title: Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations.
abstract: We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n ∼ 350,000) and height (n ∼ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the LifeLines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 14% of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for LifeLines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BMI methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction.
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia; University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9713 AV, the Netherlands.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Bonder
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Riccardo E
authors.initials: RE
authors.lastname: Marioni
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia; University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9713 AV, the Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Liewald
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: Framingham Heart Study and Boston University School of Medicine, Boston, MA 01702, USA; Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA; Population Studies Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892-7936, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Mendelson
authors.affiliation: Department of Biostatistics, Boston University, Boston, MA 02118, USA.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Hebrew Senior Life, Harvard Medical School, Boston, MA 02131, USA.
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: Departments of Epidemiology and Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.affiliation: Population Studies Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892-7936, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9713 AV, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9713 AV, the Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia; University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD 4072, Australia; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK. Electronic address: peter.visscher@uq.edu.au.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001827:Body Height / Q000235:genetics*; D015992:Body Mass Index; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D009426:Netherlands; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D012606:Scotland