Mendelian randomization and pleiotropy analysis

Xiaofeng Zhu

Quant. Biol. ›› 2021, Vol. 9 ›› Issue (2) : 122 -132.

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Quant. Biol. ›› 2021, Vol. 9 ›› Issue (2) : 122 -132. DOI: 10.1007/s40484-020-0216-3
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Mendelian randomization and pleiotropy analysis

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Abstract

Background: Mendelian randomization (MR) analysis has become popular in inferring and estimating the causality of an exposure on an outcome due to the success of genome wide association studies. Many statistical approaches have been developed and each of these methods require specific assumptions.

Results: In this article, we review the pros and cons of these methods. We use an example of high-density lipoprotein cholesterol on coronary artery disease to illuminate the challenges in Mendelian randomization investigation.

Conclusion: The current available MR approaches allow us to study causality among risk factors and outcomes. However, novel approaches are desirable for overcoming multiple source confounding of risk factors and an outcome in MR analysis.

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Keywords

Mendelian randomization / causality / summary statistics / confounding / instrumental variable

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Xiaofeng Zhu. Mendelian randomization and pleiotropy analysis. Quant. Biol., 2021, 9(2): 122-132 DOI:10.1007/s40484-020-0216-3

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References

[1]

Schatzkin, A., Lanza, E., Corle, D., Lance, P., Iber, F., Caan, B., Shike, M., Weissfeld, J., Burt, R., Cooper, M. R., (2000) Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. N. Engl. J. Med., 342, 1149–1155

[2]

The Heart Outcomes Prevention Evaluation Study Investigators. (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. N. Engl. J. Med., 342, 154–160

[3]

Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med., 330, 1029–1035

[4]

Sesso, H. D., Buring, J. E., Christen, W. G., Kurth, T., Belanger, C., MacFadyen, J., Bubes, V., Manson, J. E., Glynn, R. J. and Gaziano, J. M. (2008) Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA, 300, 2123–2133

[5]

Davey Smith, G. and Ebrahim, S. (2001) Epidemiology–is it time to call it a day? Int. J. Epidemiol., 30, 1–11

[6]

Fewell, Z., Davey Smith, G. and Sterne, J. A. (2007) The impact of residual and unmeasured confounding in epidemiologic studies: a simulation study. Am. J. Epidemiol., 166, 646–655

[7]

Evans, D. M. and Davey Smith, G. (2015) Mendelian randomization: new applications in the coming age of hypothesis-free causality. Annu. Rev. Genomics Hum. Genet., 16, 327–350

[8]

Davey Smith, G. and Hemani, G. (2014) Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet., 23, R89–R98

[9]

Katan, M. B. (1986) Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet, 327, 507–508

[10]

Visscher, P. M., Wray, N. R., Zhang, Q., Sklar, P., McCarthy, M. I., Brown, M. A. and Yang, J. (2017) 10 years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet., 101, 5–22

[11]

Davey Smith, G. and Ebrahim, S. (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol., 32, 1–22

[12]

VanderWeele, T. J., Tchetgen Tchetgen, E. J., Cornelis, M. and Kraft, P. (2014) Methodological challenges in Mendelian randomization. Epidemiology, 25, 427–435

[13]

Watanabe, K., Stringer, S., Frei, O., Umićević Mirkov, M., Polderman, T. J. C., van der Sluis, S., Andreassen, O. A., Neale, B. M. and Posthuma, D. (2018) A global view of pleiotropy and genetic architecture in complex traits. Nat. Genet., 51, 1339–1134

[14]

Solovieff, N., Cotsapas, C., Lee, P. H., Purcell, S. M. and Smoller, J. W. (2013) Pleiotropy in complex traits: challenges and strategies. Nat. Rev. Genet., 14, 483–495

[15]

Zhu, X., Feng, T., Tayo, B. O., Liang, J., Young, J. H., Franceschini, N., Smith, J. A., Yanek, L. R., Sun, Y. V., Edwards, T. L., (2015) Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension. Am. J. Hum. Genet., 96, 21–36

[16]

Sleiman, P. M. and Grant, S. F. (2010) Mendelian randomization in the era of genomewide association studies. Clin. Chem., 56, 723–728

[17]

Angrist, J. D., Imbens, G. W. and Rubin, D. B. (1996) Identification of causal effects using instrumental variables. J. Am. Stat. Assoc., 91, 444–455

