2017).
• Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013).
  Article PubMed CAS Google Scholar
• Mokry, L. E., Ahmad, O., Forgetta, V., Thanassoulis, G. & Richards, J. B. Mendelian randomisation applied to drug development in cardiovascular disease: a review. J. Med. Genet. 52, 71–79 (2015).
  Article PubMed CAS Google Scholar
• Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658–665 (2013).
  Article PubMed PubMed Central Google Scholar
• Pasaniuc, B. et al. Fast and accurate imputation of summary statistics enhances evidence of functional enrichment. Bioinformatics 30, 2906–2914 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• 1000 Genomes Project Consortium. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
  Article CAS Google Scholar