Kathrine Thibeault

Université de Sherbrooke

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Luigi Bouchard

Université de Sherbrooke

Marie‐France Hivert

Harvard Pilgrim Health Care

Patrice Perron

Université de Sherbrooke

Renée Guérin

Université de Sherbrooke

Pierre‐Étienne Jacques

Université de Sherbrooke

Andrée‐Anne Clément

Université de Sherbrooke

Véronique Desgagné

Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay–Lac-Saint-Jean

Frédérique White

Université de Sherbrooke

Cécilia Légaré

University at Albany, State University of New York

Michelle S. Scott

Université de Sherbrooke

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Université de Sherbrooke

Centre Hospitalier Universitaire de Sherbrooke

Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay–Lac-Saint-Jean

Université de Montréal

Cégep de Chicoutimi

Université du Québec à Chicoutimi

Université Laval

Centre Hospitalier Universitaire Sainte-Justine

Harvard University

Harvard Pilgrim Health Care

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First Trimester Plasma MicroRNA Levels Predict Risk of Developing Gestational Diabetes Mellitus

Frontiers in Endocrinology (2022)

Cécilia Légaré Véronique Desgagné Kathrine Thibeault Frédérique White Andrée‐Anne Clément

Aims Our objective is to identify first-trimester plasmatic miRNAs associated with and predictive of GDM. Methods We quantified miRNA using next-generation sequencing in discovery (Gen3G: n = 443/GDM = 56) and replication (3D: n = 139/GDM = 76) cohorts. We have diagnosed GDM using a 75-g oral glucose tolerance test and the IADPSG criteria. We applied stepwise logistic regression analysis among replicated miRNAs to build prediction models. Results We identified 17 miRNAs associated with GDM development in both cohorts. The prediction performance of hsa-miR-517a-3p|hsa-miR-517b-3p, hsa-miR-218-5p, and hsa-let7a-3p was slightly better than GDM classic risk factors (age, BMI, familial history of type 2 diabetes, history of GDM or macrosomia, and HbA1c) (AUC 0.78 vs. 0.75). MiRNAs and GDM classic risk factors together further improved the prediction values [AUC 0.84 (95% CI 0.73–0.94)]. These results were replicated in 3D, although weaker predictive values were obtained. We suggest very low and higher risk GDM thresholds, which could be used to identify women who could do without a diagnostic test for GDM and women most likely to benefit from an early GDM prevention program. Conclusions In summary, three miRNAs combined with classic GDM risk factors provide excellent prediction values, potentially strong enough to improve early detection and prevention of GDM.

10.3389/fendo.2022.928508

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Placental Epigenome-Wide Association Study Identified Loci Associated with Childhood Adiposity at 3 Years of Age

International Journal of Molecular Sciences (2020)

Valérie Gagné‐Ouellet Édith Breton Kathrine Thibeault Carol‐Ann Fortin Véronique Desgagné

The aim of this study was to identify placental DNA methylation (DNAm) variations associated with adiposity at 3 years of age. We quantified placental DNAm using the Infinium MethylationEPIC BeadChips. We assessed associations between DNAm at single-CpGs and skinfold thickness using robust linear regression models adjusted for gestational age, child’s sex, age at follow-up and cellular heterogeneity. We sought replication of DNAm association with child adiposity in an independent cohort. We quantified placental mRNA levels for annotated gene using qRT-PCR and tested for correlation with DNAm. Lower DNAm at cg22593959 and cg22436429 was associated with higher adiposity (β = −1.18, q = 0.002 and β = −0.82, q = 0.04). The cg22593959 is located in an intergenic region (chr7q31.3), whereas cg22436429 is within the TFAP2E gene (1p34.3). DNAm at cg22593959 and cg22436429 was correlated with mRNA levels at FAM3C (rs = −0.279, p = 0.005) and TFAP2E (rs = 0.216, p = 0.03). In an independent cohort, the association between placental DNAm at cg22593959 and childhood adiposity was of similar strength and direction (β = −3.8 ± 4.1, p = 0.36), yet non-significant. Four genomic regions were also associated with skinfold thickness within FMN1, MAGI2, SKAP2 and BMPR1B genes. We identified placental epigenetic variations associated with adiposity at 3 years of age suggesting that childhood fat accretion patterns might be established during fetal life.

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Epigenome

10.3390/ijms21197201

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Additional file 6 of Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy

Figshare (2022)

Cécilia Légaré Andrée‐Anne Clément Véronique Desgagné Kathrine Thibeault Frédérique White

Additional file 6. Supplementary Table 3. Top 10 miRNAs differentially abundant in plasma from pregnant women at first trimester compared to that of non-pregnant women that are not encoded in known pregnancy-related miRNAs clusters.

Variation (astronomy)

10.6084/m9.figshare.18461892

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Identification and application of plasmatic microRNA expression quantitative trait loci (miR-QTL) at first trimester of pregnancy

medRxiv (Cold Spring Harbor Laboratory) (2021)

Frédérique White Marika Groleau Samuel Côté Cécilia Légaré Kathrine Thibeault

Abstract Background MicroRNAs (miRNAs) are a class of small non-coding RNAs regulating gene expression. They are involved in many biological processes, including adaptation to pregnancy. The identification of genetic variants associated with gene expression, known as expression quantitative trait loci (eQTL), helps to understand the underlying molecular mechanisms and determinants of complex diseases. Using data from the prospective pre-birth Gen3G cohort, we investigated associations between maternal genotypes and plasmatic miRNA levels measured during the first trimester of pregnancy of 369 women. Results Assessing the associations between about 2 million SNPs and miRNA proximal pairs using best practices from the GTEx consortium, a total of 22,140 significant eQTLs involving 147 unique miRNAs were identified. Elastic-net regressions were applied to select the most relevant SNPs to build genetic risk scores (GRS) for each of these 147 miRNAs. For about half of the circulating miRNAs, the GRS captured >10% of the variance abundance. As a demonstration of the usefulness of the identified eQTLs and derived GRS, we used the GRSs as instrumental variables to test for association between the circulating levels of miRNAs quantified before the 16th week of pregnancy and the development of pregnancy complications (gestational diabetes [GDM] or pre-eclampsia [PE]) developing more than three months later on average. Using predicted miRNA levels derived from instrumental variables, we found 18 significant associations of miRNAs with potential support of causal inference for GDM or PE. Conclusions Our results represent a valuable resource to understand miRNA regulation and highlight the potential of genetic instruments in predicting circulating miRNA levels and their possible contribution in disease development.

Genome-wide Association Study

Genetic Association

10.1101/2021.11.30.21267083

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Maternal glycemia in pregnancy is longitudinally associated with blood DNAm variation at the FSD1L gene from birth to 5 years of age

Clinical Epigenetics (2023)

Amélie Taschereau Kathrine Thibeault Catherine Allard Diana L. Juvinao-Quintero Patrice Perron

Abstract Background In utero exposure to maternal hyperglycemia has been associated with an increased risk for the development of chronic diseases in later life. These predispositions may be programmed by fetal DNA methylation (DNAm) changes that persist postnatally. However, although some studies have associated fetal exposure to gestational hyperglycemia with DNAm variations at birth, and metabolic phenotypes in childhood, no study has yet examined how maternal hyperglycemia during pregnancy may be associated with offspring DNAm from birth to five years of age . Hypothesis Maternal hyperglycemia is associated with variation in offspring DNAm from birth to 5 years of age. Methods We estimated maternal hyperglycemia using the area under the curve for glucose (AUC glu ) following an oral glucose tolerance test conducted at 24–30 weeks of pregnancy. We quantified DNAm levels in cord blood ( n = 440) and peripheral blood at five years of age ( n = 293) using the Infinium MethylationEPIC BeadChip (Illumina). Our total sample included 539 unique dyads (mother–child) with 194 dyads having DNAm at both time-points. We first regressed DNAm M -values against the cell types and child age for each time-point separately to account for the difference by time of measurement for these variables. We then used a random intercept model from the linear mixed model (LMM) framework to assess the longitudinal association between maternal AUCglu and the repeated measures of residuals of DNAm. We adjusted for the following covariates as fixed effects in the random intercept model: maternal age, gravidity, smoking status, child sex, maternal body mass index (BMI) (measured at first trimester of pregnancy), and a binary variable for time-point. Results In utero exposure to higher maternal AUC glu was associated with lower offspring blood DNAm levels at cg00967989 located in FSD1L gene ( β = − 0.0267, P = 2.13 × 10 –8 ) in adjusted linear regression mixed models. Our study also reports other CpG sites for which DNAm levels were suggestively associated ( P < 1.0 × 10 –5 ) with in utero exposure to gestational hyperglycemia. Two of these (cg12140144 and cg07946633) were found in the promotor region of PRDM16 gene ( β : − 0.0251, P = 4.37 × 10 –07 and β : − 0.0206, P = 2.24 × 10 –06 , respectively). Conclusion Maternal hyperglycemia is associated with offspring DNAm longitudinally assessed from birth to 5 years of age.

