Distinguishing genetic correlation from causation across 52 diseases and complex traits

Abstract

Mendelian randomization, a method to infer causal relationships, is confounded by genetic correlations reflecting shared etiology. We developed a model in which a latent causal variable mediates the genetic correlation; trait 1 is partially genetically causal for trait 2 if it is strongly genetically correlated with the latent causal variable, quantified using the genetic causality proportion. We fit this model using mixed fourth moments \({\it{E}}({\it{\alpha }}_1^2{\it{\alpha }}_1{\it{\alpha }}_2)\) and \({\it{E}}\left( {{\it{\alpha }}_2^2{\it{\alpha }}_1{\it{\alpha }}_2} \right)\) of marginal effect sizes for each trait; if trait 1 is causal for trait 2, then SNPs affecting trait 1 (large \({\it{\alpha }}_1^2\)) will have correlated effects on trait 2 (large α1α2), but not vice versa. In simulations, our method avoided false positives due to genetic correlations, unlike Mendelian randomization. Across 52 traits (average n = 331,000), we identified 30 causal relationships with high genetic causality proportion estimates. Novel findings included a causal effect of low-density lipoprotein on bone mineral density, consistent with clinical trials of statins in osteoporosis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Illustration of the LCV model.
Fig. 2: Null simulations with no LD to assess calibration.
Fig. 3: Causal simulations with no LD to assess power.
Fig. 4: Partially or fully genetically causal relationships between selected complex traits.

Data availability

UK Biobank summary statistics are publicly available at http://data.broadinstitute.org/alkesgroup/UKBB/.

Change history

  • 06 November 2018

    In the version of this article originally published, there were errors in equations. In the HTML and PDF, the initial term of equation 10 was estimated GCP but should have been estimated standard error, while a ‘hat’ was missing from the first alpha in the second term of the expression at the end of the paragraph following equation (6) in the Methods. In addition, in the abstract in the PDF, a subscript 1 was used instead of a subscript 2 for the final term of the first fourth-moment expression. These errors have been corrected in the HTML, PDF and print versions of the paper.

References

  1. 1.

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

    Article  Google Scholar 

  2. 2.

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

    CAS  Article  Google Scholar 

  3. 3.

    Voight, B. F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380, 572–580 (2012).

    CAS  Article  Google Scholar 

  4. 4.

    Do, R. et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45, 1345–1352 (2013).

    CAS  Article  Google Scholar 

  5. 5.

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

    Article  Google Scholar 

  6. 6.

    Kang, H. et al. Instrumental variables estimation with some invalid instruments and its application to Mendelian randomization. J. Am. Stat. Assoc. 111, 132–144 (2016).

    CAS  Article  Google Scholar 

  7. 7.

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

    Article  Google Scholar 

  8. 8.

    Bowden, J. et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40, 304–314 (2016).

    Article  Google Scholar 

  9. 9.

    Hemani, G. et al. The MR-Base platform supports systematic causal inference across the phenome. eLife 7, e34408 (2018).

    Article  Google Scholar 

  10. 10.

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

    Article  Google Scholar 

  11. 11.

    Pickrell, J. K. et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48, 709–717 (2016).

    CAS  Article  Google Scholar 

  12. 12.

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

    CAS  Article  Google Scholar 

  13. 13.

    Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).

    CAS  Article  Google Scholar 

  14. 14.

    Paaby, A. B. & Rockman, M. V. The many faces of pleiotropy. Trends Genet. 29, 63–73 (2013).

    Article  Google Scholar 

  15. 15.

    VanderWeele, T. J. et al. Methodological challenges in Mendelian randomization. Epidemiology 25, 427–435 (2014).

    Article  Google Scholar 

  16. 16.

    Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).

    CAS  Article  Google Scholar 

  17. 17.

    Welsh, P. et al. Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach. J. Clin. Endocrinol. Metab. 95, 93–99 (2010).

    CAS  Article  Google Scholar 

  18. 18.

    Vimaleswaran, K. S. et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 10, e1001383 (2013).

    Article  Google Scholar 

  19. 19.

    Bulik-Sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Yang, J. et al. Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Nat. Genet. 47, 1114–1120 (2015).

    CAS  Article  Google Scholar 

  21. 21.

    Kolesar, M. et al. Identification and inference with many invalid instruments. J. Bus. Econ. Stat. 33, 474–484 (2015).

    Article  Google Scholar 

  22. 22.

    Burgess, S. & Thompson, S. G. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur. J. Epidemiol. 32, 377–389 (2017).

    Article  Google Scholar 

  23. 23.

    Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).

    Article  Google Scholar 

  24. 24.

    Bycroft, C. et al. Genome-wide genetic data on ~500,000 UK Biobank participants. Preprint at bioRxiv https://doi.org/10.1101/166298 (2017).

  25. 25.

    Loh, P. R. et al. Mixed-model association for biobank-scale datasets. Nat. Genet. 50, 906–908 (2018).

    CAS  Article  Google Scholar 

  26. 26.

