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

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.

Mitochondrial genetic variants identified to be associated with posttraumatic stress disorder.

Despite the fact that mitochondrial dysfunctions are increasingly recognized as key components in stress-related mental disorders, very little is known about the association between posttraumatic stress disorder (PTSD) and mitochondrial variants. To identify susceptibility mitochondrial genes for PTSD, we analyzed a total number of 978 mitochondrial single-nucleotide polymorphisms (mtSNPs) in a sample of 1238 individuals participating in the KORA (Cooperative Health Research in the Region of Augsburg) study. Participants were classified with 'no PTSD', 'partial PTSD' or 'full PTSD' by applying the Posttraumatic Diagnostic Scale and the Impact of Event Scale. To assess PTSD-mtSNP association while taking heteroplasmy into account, we used the raw signal intensity values measured on the microarray and applied linear regression. Significant associations were obtained between full versus no PTSD and two mtSNPs; mt8414C->T (ß=-0.954±0.06, Padjusted=0.037) located in adenosine triphosphate (ATP) synthase subunit 8 (MT-ATP8) and mt12501G->A (ß=-1.782±0.40, Padjusted=0.015) located in the NADH dehydrogenase subunits 5 (MT-ND5). Heteroplasmy for the two variants towards a larger number of the respective minor alleles increases the risk of having PTSD. NADH dehydrogenase and ATP synthase are both linked to the regulation of reactive oxygen species. Our results highlight the important role of the mitochondrial genome among the factors that contribute to the risk of PTSD. Mitochondrial genetic variants may be more important than has previously been assumed, leading to further insights regarding effects of existing medications, or even to the development of innovative treatments. As this is the first mitochondrial genome-wide association study for PTSDs, further analyses are needed to follow up on the present findings.

A common atopy-associated variant in the Th2 cytokine locus control region impacts transcriptional regulation and alters SMAD3 and SP1 binding.

BACKGROUND: Type 2 immune responses directed by Th2 cells and characterized by the signature cytokines IL4, IL5, and IL13 play major pathogenic roles in atopic diseases. Single nucleotide polymorphisms in the human Th2 cytokine locus in particular in a locus control region within the DNA repair gene RAD50, containing several RAD50 DNase1-hypersensitive sites (RHS), have been robustly associated with atopic traits in genome-wide association studies (GWAS). Functional variants in IL13 have been intensely studied, whereas no causative variants for the IL13-independent RAD50 signal have been identified yet. This study aimed to characterize the functional impact of the atopy-associated polymorphism rs2240032 located in the human RHS7 on cis-regulatory activity and differential binding of transcription factors. METHODS: Differential transcription factor binding was analyzed by electrophoretic mobility shift assays (EMSAs) with Jurkat T-cell nuclear extracts. Identification of differentially binding factors was performed using mass spectrometry (LC-MS/MS). Reporter vector constructs carrying either the major or minor allele of rs2240032 were tested for regulating transcriptional activity in Jurkat and HeLa cells. RESULTS: The variant rs2240032 impacts transcriptional activity and allele-specific binding of SMAD3, SP1, and additional putative protein complex partners. We further demonstrate that rs2240032 is located in an RHS7 subunit which itself encompasses repressor activity and might be important for the fine-tuning of transcription regulation within this region. CONCLUSION: The human RHS7 critically contributes to the regulation of gene transcription, and the common atopy-associated polymorphism rs2240032 impacts transcriptional activity and transcription factor binding.