[18]

Verbanck, M., Chen, C. Y., Neale, B. and Do, R. (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet., 50, 693–698

[19]

Burgess, S., Butterworth, A. and Thompson, S. G. (2013) Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol., 37, 658–665

[20]

Bowden, J., Del Greco M, F., Minelli, C., Davey Smith, G., Sheehan, N. and Thompson, J. (2017) A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat. Med., 36, 1783–1802

[21]

Borenstein, M., Hedges, L., Higgins, J. and Rothstein, H. (2009) Generality of the basic inverse-variance method. In: Introduction to Meta-analysis. Wiley

[22]

Bowden, J., Davey Smith, G. and Burgess, S. (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol., 44, 512–525

[23]

Egger, M., Davey Smith, G., Schneider, M. and Minder, C. (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629–634

[24]

Zhu, X., Li, X., Xu, R., Wang, T. (2020) An iterative approach to detect pleiotropy and perform Mendelian randomization analysis using GWAS summary statistics. Under review

[25]

Bowden, J., Davey Smith, G., Haycock, P. C. and Burgess, S. (2016) Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol., 40, 304–314

[26]

Hartwig, F. P., Davey Smith, G. and Bowden, J. (2017) Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int. J. Epidemiol., 46, 1985–1998

[27]

Bickel, D. R. (2003) Robust and efficient estimation of the mode of continuous data: the mode as a viable measure of central tendency. J. Stat. Comput. Simul., 73, 899–912

[28]

Bickel, D. R. and Fruhwirth, R. (2006) On a fast, robust estimator of the mode: Comparisons to other robust estimators with applications. Comput. Stat. Data Anal., 50, 3500–3530

[29]

Huber, P. J. and Ronchetti, E. (2009) Robust Statistics, 2nd edition, Hoboken, N.J. (ed.).Wiley

[30]

Rees, J. M. B., Wood, A. M., Dudbridge, F. and Burgess, S. (2019) Robust methods in Mendelian randomization via penalization of heterogeneous causal estimates. PLoS One, 14, e0222362

[31]

Koller, M. and Stahel, W. A. (2011) Sharpening Wald-type inference in robust regression for small samples. Comput. Stat. Data Anal., 55, 2504–2515

[32]

Tibshirani, R. (1996) Regression shrinkage and selection via the Lasso. J. R. Stat. Soc. B, 58, 267–288

[33]

Kang, H., Zhang, A. R., Cai, T. T. and Small, D. S. (2016) Instrumental variables estimation with some invalid instruments and its application to Mendelian randomization. J. Am. Stat. Assoc., 111, 132–144

[34]

Windmeijer, F., Farbmacher, H., Davies, N. and Davey Smith, G. (2019) On the use of the Lasso for instrumental variables estimation with some invalid instruments. J. Am. Stat. Assoc., 114, 1339–1350

[35]

Qi, G. and Chatterjee, N. (2019) Mendelian randomization analysis using mixture models for robust and efficient estimation of causal effects. Nat. Commun., 10, 1941

[36]

Park, H., Li, X., Song, Y. E., He, K. Y. and Zhu, X. (2016) Multivariate analysis of anthropometric traits using summary statistics of genome-wide association studies from GIANT consortium. PLoS One, 11, e0163912

[37]

Bulik-Sullivan, B. K., Loh, P. R., Finucane, H. K., Ripke, S., Yang, J., the Schizophrenia Working Group of the Psychiatric Genomics Consortium, Patterson, N., Daly, M. J., Price, A. L. and Neale, B. M. (2015) LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet., 47, 291–295

[38]

Burgess, S., Davey Smith, G., Davies, N. M., Dudbridge, F., Gill, D., Glymour, M. M., Hartwig, F. P., Holmes, M. V., Minelli, C., Relton, C. L., (2019) Guidelines for performing Mendelian randomization investigations. Wellcome Open Res., 4, 186

[39]

Hernán, M. A. and Robins, J. M. (2006) Instruments for causal inference: an epidemiologist’s dream? Epidemiology, 17, 360–372

[40]

Labrecque, J. A. and Swanson, S. A. (2019) Interpretation and potential biases of Mendelian randomization estimates with time-varying exposures. Am. J. Epidemiol., 188, 231–238

[41]