    Holmes, M. V., Ala-Korpela, M. & Davey Smith, G. Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. Nat. Rev. Cardiol. 14, 577–590 (2017).

    CAS  Article  Google Scholar 

  27. 27.

    Davey Smith, G. et al. The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study. BMJ 339, b5043 (2009).

    Article  Google Scholar 

  28. 28.

    Nordestgaard, B. G. et al. The effect of elevated body mass index on ischemic heart disease risk: causal estimates from a Mendelian randomisation approach. PLoS Med. 9, e1001212 (2012).

    Article  Google Scholar 

  29. 29.

    Hägg, S. et al. Adiposity as a cause of cardiovascular disease: a Mendelian randomization study. Int. J. Epidemiol. 44, 578–586 (2015).

    Article  Google Scholar 

  30. 30.

    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).

    CAS  Article  Google Scholar 

  31. 31.

    Klein, I. & Ojamaa, K. Thyroid hormone and the cardiovascular system. N. Engl. J. Med. 344, 501–509 (2001).

    CAS  Article  Google Scholar 

  32. 32.

    Grais, I. M. & Sowers, J. R. Thyroid and the heart. Am. J. Med. 127, 691–698 (2014).

    CAS  Article  Google Scholar 

  33. 33.

    Zhao, J. V. & Schooling, C. M. Thyroid function and ischemic heart disease: a Mendelian randomization study. Sci. Rep. 7, 8515 (2017).

    Article  Google Scholar 

  34. 34.

    Monzani, F. et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 86, 1110–1115 (2001).

    CAS  Article  Google Scholar 

  35. 35.

    Meier, C. et al. TSH-controlled l-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J. Clin. Endocrinol. Metab. 86, 4430–4863 (2001).

    Article  Google Scholar 

  36. 36.

    Monzani, F. et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 89, 2099–2106 (2004).

    CAS  Article  Google Scholar 

  37. 37.

    Razvi, S. et al. The beneficial effect of l-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J. Clin. Endocrinol. Metab. 92, 1715–1723 (2007).

    CAS  Article  Google Scholar 

  38. 38.

    Nagasaki, T. et al. Decrease of brachial-ankle pulse wave velocity in female subclinical hypothyroid patients during normalization of thyroid function: a double-blind, placebo-controlled study. Eur. J. Endocrinol. 160, 409–415 (2009).

    CAS  Article  Google Scholar 

  39. 39.

    Chaker, L. et al. Thyroid function and risk of type 2 diabetes: a population-based prospective cohort study. BMC Med. 14, 150 (2016).

    Article  Google Scholar 

  40. 40.

    Brenta, G. et al. Acute thyroid hormone withdrawal in athyreotic patients results in a state of insulin resistance. Thyroid 19, 665–669 (2009).

    CAS  Article  Google Scholar 

  41. 41.

    Wang, Z. et al. Effects of statins on bone mineral density and fracture risk: a PRISMA-compliant systematic review and meta-analysis. Medicine 95, e3042 (2016).

    CAS  Article  Google Scholar 

  42. 42.

    Yerges, L. M. et al. Decreased bone mineral density in subjects carrying familial defective apolipoprotein B-100. J. Clin. Endocrinol. Metab. 98, E1999–E2005 (2013).

    Article  Google Scholar 

  43. 43.

    Sanjak, J. S. et al. Evidence of directional and stabilizing selection in contemporary humans. Proc. Natl Acad. Sci. USA 115, 151–156 (2018).

    CAS  Article  Google Scholar 

  44. 44.

    Price, G. R. Selection and covariance. Nature 227, 520–521 (1970).

    CAS  Article  Google Scholar 

  45. 45.

    Clarke, T. K. et al. Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population. Mol. Psychiatry 21, 419–425 (2016).

    Article  Google Scholar 

  46. 46.

    Davies, G. et al. Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N = 112,151). Mol. Psychiatry 21, 758–767 (2016).

    CAS  Article  Google Scholar 

  47. 47.

    Keller, M. C. & Miller, G. Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best? Behav. Brain Sci. 29, 385–404 (2006).

    Article  Google Scholar 

  48. 48.

    Mullins, N. et al. Reproductive fitness and genetic risk of psychiatric disorders in the general population. Nat. Commun. 8, 15833 (2017).

    CAS  Article  Google Scholar 

  49. 49.

    Ware, J. J. et al. Genome-wide meta-analysis of cotinine levels in cigarette smokers identifies locus at 4q13.2. Sci. Rep. 6, 20092 (2016).

    CAS  Article  Google Scholar 

  50. 50.

    Burgess, S. et al. Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int. J. Epidemiol. 44, 484–495 (2014).

    Article  Google Scholar 

  51. 51.

    Schoech, A. et al. Quantification of frequency-dependent genetic architectures and action of negative selection in 25 UK Biobank traits. Preprint at bioRxiv https://doi.org/10.1101/188086 (2017).

  52. 52.

    Mokry, L. E. et al. Vitamin D and risk of multiple sclerosis: a Mendelian randomization study. PLoS Med. 12, e1001866 (2015).

