A Two-Sample Mendelian Randomization Analysis Investigates Associations Between Gut Microbiota and Celiac Disease

Celiac disease (CeD) is a complex immune-mediated inflammatory condition triggered by the ingestion of gluten in genetically predisposed individuals. Literature suggests that alterations in gut microbiota composition and function precede the onset of CeD. Considering that microbiota is partly determined by host genetics, we speculated that the genetic makeup of CeD patients could elicit disease development through alterations in the intestinal microbiota. To evaluate potential causal relationships between gut microbiota and CeD, we performed a two-sample Mendelian randomization analysis (2SMR). Exposure data were obtained from the raw results of a previous genome-wide association study (GWAS) of gut microbiota and outcome data from summary statistics of CeD GWAS and Immunochip studies. We identified a number of putative associations between gut microbiota single nucleotide polymorphisms (SNPs) associated with CeD. Regarding bacterial composition, most of the associated SNPs were related to Firmicutes phylum, whose relative abundance has been previously reported to be altered in CeD patients. In terms of functional units, we linked a number of SNPs to several bacterial metabolic pathways that seemed to be related to CeD. Overall, this study represented the first 2SMR approach to elucidate the relationship between microbiome and CeD.This research was funded by the Basque Department of Health, grant numbers GVSAN2018/111086 and GVSAN2019/111085 to J.R.B. and N.F.-J., respectively

A Systematic Two-Sample Mendelian Randomization Analysis Identifies Shared Genetic Origin of Endometriosis and Associated Phenotypes

Endometriosis, one of the most common gynecological disorders, is a complex disease characterized by the growth of endometrial-like tissue in extra-uterine locations and is a cause of pelvic pain and infertility. Evidence from observational studies indicate that endometriosis usually appears together with several other phenotypes. These include a list of autoimmune diseases, most of them more prevalent in women, anthropometric traits associated with leanness in the adulthood, as well as female reproductive traits, including altered hormone levels and those associated with a prolonged exposure to menstruation. However, the biological mechanisms underlying their co-morbidity remains unknown. To explore whether those phenotypes and endometriosis share a common genetic origin, we performed a systematic Two-Sample Mendelian Randomization (2SMR) analysis using public GWAS data. Our results suggest potential common genetic roots between endometriosis and female anthropometric and reproductive traits. Particularly, our data suggests that reduced weight and BMI might be mediating the genetic susceptibility to suffer endometriosis. Furthermore, data on female reproductive traits strongly suggest that genetic variants that predispose to a more frequent exposure to menstruation, through earlier age at menarche and shorter menstrual cycles, might also increase the risk to suffer from endometriosis

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.This research was funded by the Basque Department of Health, grant numbers 2020111043, 2018111086 and 2019111085 to I.G.-S., J.R.B. and N.F.-J., respectively

A meta-analysis of pre-pregnancy maternal body mass index and placental DNA methylation identifies 27 CpG sites with implications for mother-child health

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenome-wide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings.We would like to thank the Pregnancy and Childhood Epigenetics (PACE) consortium, as well as all the families that participated in these studies for their generous contribution. This work was partially funded by GVSAN2018111086 from the Basque Department of Health and PI18/01142 from ISCIII - Spanish Ministry of Science and Innovation - cofounded by the ERDF “A way to make Europe” to JRB and LSM, respectively; and by the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL) (NutriPROGRAM). ACP was supported by grant GVSAN2019111085 from the Basque Department of Health to NFJ. Detailed acknowledgements and funding for each participating cohort are described in Supplementary Note 1

A mendelian randomization search for functionally relevant celiac desease susceptibility variants in stimulated monocytes