dNaM

10.1186/s13148-023-01524-7

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Citations (8)

Additional file 5 of Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy

Figshare (2022)

Cécilia Légaré Andrée‐Anne Clément Véronique Desgagné Kathrine Thibeault Frédérique White

Additional file 5. Supplementary Table 2. miRNAs differentially abundant in plasma from pregnant women at first trimester compared to that of non-pregnant women and localized within the C14MC, C19MC and 371-3 clusters.

Variation (astronomy)

10.6084/m9.figshare.18461889

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Additional file 9 of Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy

Figshare (2022)

Cécilia Légaré Andrée‐Anne Clément Véronique Desgagné Kathrine Thibeault Frédérique White

Additional file 9. Supplementary Table 6. miRNAs associated with pregnancy analysis corrected for age, BMI and glycemia as well as run and sequencing lane.

Variation (astronomy)

10.6084/m9.figshare.18461904

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First trimester circulating miR-194-5p and miR-1278 improve prediction of preeclampsia

Pregnancy Hypertension (2023)

Andrée‐Anne Clément Cécilia Légaré Véronique Desgagné Kathrine Thibeault Frédérique White

Second trimester

10.1016/j.preghy.2023.10.011

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Additional file 4 of Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy

Figshare (2022)

Cécilia Légaré Andrée‐Anne Clément Véronique Desgagné Kathrine Thibeault Frédérique White

Additional file 4. Supplementary Table 1. Complete list of miRNAs differentially abundant in plasma from pregnant women at first trimester compared to non-pregnant women.

Variation (astronomy)

10.6084/m9.figshare.18461886

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Placental NEGR1 DNA methylation is associated with BMI and neurodevelopment in preschool-age children

Epigenetics (2019)

Édith Breton Valérie Gagné‐Ouellet Kathrine Thibeault R Guérin Rj Van Lieshout

Studies have linked maternal pre-pregnancy obesity and hyperglycaemia with metabolic and neurodevelopmental complications in childhood. DNA methylation (DNAm) might enable foetal adaptations to environmental adversities through important gene loci. NEGR1 is involved in both energy balance and behaviour regulation. The aim of this study was to investigate associations between placental DNAm at the NEGR1 gene locus and childhood anthropometric and neurodevelopmental profiles in preschoolers. We analysed 276 mother-child dyads from Gen3G, a prospective birth cohort from Sherbrooke. At 3yo (40.4 ± 3.0 months), we measured body mass index (BMI) and the mothers reported on offspring neurobehavior using the Strengths and Difficulties Questionnaire (SDQ). We quantified DNAm levels at 30 CpGs at the NEGR1 locus using the MethylationEPIC Array in placental biopsies. DNAm at four CpGs located before NEGR1 second exon predicted child's BMI z-score (cg26153364: β=-0.16 ± 0.04; p=0.008, cg23166710: β=0.14 ± 0.08; p=0.03) and SDQ total score (cg04932878: β=0.22 ± 1.0; p= 3.0x10-4, cg16525738: β=-0.14 ± 0.18; p=0.01, cg23166710: β=-0.13 ± 0.36; p= 0.04), explaining 4.2% (p=0.003) and 7.3% (p= 1.3 x 10-4) of BMI-z and SDQ variances. cg23166710 was associated with both childhood phenotypes and correlated with NEGR1 placental expression (r=-0.22, p=0.04), suggesting its possible functional role. Together, maternal metabolic characteristics during pregnancy with NEGR1 DNAm levels explained 7.4% (p=4.2 x 10-4) of BMI-z and 14.2% (p=2.8 x 10-7) of SDQ variance at 3yo. This longitudinal study suggests that placental NEGR1 DNAm is associated with adiposity and neurodevelopment in preschool children and highlights its potential role in their comorbidity.

10.1080/15592294.2019.1666653

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Citations (8)