Swanson, S. A., Labrecque, J. and Hernán, M. A. (2018) Causal null hypotheses of sustained treatment strategies: What can be tested with an instrumental variable? Eur. J. Epidemiol., 33, 723–728

[42]

Franceschini, N., Fox, E., Zhang, Z., Edwards, T. L., Nalls, M. A., Sung, Y. J., Tayo, B. O., Sun, Y. V., Gottesman, O., Adeyemo, A., (2013) Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations. Am. J. Hum. Genet., 93, 545–554

[43]

Liang, J., Le, T. H., Edwards, D. R. V., Tayo, B. O., Gaulton, K. J., Smith, J. A., Lu, Y., Jensen, R. A., Chen, G., Yanek, L. R., (2017) Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. PLoS Genet., 13, e1006728

[44]

Smith, G. D., Davies, N. M., Dimou, N., Egger, M., Gallo, V., Golub, R., Higgins, J. P. T., Langenberg, C., Loder, E. W., Richards, J. B., (2020) STROBE-MR: Guidelines for strengthening the reporting of Mendelian randomization studies. PeerJ Preprints 7, e27857v1

[45]

Burgess, S., Bowden, J., Fall, T., Ingelsson, E. and Thompson, S. G. (2017) Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology, 28, 30–42

[46]

Pickrell, J. (2015) Fulfilling the promise of Mendelian randomization. bioRxiv, 018150

[47]

Davey Smith, G. (2015) Mendelian randomization: a premature burial? bioRxiv, 021386

[48]

Jordan, D. M., Verbanck, M. and Do, R. (2019) HOPS: a quantitative score reveals pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases. Genome Biol., 20, 222

[49]

The Emerging Risk Factors Collaboration (2009) Major lipids, apolipoproteins, and risk of vascular disease. JAMA, 302, 1993–2000

[50]

Lewington, S., Whitlock, G., Clarke, R., Sherliker, P., Emberson, J., Halsey, J., Qizilbash, N., Peto, R., Collins, R., Collins, R., (2007) Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet, 370, 1829–1839

[51]

Voight, B. F., Peloso, G. M., Orho-Melander, M., Frikke-Schmidt, R., Barbalic, M., Jensen, M. K., Hindy, G., Hólm, H., Ding, E. L., Johnson, T., (2012) Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet, 380, 572–580

[52]

Geller, A. S., Polisecki, E. Y., Diffenderfer, M. R., Asztalos, B. F., Karathanasis, S. K., Hegele, R. A. and Schaefer, E. J. (2018) Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. J. Lipid Res., 59, 2421–2435

[53]

Holmes, M. V., Asselbergs, F. W., Palmer, T. M., Drenos, F., Lanktree, M. B., Nelson, C. P., Dale, C. E., Padmanabhan, S., Finan, C., Swerdlow, D. I., (2015) Mendelian randomization of blood lipids for coronary heart disease. Eur. Heart J., 36, 539–550

[54]

Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., Maller, J., Sklar, P., de Bakker, P. I., Daly, M. J., (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet., 81, 559–575

[55]

Cortes, A., Albers, P. K., Dendrou, C. A., Fugger, L. and McVean, G. (2020) Identifying cross-disease components of genetic risk across hospital data in the UK Biobank. Nat. Genet., 52, 126–134

[56]

Burgess, S. and Thompson, S. G. (2015) Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am. J. Epidemiol., 181, 251–260

[57]

Davies, R. B. (1980) The distribution of a linear combination of χ2 random variables. J. R. Stat. Soc. C Appl. Stat., 29, 323–333

[58]

Richardson, T. G., Harrison, S., Hemani, G. and Davey Smith, G. (2019) An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome. eLife, 8, e43657

[59]

Bentley, A. R., Sung, Y. J., Brown, M. R., Winkler, T. W., Kraja, A. T., Ntalla, I., Schwander, K., Chasman, D. I., Lim, E., Deng, X., (2019) Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. Nat. Genet., 51, 636–648

[60]

Sung, Y. J., Winkler, T. W., de Las Fuentes, L., Bentley, A. R., Brown, M. R., Kraja, A. T., Schwander, K., Ntalla, I., Guo, X., Franceschini, N., (2018) A Large-scale multi-ancestry genome-wide study accounting for smoking behavior identifies multiple significant loci for blood pressure. Am. J. Hum. Genet., 102, 375–400

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