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Background  Major challenges in understanding the functional consequences of genetic risk factors for human disease are which tissues and cell types are affected and the limited availability of suitable tissue. The aim of this study was to evaluate tissue-specific genotype-epigenetic characteristics in DNA samples from both endometrium and blood collected from women at different stages of the menstrual cycle and relate results to genetic risk factors for reproductive traits and diseases.    Results  We analysed DNA methylation (DNAm) data from endometrium and blood samples from 66 European women. Methylation profiles were compared between stages of the menstrual cycle, and changes in methylation overlaid with changes in transcription and genotypes. We observed large changes in methylation (27,262 DNAm probes) across the menstrual cycle in endometrium that were not observed in blood. Individual genotype data was tested for association with methylation at 443,016 and 443,101 DNAm probes in endometrium and blood respectively to identify methylation quantitative trait loci (mQTLs). A total of 4546 sentinel  cis -mQTLs ( P  < 1.13 × 10 −10 ) and 434 sentinel  trans -mQTLs ( P  < 2.29 × 10 −12 ) were detected in endometrium and 6615 sentinel  cis -mQTLs ( P  < 1.13 × 10 −10 ) and 590 sentinel  trans -mQTLs ( P  < 2.29 × 10 −12 ) were detected in blood. Following secondary analyses, conducted to test for overlap between mQTLs in the two tissues, we found that 62% of endometrial  cis -mQTLs were also observed in blood and the genetic effects between tissues were highly correlated. A number of mQTL SNPs were associated with reproductive traits and diseases, including one mQTL located in a known risk region for endometriosis (near  GREB1 ).    Conclusions  We report novel findings characterising genetic regulation of methylation in endometrium and the association of endometrial mQTLs with endometriosis risk and other reproductive traits and diseases. The high correlation of genetic effects between tissues highlights the potential to exploit the power of large mQTL datasets in endometrial research and identify target genes for functional studies. However, tissue-specific methylation profiles and genetic effects also highlight the importance of also using disease-relevant tissues when investigating molecular mechanisms of disease risk.    Electronic supplementary material  The online version of this article (10.1186/s13148-019-0648-7) contains supplementary material, which is available to authorized users.

Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases