An epigenome-wide association study meta-analysis of educational attainment

Richard Karlsson Linnér ,A G Uitterlinden,Y Wang,Caroline L Relton ,Daniëlle Posthuma ,John M Starr ,Ian J Deary ,Cornelius A Rietveld ,Kyoko Watanabe ,Roger L Milne ,Paolo Víneis ,Gianluca Severi ,Giovanni Fiorito ,Silva Kasela ,Philipp Koellinger ,Christian Gieger ,Annette Peters ,Olli T Raitakari ,George Davey Smith ,Lude Franke ,Anni Joensuu ,Miina Ollikainen ,Sarah E Harris ,Khadeeja Ismail ,Jadwiga Buchwald ,Erdogan Taskesen ,Markus Perola ,Allison Hodge ,Mika Kähönen ,Margaret J Wright ,Laura Baglietto ,Alison Pattie ,Antti Latvala ,Lili Milani ,Nicola J Armstrong ,Nicholas G Martin ,Ilkka Seppälä ,Neil M Davies ,Pooja R Mandaviya ,Magnus Johannesson ,Allan F Mcrae ,Mikko Hurme ,Clemens Baumbach ,Riccardo E Marioni ,Karen A Mather ,Kirsi Auro ,Jaakko Kaprio ,Nancy L Pedersen ,Sarah E Medland ,Cisca Wijmenga ,Andres Metspalu ,Elisabeth B Binder ,Steve Horvath ,Stella Iurato ,Katri Räikkönen ,Graham G Giles ,Sara Hägg ,Patrik Karell ,Silvia Polidoro ,Perminder S Sachdev ,Terho Lehtimäki ,Marc Jan Bonder ,Lisette Stolk ,Jari Lahti ,Joyce B J Van Meurs ,Pekka Jousilahti ,Tõnu Esko ,Andrew Simpkin ,Mélanie Waldenberger ,Joel Eriksson ,Daniel J Benjamin

doi:10.1038/mp.2017.210

Abstract

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications—in our case, CpG methylation—and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Highlights

IntroductionThe epigenome has been shown to be associated with biological factors such as disease status.[1,2] there is a widespread perception in the social sciences that a variety of social environmental factors have an effect on the epigenome,[3,4,5,6,7,8,9,10] virtually all of the replicated evidence to date in humans relates to environmental factors that have a fairly direct biological impact, such as smoking,[11,12,13] alcohol consumption[14,15] and excess energy intake resulting in increased body mass index (BMI).[16,17] Here we study the associations between epigenetic modifications—the methylation of cytosine–guanine pairs connected by a phosphate link (CpG methylation)—and educational attainment (EA)
Each of these probes explains 0.3–0.7% of the variance in educational attainment (EA)—effect sizes somewhat smaller than the largest epigenomewide association study (EWAS) effects that have been observed for body mass index (BMI) and many times smaller than those observed for alcohol consumption, smoking and especially maternal smoking during pregnancy
The EWAS we report here is among the largest conducted to date, our sample size of 10 767 individuals is only large enough to identify nine probes associated with EA at the conventional epigenome-wide significance threshold

Summary

Introduction

The epigenome has been shown to be associated with biological factors such as disease status.[1,2] there is a widespread perception in the social sciences that a variety of social environmental factors have an effect on the epigenome,[3,4,5,6,7,8,9,10] virtually all of the replicated evidence to date in humans relates to environmental factors that have a fairly direct biological impact, such as smoking,[11,12,13] alcohol consumption[14,15] and excess energy intake resulting in increased body mass index (BMI).[16,17] Here we study the associations between epigenetic modifications—the methylation of cytosine–guanine pairs connected by a phosphate link (CpG methylation)—and educational attainment (EA). EA is biologically distal, and yet it is arguably among the most important life-shaping experiences for individuals in modern societies. We report the results of a large-scale epigenomewide association study (EWAS) meta-analysis of EA. By metaanalyzing harmonized EWAS results across 27 cohort studies, we were able to attain an overall sample size of 10 767 individuals of recent European ancestry, making this study one of the largest EWAS to date.[13,15,18] A large sample size is important because little is known about plausible EWAS effect sizes for complex phenotypes such as EA, and an underpowered analysis would run a high risk of both false negatives and false positives.[19,20]

Methods

Discussion

Conclusion