    Article  Google Scholar 

  53. 53.

    Gamazon, E. R. et al. A gene-based association method for mapping traits using reference transcriptome data. Nat. Genet. 47, 1091–1098 (2015).

    CAS  Article  Google Scholar 

  54. 54.

    Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245–252 (2016).

    CAS  Article  Google Scholar 

  55. 55.

    Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet. 48, 481–487 (2016).

    CAS  Article  Google Scholar 

  56. 56.

    GTEx Consortium et al. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).

    Article  Google Scholar 

  57. 57.

    Lyall, D. M. et al. Association of body mass index with cardiometabolic disease in the UK Biobak: a Mendelian randomization study. JAMA Cardiol. 2, 882–889 (2017).

    Article  Google Scholar 

  58. 58.

    Child, D. The Essentials of Factor Analysis. (A&C Black, London, 1990).

    Google Scholar 

  59. 59.

    Comon, P. Independent component analysis, a new concept? Signal Process. 36, 287–314 (1994).

    Article  Google Scholar 

  60. 60.

    UK10K Consortium. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).

    Article  Google Scholar 

Download references

Acknowledgements

We are grateful to B. Neale, S. Raychaudhuri, C. Patel, S. Kathiresan, B. Pasaniuc, and H. Finucane for helpful discussions and to P.-R. Loh and S. Gazal for producing BOLT-LMM summary statistics for UK Biobank traits. This research was conducted using the UK Biobank Resource under Application #16549 and was funded by National Institutes of Health grants R01 MH107649, U01 CA194393, and R01 MH101244.

Author information

Affiliations

Authors

Contributions

L.J.O. and A.L.P. conceived the methods, designed the analyses, and wrote the manuscript. L.J.O. performed the analyses.

Corresponding authors

Correspondence to Luke J. O’Connor or Alkes L. Price.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Integrated supplementary information

Supplementary Figure 1 Null and causal simulations with no LD and LCV model violations.

ag, We report the positive rate (α = 0.05 for null simulations, α = 0.001 for causal simulations) for two-sample MR, MR-Egger, Bidirectional MR and LCV. ac correspond to Gaussian mixture model extensions of the models in Fig. 2b-d. f and g correspond to causal analogs of the models in a and d, respectively. We also display scatterplots illustrating the bivariate distribution of true SNP effect sizes on the two traits. a, Null simulation with nonzero SNP effects drawn from a mixture of Gaussian distributions; one mixture component has correlated effects on each trait. b, Null simulation with SNP effects drawn from a mixture of Gaussian distributions, and differential polygenicity between the two traits. c, Null simulation with SNP effects drawn from a mixture of Gaussian distributions and unequal power between the two traits. d, Null simulation with two intermediaries having different effects on each trait. e, Null simulation with two intermediaries having different effects on each trait and unequal polygenicity for the two intermediaries. f, Causal simulation with SNP effects drawn from a mixture of Gaussian distributions; all SNPs affecting trait 1 also affect trait 2, but the relative effect sizes were noisy. g, Causal simulation with an additional genetic confounder (i.e., a second intermediary) mediating part of the genetic correlation. Results for each panel are based on 1,000 simulations. Numerical results are reported in Supplementary Tables 4 and 5, which also include comparisons to MR-WME and MR-MBE.

Supplementary Figure 2 Mean GCP estimates in simulations with LCV model violations.

Error bars show s.d. based on 1,000 simulations. a, Null simulation with two intermediaries having possibly unequal polygenicity. The two intermediaries had either a slightly, moderately, or highly heterogenous effect on the two traits; that is, when heterogeneity was high, intermediary 1 had a much larger effect on trait 1 while intermediary 2 had a much larger effect on trait 2. Then, we specified a certain difference in polygenicity between the two traits (measured by the proportion of causal SNPs). b, Causal simulation with an additional latent confounder. The latent confounder explained a low, medium, or high proportion of the genetic correlation. We varied the polygenicity of the confounder and of the causal trait, such that a 16× difference in polygenicity indicates that 16× more SNPs were causal for the causal trait than for the genetic confounder.

Supplementary Figure 3 Unbiasedness of posterior mean GCP estimates in simulations with LD and random true GCP values.

Estimated values of GCP were binned and averaged, and mean true values of GCP are plotted for each bin, with standard errors. Points above the line indicate that GCP estimates were downward biased (toward –1). a, Ascertained simulations (43%) with significant genetic correlation (P < 0.05) and evidence for partial causality (P < 0.001). Only bins with a count of at least 10 are plotted. b, All 10,000 simulations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 2–11 and 13–17, and Supplementary Note

Reporting Summary

Supplementary Table 1

Simulation parameters

Supplementary Table 12

LCV and MR results for all trait pairs

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

O’Connor, L.J., Price, A.L. Distinguishing genetic correlation from causation across 52 diseases and complex traits. Nat Genet 50, 1728–1734 (2018). https://doi.org/10.1038/s41588-018-0255-0

Download citation

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing