Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa

Maternal immune challenge during early embryo development affects blastocyst cell lineage ration and postnatal phenotype

Maternal infection during gestation is an established cause of abortion, premature birth and intrauterine growth restriction. In addition, there is a strong association between activation of the maternal immune response during mid-gestation and neurological abnormalities in the offspring. At present little is known about the consequences of maternal immune activation during early gestation. The preimplantation embryo has been identified as a critical developmental stage during which environment can program changes to postnatal phenotype. Here, we investigated the sensitivity of preimplantation mouse embryos to maternal immune challenge in the short- and long-term. Virgin female MF-1 mice were mated and randomly assigned to one of four treatment groups; control (saline only), 10, 50 or 150µg/kg of bodyweight lipopolysaccharide (LPS; Salmonella enterica enteritidis). On gestational day 0.5 (GD0.5), successfully mated females were injected intraperitoneally with saline or LPS dose. Mice were either culled at GD3.5 to assess short-term consequences in blastocysts or allowed to go to term to investigate potential long-term changes in offspring body mass, behaviour and systolic blood pressure (SBP). All postnatal data were analysed using a multilevel random effects regression model (SPSS) which takes into account the hierarchical nature of the dataset. Blastocysts were differentially labelled to assess inner cell mass (ICM) and trophectoderm (TE) cell numbers. Blastocysts from 10µg/kg LPS mothers had more TE cells than those from control mothers (p<0.05). Blastocysts from 50 and 150µg/kg LPS mothers had fewer ICM cells than blastocysts from control mothers (p<0.05). These effects lead to a reduced ICM:TE cell ratio at each LPS dose compared with control (p<0.05). At birth, pups were weighed and litter size adjusted to 3 males and 3 females where possible. Offspring were weighed weekly thereafter and underwent a series of behavioural tests and SBP measurements (tail cuff) until 30 weeks of age. No difference in gestation length or male:female offspring ratio was observed between treatment groups. Interestingly, 10µg/kg LPS mothers had larger litters than control mothers (p<0.01). Body weight was not different between treatment groups at any time point. In the open field behavioural test, both male and female offspring from LPS treated mothers displayed reduced levels of exploratory behaviour compared with controls. For example, male offspring from 150µg/kg LPS mothers displayed fewer rears and jumps than control males at 20 weeks (p<0.05). Furthermore, males from 10µg/kg LPS mothers had elevated SBP at 28 weeks (p<0.05), but females showed no difference in SBP at any time point. These data indicate the sensitivity of the preimplantation mouse embryo to maternal immune activation in vivo leading to altered blastocyst cell allocation, increased litter size (in the lowest dose LPS treatment group) and altered developmental potential; including abnormal behaviour and elevated blood pressure in adult life (also in the lowest dose LPS treatment group). This work serves to highlight maternal immune activation during preimplantation developmentas an important route by which adverse changes in postnatal phenotype can potentially arise; and emphasises the importance of further study into this emerging area of research. This research is funded by a BBSRC studentship (to CLW) and by NIH and MRC grants (to TPF)

Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease

Poor maternal nutrition during pregnancy can alter postnatal phenotype and increase susceptibility to adult cardiovascular and metabolic diseases. However, underlying mechanisms are largely unknown. Here, we show that maternal low protein diet (LPD), fed exclusively during mouse preimplantation development, leads to offspring with increased weight from birth, sustained hypertension, and abnormal anxiety-related behavior, especially in females. These adverse outcomes were interrelated with increased perinatal weight being predictive of later adult overweight and hypertension. Embryo transfer experiments revealed that the increase in perinatal weight was induced within blastocysts responding to preimplantation LPD, independent of subsequent maternal environment during later pregnancy. We further identified the embryo-derived visceral yolk sac endoderm (VYSE) as one mediator of this response. VYSE contributes to fetal growth through endocytosis of maternal proteins, mainly via the multiligand megalin (LRP2) receptor and supply of liberated amino acids. Thus, LPD maintained throughout gestation stimulated VYSE nutrient transport capacity and megalin expression in late pregnancy, with enhanced megalin expression evident even when LPD was limited to the preimplantation period. Our results demonstrate that in a nutrient-restricted environment, the preimplantation embryo activates physiological mechanisms of developmental plasticity to stablize conceptus growth and enhance postnatal fitness. However, activation of such responses may also lead to adult excess growth and cardiovascular and behavioral diseases

Genomic reconstruction of the SARS-CoV-2 epidemic in England

AbstractThe evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.</jats:p