South Asian women are at increased risk of developing gestational diabetes (GDM). Few studies have investigated the genetic contributions to GDM risk. We investigated the association of a type 2 diabetes (T2D) polygenic risk score (PRS), on its own, and with GDM risk factors, on GDM-related traits using data from two birth cohorts in which South Asian women were enrolled during pregnancy. 837 and 4,372 pregnant South Asian women from the SouTh Asian BiRth CohorT (START) and Born in Bradford (BiB) cohort studies underwent a 75-gram glucose tolerance test. PRSs were derived using GWAS results from an independent multi-ethnic study (~18% South Asians). Associations with fasting plasma glucose (FPG); 2h post-load glucose (2hG); area under the curve glucose; and GDM were tested using linear and logistic regressions. The population attributable fraction (PAF) of the PRS was calculated. Every 1 SD increase in the PRS was associated with a 0.085 mmol/L increase in FPG ([95%CI=0.07-0.10], P=2.85 × 10-20); 0.21 mmol/L increase in 2hG ([95%CI=0.16-0.26], P=5.49 × 10-16); and a 45% increase in the risk of GDM ([95%CI=32-60%], P=2.27 × 10-14), independent of parental history of diabetes and other GDM risk factors. PRS tertile 3 accounted for 12.5% of the population's GDM alone, and 21.7% when combined with family history. A few weak PRS and GDM risk factors interactions modulating FPG and GDM were observed. Together, these results show that a T2D PRS and family history of diabetes are strongly and independently associated with multiple GDM-related traits in women of South Asian descent, an effect that could be modulated by other environmental factors.
Data from START is not publicly available, since the study is bound by consent which indicates the data will not be used by an outside group. Requests for collaboration or replication will be considered for research purposes only (no commercial use allowed, as per the study's informed consent). Requests should be addressed to the study's principal investigator (Sonia Anand, firstname.lastname@example.org) via a form which will be provided upon request by emailing email@example.com. The request will be evaluated by PIs and co-investigators, and projects deemed of scientific interest will be further evaluated/validated by local REB chair. Born in Bradford data are available for research purposes only by sending an expression of interest form downloadable from https://borninbradford.nhs.uk/wp-content/uploads/BiB_EoI_v3.1_10.05.21.doct to firstname.lastname@example.org . The proposal will be reviewed by BiB's executive team. If the request is approved, the requester will be asked to sign a Data Sharing Contract and a Data Sharing Agreement. Full details on how to access data and forms can be found here https://borninbradford.nhs.uk/research/how-to-access-data/. The code used to analyze the data is available at https://github.com/AmelLamri/Paper_T2dPrsGdm_StartBiB. All Sharable processed versions of the datasets used in the manuscript are made available as supplementary material or at https://github.com/AmelLamri/Paper_T2dPrsGdm_StartBiB.
- Sonia S Anand
- Deborah A Lawlor
- Deborah A Lawlor
- Deborah A Lawlor
- Sonia S Anand
- Sonia S Anand
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: All START and BiB participants provided informed consent. The START study was approved by local ethics committees (Hamilton Integrated Research Ethics Board [ID:10-640], William Osler Health System [ID:11-0001], and Trillium Health Partners [RCC:11-018, ID:492]). Ethical approval for all aspects of the research was granted by Bradford Research Ethics Committee [Ref 07/H1302/112].
- Edward D Janus, University of Melbourne, Australia
© 2022, Lamri et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Dysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanized H19/IGF2 imprinting control region (hIC1) on the paternal allele that exhibited H19/Igf2 dysregulation together with SRS-like growth restriction and perinatal lethality. Here, we dissect the role of H19 and Igf2 in cardiac and placental development utilizing multiple mouse models with varying levels of H19 and Igf2. We report severe cardiac defects such as ventricular septal defects and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of H19/Igf2 dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that H19/Igf2 dysregulation disrupts pathways related to extracellular matrix and proliferation of endothelial cells. Our work links the heart and placenta through regulation by H19 and Igf2, demonstrating that accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially related to the cardiac-placental axis.
Ciliates are microbial eukaryotes that undergo extensive programmed genome rearrangement, a natural genome editing process that converts long germline chromosomes into smaller gene-rich somatic chromosomes. Three well-studied ciliates include Oxytricha trifallax, Tetrahymena thermophila and Paramecium tetraurelia, but only the Oxytricha lineage has a massively scrambled genome, whose assembly during development requires hundreds of thousands of precise programmed DNA joining events, representing the most complex genome dynamics of any known organism. Here we study the emergence of such complex genomes by examining the origin and evolution of discontinuous and scrambled genes in the Oxytricha lineage. This study compares six genomes from three species, the germline and somatic genomes for Euplotes woodruffi, Tetmemena sp., and the model ciliate Oxytricha trifallax. To complement existing data, we sequenced, assembled and annotated the germline and somatic genomes of Euplotes woodruffi, which provides an outgroup, and the germline genome of Tetmemena sp.. We find that the germline genome of Tetmemena is as massively scrambled and interrupted as Oxytricha's : 13.6% of its gene loci require programmed translocations and/or inversions, with some genes requiring hundreds of precise gene editing events during development. This study revealed that the earlier-diverged spirotrich, E. woodruffi, also has a scrambled genome, but only roughly half as many loci (7.3%) are scrambled. Furthermore, its scrambled genes are less complex, together supporting the position of Euplotes as a possible evolutionary intermediate in this lineage, in the process of accumulating complex evolutionary genome rearrangements, all of which require extensive repair to assemble functional coding regions. Comparative analysis also reveals that scrambled loci are often associated with local duplications, supporting a gradual model for the origin of complex, scrambled genomes via many small events of DNA duplication and decay.