Biology subjects

Kajantie, E.

Publications and source records attributed to Kajantie, E..

5 recordsLinked to original sources

bioRxiv2026

Placental cis-eQTL analysis identifies preeclampsia-dependent genetic regulation at promoters

Background: Preeclampsia (PE) is a hypertensive pregnancy disorder with contributions from both maternal and fetal genetic factors, but how both genomes regulate placental transcription remains incompletely understood. Results: We analyzed placental 5'-end RNA sequencing data from 59 pregnancies in the FINNPEC cohort and performed separate maternal and fetal cis-eQTL analyses using gene-level expression and promoter-level expression defined as Transcript Far 5' Ends (TFE). Genotype-by-PE interaction models were used to identify genetic effects that differ according to PE status. No gene-level interaction eQTLs remained significant after multiple-testing correction, although suggestive signals included LILRB2 in the maternal and LPCAT3 in the fetal analyses. In contrast, we identified two significant syntenic promoter-level interaction eQTLs: rs12504642-TFE61820 at the FHDC1 locus in the maternal analysis and rs1557150-TFE9032 at the PPIAP31 locus in the fetal analysis. Conclusion: These findings suggest that PE-dependent genetic interaction effects may be detectable at specific transcript promoter regions even when they are not captured at annotated gene levels.

genetics↗

bioRxiv2019

Balancing Selection at HLA-G Modulates Fetal Survival, Preeclampsia and Human Birth Sex Ratio

The population sex ratio is thought to be maintained through balancing selection on rare phenotypes. However, empirical evidence for genetic influence has thus far proven elusive. We combined 1000 Genomes data and large cohorts to study human sex ratios. We found underrepresentation of male offspring in preeclampsia, a serious pregnancy disorder with uncertain pathogenesis. Genetic variation of fetal human leukocyte antigen G (HLA-G), regulating maternal anti-fetal immune responses, was found to be under balancing selection. Sex-linked downregulation of HLA-G and upregulation of interferon alpha-1 (IFNA1) expression contribute to loss of fetal immunotolerance in preeclampsia and suggest hydroxychloroquine as a treatment option. Our findings indicate that an evolutionary trade-off between fetal immunotolerance and protection against infections promotes genetic diversity in HLA-G, thereby maintaining human sex ratios. One Sentence SummaryFetal HLA-G modulates human sex ratio.

evolutionary biology↗

bioRxiv2019

Association between DNA methylation and ADHD symptoms from birth to school age: A prospective meta-analysis

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is not known. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school-age. We examined associations of DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age range 4-15 years) in 2477 children from five cohorts and DNA methylation at school-age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from ten cohorts. CpGs identified with nominal significance (p<0.05) in either of the EWAS were correlated between timepoints ({rho}=0.30), suggesting overlap in associations, however, top signals were very different. At birth, we identified nine CpGs that were associated with later ADHD symptoms (P<1*10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 located in the promotor region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which was associated with neurite outgrowth and an ADHD diagnosis in previous studies. In contrast, at school-age, no CpGs were associated with ADHD with P<1*10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

genetics↗

bioRxiv2018

Variably methylated regions in the newborn epigenome: environmental, genetic and combined influences

BackgroundEpigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. We examined the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs), defined as consecutive CpGs showing the highest variability of DNAm in 4 independent cohorts (PREDO, DCHS, UCI, MoBa, N=2,934).\n\nResultsWe used Akaikes information criterion to test which factors best explained variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E) including maternal demographic, psychosocial and metabolism related phenotypes, genotypes in cis (G), or their additive (G+E) or interaction (GxE) effects. G+E and GxE models consistently best explained variability in DNAm of VMRs across the cohorts, with G explaining the remaining sites best. VMRs best explained by G, GxE or G+E, as well as their associated functional genetic variants (predicted using deep learning algorithms), were located in distinct genomic regions, with different enrichments for transcription and enhancer marks. Genetic variants of not only G and G+E models, but also of variants in GxE models were significantly enriched in genome wide association studies (GWAS) for complex disorders.\n\nConclusionGenetic and environmental factors in combination best explain DNAm at VMRs. The CpGs best explained by G, G+E or GxE are functionally distinct. The enrichment of GxE variants in GWAS for complex disorders supports their importance for disease risk.

genetics↗

bioRxiv2017

Variants at the ADAMTS13, BGALT5, SSBP2 and TKT Loci are associated with Post-term birth.

Gestation is a crucial timepoint in human development. Deviation from a term gestational age correlates with both acute and long-term adverse health effects for the child. Both being born pre and post-term, i.e. having short and long gestational ages, are heritable and influenced by the pre- and perinatal environment. Despite the obvious heritable component, specific genetic influences underlying differences in gestational age are poorly understood. Here we identify one globally significant intronic genetic variant within the ADAMTS13 gene that is associated with prolonged gestation in 9,141 white European individuals from the 1966 and 1986 Northern Finland birth cohorts. Additional variants that reached suggestive levels of significance were identified within introns at the TKT, and ARGHAP42 genes, and in the upstream (5) intergenic regions of the B3GALT5 and SSBP2 genes. The variants near the ADAMTS13, B3GALT5, SSBP2 and TKT loci are linked to alterations in gene expression levels (cis-eQTLs). Luciferase assays confirmed the allele specific enhancer activity for the BGALT5 and TKT loci. Our findings provide the first evidence of a specific genetic influence associated with prolonged gestation.

genetics↗