Curs 2019-2020Director/a: Calle Rosingana, M. Lu

Anàlisi del metiloma i el transcriptoma de la diabetis de tipus 2

Curs 2018-2019La diabetis de tipus 2 (DMT2) o diabetes mellitus no insulinodependent és una malaltia metabòlica molt complexa que es caracteritza pel fet que les cèl·lules del nostre cos són incapaces de detectar la insulina a través dels seus receptors. El fet de desenvolupar DMT2 és el resultat de la interacció entre factors ambientals i factors heretables. En aquest Treball de Fi de Grau hem volgut explorar alguns mecanismes moleculars que poden estar associats a la diabetis tipus 2 a partir d'una aproximació multi-òmica que integri informació epigenòmica i transcriptòmica. Per això, hem partit de les dades públiques de l’estudi (GSE65058): Kirchner H, Sinha I, Gao H, Ruby MA et al. Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients. Mol Metab 2016 Mar;5(3):171-183. PMID: 26977391, que te per objectiu descobrir les contribucions epigenètiques en aquesta malaltia. Concretament, hem pogut analitzar els nivells de metilació i d'expressió gènica de pacients amb diabetis de Tipus 2 (DMT2) i controls sans “ND” obtingudes en aquest estudi. Així doncs, l’objectiu de partida del present Treball de Fi de Grau és poder aportar llum sobre els mecanismes moleculars associats al desenvolupament de la diabetis de tipus 2 a partir de l'estudi de la possible relació entre el perfil d’expressió gènic i els nivells de metilació dels diabètics de tipus 2. Tant l’anàlisi del transcriptoma com el del metiloma, s’han dut a terme mitjançant el programa estadístic R, en el qual s’han utilitzat diverses llibreries de Bioconductor específiques per a cada tipus de dades. En els resultats de l’anàlisi del transcriptoma vam identificar 4 sondes diferencialment expressades, on només una d’elles havia estat descrita anteriorment. En canvi pel metiloma diversos dinucleòtids CpG es trobaven diferencialment metilats. En el procés d'integració dels dos nivells d'informació molecular no vam poder identificar relacions rellevants, com per exemple dinucleòtids CpG que poguessin afectar l’expressió del gens diferencialment expressats que havíem descrit en l'anàlisi del transcriptoma. De manera que aquests resultats deixen la porta oberta a noves vies d’investigació sobre les causes i les vies biològiques associades a la diabetis de tipus 2

Prenatal crosstalk between environment and genetics: the impact of placental DNA methylation on future health

Contiene los apéndices de la tesis doctoral "Prenatal crosstalk between environment and genetics: the impact of placental DNA methylation on future health"

Prenatal maternal smoke, DNA methylation, and multi-omics of tissues and child health

Purpose of review: Maternal tobacco smoking during pregnancy is of public health concern, and understanding the biological mechanisms can help to promote smoking cessation campaigns. This non-systematic review focuses on the effects of maternal smoking during pregnancy on offspring's epigenome, consistent in chemical modifications of the genome that regulate gene expression. Recent findings: Recent meta-analyses of epigenome-wide association studies have shown that maternal smoking during pregnancy is consistently associated with offspring's DNA methylation changes, both in the placenta and blood. These studies indicate that effects on blood DNA methylation can persist for years, and that the longer the duration of the exposure and the higher the dose, the larger the effects. Hence, DNA methylation scores have been developed to estimate past exposure to maternal smoking during pregnancy as biomarkers. There is robust evidence for DNA methylation alterations associated with maternal smoking during pregnancy; however, the role of sex, ethnicity, and genetic background needs further exploration. Moreover, there are no conclusive studies about exposure to low doses or during the preconception period. Similarly, studies on tissues other than the placenta and blood are scarce, and cell-type specificity within tissues needs further investigation. In addition, biological interpretation of DNA methylation findings requires multi-omics data, poorly available in epidemiological settings. Finally, although several mediation analyses link DNA methylation changes with health outcomes, they do not allow causal inference. For this, a combination of data from multiple study designs will be essential in the future to better address this topic.The study has received funding from the H2020-EU.3.1.2.—Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). Marta Cosin-Tomas is funded by a Beatriu de Pinós Postdoctoral Contract awarded by Generalitat de Catalunya-AGAUR and European Commission- Horizon 2020 (2019 BP 00107). Ariadna Cilleros-Portet is funded by a grant from the Health Department of the Basque Government to Nora Fernandez-Jimenez (GVSAN-2019111085). Sofía Aguilar-Lacasaña is funded by a FI-AGAUR Predoctoral contract awarded by the Agència de Gestió d'Ajuts Universitaris i de Recerca (2022 FI_B 00797), Generalitat de Catalunya – Fons Social Europeu. We received support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program

Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk

Background: Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.5/DQ2.2 heterozygous. Both the HLA-DQ2-positive high genetic risk individuals and those that have developed the disease have altered intestinal microbiota, but it remains unclear whether these alterations are a cause or a consequence of CeD. Objective: To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals. Materials and Methods: We performed a bidirectional Two-Sample Mendelian Randomization (2SMR) test using summary statistics from the largest publicly available Genome-Wide Association Study (GWAS) of GM and the summary statistics of the Immunochip CeD study of those individuals with the HLA-DQ2 high-risk haplotype. To test whether changes in GM composition were causally linked to CeD, GM data were used as exposure and CeD data as outcome; to test for reverse causation, the exposure and outcome datasets were inverted. Results: We identified several bacteria from Ruminococcaceae and Lachnospiraceae families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of Veillonellaceae family might be causal in the development of CeD, while alterations in Pasteurellaceae family might be a consequence of the disease itself. Conclusion: Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 099355