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. 2018 Sep 27;19(1):136.
doi: 10.1186/s13059-018-1514-1.

Epigenetic prediction of complex traits and death

Daniel L McCartney  1 , Robert F Hillary  1 , Anna J Stevenson  1 , Stuart J Ritchie  2   3 , Rosie M Walker  1 , Qian Zhang  4 , Stewart W Morris  1 , Mairead L Bermingham  1 , Archie Campbell  1 , Alison D Murray  5 , Heather C Whalley  6 , Catharine R Gale  2   3 , David J Porteous  1   2 , Chris S Haley  7 , Allan F McRae  4 , Naomi R Wray  4 , Peter M Visscher  2   4 , Andrew M McIntosh  1   2   6 , Kathryn L Evans  1 , Ian J Deary  2   3 , Riccardo E Marioni  8   9
Affiliations

Epigenetic prediction of complex traits and death

Daniel L McCartney et al. Genome Biol. .

Abstract

Background: Genome-wide DNA methylation (DNAm) profiling has allowed for the development of molecular predictors for a multitude of traits and diseases. Such predictors may be more accurate than the self-reported phenotypes and could have clinical applications.

Results: Here, penalized regression models are used to develop DNAm predictors for ten modifiable health and lifestyle factors in a cohort of 5087 individuals. Using an independent test cohort comprising 895 individuals, the proportion of phenotypic variance explained in each trait is examined for DNAm-based and genetic predictors. Receiver operator characteristic curves are generated to investigate the predictive performance of DNAm-based predictors, using dichotomized phenotypes. The relationship between DNAm scores and all-cause mortality (n = 212 events) is assessed via Cox proportional hazards models. DNAm predictors for smoking, alcohol, education, and waist-to-hip ratio are shown to predict mortality in multivariate models. The predictors show moderate discrimination of obesity, alcohol consumption, and HDL cholesterol. There is excellent discrimination of current smoking status, poorer discrimination of college-educated individuals and those with high total cholesterol, LDL with remnant cholesterol, and total:HDL cholesterol ratios.

Conclusions: DNAm predictors correlate with lifestyle factors that are associated with health and mortality. They may supplement DNAm-based predictors of age to identify the lifestyle profiles of individuals and predict disease risk.

Keywords: Ageing; DNA methylation; Mortality; Polygenic scores; Prediction.

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Conflict of interest statement

Ethics approval and consent to participate

All components of GS received ethical approval from the NHS Tayside Committee on Medical Research Ethics (REC Reference Number: 05/S1401/89). GS has also been granted Research Tissue Bank status by the Tayside Committee on Medical Research Ethics (REC Reference Number: 10/S1402/20), providing generic ethical approval for a wide range of uses within medical research.

Ethical permission for the LBC1936 was obtained from the Multi-Centre Research Ethics Committee for Scotland (MREC/01/0/56) and the Lothian Research Ethics Committee (LREC/2003/2/29). Written informed consent was obtained from all participants.

All experimental methods were in accordance with the Helsinki declaration.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
DNAm and polygenic prediction of health and lifestyle factors. Proportion of phenotypic variance explained (R2) is plotted for eight traits: BMI; smoking; alcohol consumption (alcohol); education; total cholesterol (TC); HDL cholesterol (HDL); LDL with remnant cholesterol (LDL); and total:HDL cholesterol ratio (TC:HDL) based on each trait’s polygenic score (blue), DNA methylation-based score (green), and additive genetic + epigenetic score (orange)
Fig. 2
Fig. 2
ROC analysis for DNAm predictors of alcohol, smoking, education, BMI, and cholesterol-related variables. Shown are ROC curves for predicting alcohol consumption, smoking status, obesity, and education (left), and cholesterol levels (right) Obese and non-obese are defined as BMI > 30 and ≤ 30 kg/m2; moderate-to-heavy and non-to-light drinkers defined as drinking > 21 and ≤ 21 units (men) or > 14 and ≤ 14 units (women) of alcohol per week; highly educated individuals had > 11 years of full-time education, compared to low-to-average education (≤ 11 years). High cholesterol levels were defined based on NHS guidelines (https://www.nhs.uk/conditions/high-cholesterol/: > 5 mmol/L for total cholesterol, > 3 mmol/L for LDL cholesterol, > 1 mmol/L for HDL cholesterol, and ≥ 4 for total:HDL cholesterol ratios)
Fig. 3
Fig. 3
HRs for epigenetic (DNAm) predictors of mortality. Forest plots show HRs for DNAm scores for health and lifestyle factors. Effect sizes are per standard deviation with the exception of phenotypic smoking, for which never smokers are used as a reference group. Horizontal lines represent 95% CIs
See this image and copyright information in PMC

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