The Effect of Genetic Variation on the Placental Transcriptome in Humans

Kikas, Triin; Rull, Kristiina; Beaumont, Robin N; Freathy, Rachel M.; Laan, Maris

doi:10.3389/fgene.2019.00550

Cited by 18 publications

(13 citation statements)

References 58 publications

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“…Further, MLH1, LRRFIP2 , and GOLGA4 associated with these overall genetic components were highly expressed in the placenta and modulated by pathological placental processes such as preeclampsia and intrauterine growth restriction but not in other disease processes (31). Problematically, however, recent papers did not observe that the KLS associated SNPs identified in this study had substantial effects on placental expression of these genes (31, 32, 91, 92). Further, TRANK1- region polymorphisms are not known maternal or fetal genetic factors associated with low birth weight (93-95), prematurity (96), or birth complications (91, 97) in large samples, and were not associated with birth difficulties in a small sample of 198 controls similarly ascertained to our KLS subjects for birth difficulties.…”

Section: Discussioncontrasting

confidence: 80%

“…Problematically, however, recent papers did not observe that the KLS associated SNPs identified in this study had substantial effects on placental expression of these genes (31, 32, 91, 92). Further, TRANK1- region polymorphisms are not known maternal or fetal genetic factors associated with low birth weight (93-95), prematurity (96), or birth complications (91, 97) in large samples, and were not associated with birth difficulties in a small sample of 198 controls similarly ascertained to our KLS subjects for birth difficulties. Finally, this hypothesis would not explain the time dependency/cohort effect of the TRANK1 association we observed with KLS, which is likely due to improved or changes in perinatal care with time.…”

Section: Discussioncontrasting

confidence: 80%

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Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Ambati

Hillary

Leu‐Semenescu

et al. 2021

Preprint

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Kleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome wide association study in 673 KLS cases collected over 14 years, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (OR=1.48,rs71947865,p=8.6×10−9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3’ region of TRANK1 gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with TRANK1 rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years and found that recent cases had a significantly reduced TRANK1 rs71947865 association. While theTRANK1 rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, the TRANK1 rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR=1.54;p=0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo r2=0.15;p<2.0×10−22 at p=0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, behavioral rhythmicity, and bipolar disorder, and indicates that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.Significance StatementGenetic markers in TRANK1 gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin Syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment are suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in the TRANK1 gene region may predispose to KLS when patients have had a difficult birth, suggesting that TRANK1 gene region modulate newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impact birth and KLS.

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Section: Discussioncontrasting

confidence: 80%

Section: Discussioncontrasting

confidence: 80%

Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Ambati

Hillary

Leu‐Semenescu

et al. 2021

Preprint

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“…We then tested for colocalization between multiple consecutive miscarriage and plasma protein levels 55 and expression levels in 49 different tissues 56 , 57 using coloc 58 ( Supplementary Methods ). Colocalization can highlight potential mediating genes and tissues by investigating the likelihood of a shared causal variant between a disease and e.g.…”

Section: Resultsmentioning

confidence: 99%

The genetic architecture of sporadic and multiple consecutive miscarriage

et al. 2020

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Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

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“…Fetal growth was evaluated using the gestational age and sex adjusted weight centiles based on the Estonian Medical Birth Registry data (Sildver et al, 2015). Details of the REPROMETA and HAPPY PREGNANCY studies are provided in Supplementary Methods and in recent publications (Kikas et al, 2019(Kikas et al, , 2020.…”

Section: Cohorts For the Genetic Association Testing Between Mir-eqtls And Term Pregnancy Traitsmentioning

confidence: 99%

Coordinated Expressional Landscape of the Human Placental miRNome and Transcriptome

Inno

Kikas

Lillepea

et al. 2021

Front. Cell Dev. Biol.

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Placenta is a unique organ that serves its own function, and contributes to maternal gestational adaptation and fetal development. Coordination of its transcriptome to satisfy all the maternal-fetal needs across gestation is not fully understood. MicroRNAs are powerful transcriptome modulators capable to adjust rapidly the expression level and dynamics of large gene sets. This MiR-Seq based study presents a multi-omics investigation of the human placental miRNome and its synergy with the transcriptome. The analysis included 52 placentas representing three trimesters of normal pregnancy, and term cases of late-onset preeclampsia (LO-PE), gestational diabetes and affected fetal growth. Gestational-age dependent differential expression (FDR < 0.05) was detected for 319 of 417 tested miRNAs (76.5%). A shared list of target genes of dynamic miRNAs suggested their coordinated action. The most abundant miR-143-3p revealed as a marker for pregnancy progression. The data suggested critical, but distinct roles of placenta-specific imprinted C19MC and C14MC miRNA clusters. Paternally encoded primate-specific C19MC was highly transcribed during first trimester, potentially fine-tuning the early placental transcriptome in dosage-sensitive manner. Maternally encoded eutherian C14MC showed high expression until term, underlining its key contribution across gestation. A major shift in placental miRNome (16% miRNAs) was observed in LO-PE, but not in other term pregnancy complications. Notably, 13/38 upregulated miRNAs were transcribed from C19MC and only one from C14MC, whereas 11/28 downregulated miRNAs represented C14MC and none C19MC. miR-210-3p, miR-512-5p, miR-32-5p, miR-19a-3p, miR-590-3p, miR-379-5p were differentially expressed in LO-PE and cases of small-for-gestational-age newborns, supporting a shared etiology. Expression correlation analysis with the RNA-Seq data (16,567 genes) of the same samples clustered PE-linked miRNAs into five groups. Large notable clusters of miRNA–gene pairs showing directly and inversely correlated expression dynamics suggested potential functional relationships in both scenarios. The first genome-wide study of placental miR-eQTLs identified 66 placental SNVs associated with the expression of neighboring miRNAs, including PE-linked miRNAs miR-30a-5p, miR-210-3p, miR-490-3p and miR-518-5p. This study provided a rich catalog of miRNAs for further in-depth investigations of their individual and joint effect on placental transcriptome. Several highlighted miRNAs may serve as potential biomarkers for pregnancy monitoring and targets to prevent or treat gestational disorders.

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The Effect of Genetic Variation on the Placental Transcriptome in Humans

Cited by 18 publications

References 58 publications

Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

The genetic architecture of sporadic and multiple consecutive miscarriage

Coordinated Expressional Landscape of the Human Placental miRNome and Transcriptome

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