Biology subjects

MacIntyre, D.

Publications and source records attributed to MacIntyre, D..

3 recordsLinked to original sources

bioRxiv2025

Late-Onset Preeclampsia is characterised by Accelerated Placental Aging

Late-onset preeclampsia (LOPE) is a major pregnancy complication characterised by hypertension and placental dysfunction, resolving only upon delivery. Here, we show that LOPE placentae undergo accelerated molecular aging, marked by telomere attrition, DNA damage and trophoblast senescence. Using primary placental tissue and trophoblast organoids, we demonstrate oxidative stress as a driver of telomere shortening and angiogenic imbalance. Inflammation did not alter placental aging trajectories. Antioxidant treatment (superoxide dismutase) preserved telomere length, reduced DNA damage and restored angiogenic balance, highlighting oxidative stress as a modifiable determinant of placental aging. We identify reduced expression of telomeric repeat-containing RNAs (TERRAs) as a molecular hallmark of LOPE, and show that antisense oligonucleotide-mediated TERRA depletion exacerbates telomere erosion and senescence. Together, these findings delineate oxidative stress and TERRA loss as mechanisms driving placental decline, establish trophoblast organoids as a tractable model of placental aging, and reveal potential therapeutic avenues for mitigating preeclampsia-associated placental dysfunction.

developmental biology↗

bioRxiv2018

Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland.

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77x10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53kb downstream PIWIL4; p = 4.95x10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46x10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00x10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77x10-6). Polygenic risk scores (PRS) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91x10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

genetics↗

bioRxiv2018

Replication of the diathesis-stress model for depression in Generation Scotland.

Depression has well-established influences from genetic and environmental risk factors. This has led to the diathesis-stress theory, which assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. Recently, Colodro-Conde et al. empirically tested this theory, using the polygenic risk score for major depressive disorder (PRS, genes) and stressful life events (SLE, environment) effects on depressive symptoms, identifying significant GxE effects with an additive contribution to liability. We have tested the diathesis-stress theory on an independent sample of 4 919 individuals.\n\nWe identified nominally significant positive GxE effects in the full cohort (R2 = 0.08%, p = 0.049) and in women (R2 = 0.19%, p = 0.017), but not in men (R2 = 0.15%, p = 0.07). GxE effects were nominally significant, but only in women, when SLE were split into those in which the respondent plays an active or passive role (R2 = 0.15%, p = 0.038; R2 = 0.16%, p = 0.033, respectively). High PRS increased the risk of depression in participants reporting high numbers of SLE (p = 2.86 x 10-4). However, in those participants who reported no recent SLE, a higher PRS appeared to increase the risk of depressive symptoms in men ({beta} = 0.082, p = 0.016) but had a protective effect in women ({beta} = -0.061, p = 0.037). This difference was nominally significant (p = 0.017). Our study reinforces the evidence of additional risk in the aetiology of depression due to GxE effects. However, larger sample sizes are required to robustly validate these findings.

genomics↗