Biology subjects

Christofidou, P.

Publications and source records attributed to Christofidou, P..

4 recordsLinked to original sources

bioRxiv2026

Conserved Human CpG Dinucleotides Identify Enriched Ageing-related Signals in Developmental Pathways and the Brain

The DNA methylome changes with age. This is observed as both random drift, but also consistent alterations within certain genomic loci enabling the construction of precise age predictors. However, the functionality of these ageing-related modifications remains largely undefined. The CpG dinucleotide is the principal sequence target for these epigenetic DNA marks in differentiated cells. Here, for functional insight, we identified ultra-conserved CpGs (ucCpGs, n [~]167k) lacking observed sequence mutation in large-scale human whole genome datasets (>576k). ucCpGs were enriched, as expected, in lowly-methylated CpG dense loci, due to methylated cytosine hypermutability. Additionally, ucCpGs demonstrated pathogenic evidence (CADD, ClinVar), and enrichment in four-fold degenerate sites, as well as within developmental and ageing-related gene families (AP-2, HOX-L, C2H2-ZNF, etc). Extreme ucCpG clusters ([≥]16 ucCpGs/kb) were enriched for brain-expressed genes, as well as developmental and ageing/mortality pathways. ucCpGs also strongly co-located within ageing-related Differentially Methylated Regions (age-DMRs), highlighting Clustered Protocadherin Gamma, as well as HSPA2 and LHFPL4 genes. These findings further support that functional components of DNAm ageing are intertwined with developmental pathways.

genomics↗

bioRxiv2021

Antiviral Antibody Epitope Selection is a Heritable Trait

There is enormous variability in human immune responses to viral infections. However, the genetic factors that underlie this variability are not well characterized. We used VirScan, a high-throughput viral epitope scanning technology, to analyze the antibody binding specificities of twins and SNP-genotyped individuals. These data were used to estimate the heritability and identify genomic loci associated with antibody epitope selection, response breadth, and the control of Epstein-Barr Virus (EBV) viral load. We identified 4 epitopes of EBV that were heritably targeted, and at least two EBNA-2 binding specificities that were associated with variants in the MHC class-II locus. We identified an EBV serosignature that predicted viral load in white blood cells and was associated with genetic variants in the MHC class-I locus. Our study provides a new framework for identifying genes important for pathogen immunity, with specific implications for the genetic architecture of EBV humoral responses and the control of viral load. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

genetics↗

bioRxiv2021

Within-sibship GWAS improve estimates of direct genetic effects

Estimates from genome-wide association studies (GWAS) represent a combination of the effect of inherited genetic variation (direct effects), demography (population stratification, assortative mating) and genetic nurture from relatives (indirect genetic effects). GWAS using family-based designs can control for demography and indirect genetic effects, but large-scale family datasets have been lacking. We combined data on 159,701 siblings from 17 cohorts to generate population (between-family) and within-sibship (within-family) estimates of genome-wide genetic associations for 25 phenotypes. We demonstrate that existing GWAS associations for height, educational attainment, smoking, depressive symptoms, age at first birth and cognitive ability overestimate direct effects. We show that estimates of SNP-heritability, genetic correlations and Mendelian randomization involving these phenotypes substantially differ when calculated using within-sibship estimates. For example, genetic correlations between educational attainment and height largely disappear. In contrast, analyses of most clinical phenotypes (e.g. LDL-cholesterol) were generally consistent between population and within-sibship models. We also report compelling evidence of polygenic adaptation on taller human height using within-sibship data. Large-scale family datasets provide new opportunities to quantify direct effects of genetic variation on human traits and diseases.

genetics↗

bioRxiv2018

Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions

Endometriosis is a common complex inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus, mainly in the pelvic area. It is associated with chronic pelvic pain and infertility, and its pathogenesis remains poorly understood. The disease is typically classified according to the revised American Fertility Society (rAFS) 4-stage surgical assessment system, although stage does not correlate well with symptomatology or prognosis. Previously identified genetic variants mainly are associated with stage III/IV disease, highlighting the need for further phenotype-stratified analysis that requires larger datasets. We conducted a meta-analysis of 15 genome-wide association studies (GWAS) and a replication analysis, including 58,115 cases and 733,480 controls in total, and sub-phenotype analyses of stage I/II, stage III/IV and infertility-associated endometriosis cases. This revealed 27 genetic loci associated with endometriosis at the genome-wide p-value threshold (P<5x10-8), 13 of which are novel and an additional 8 novel genes identified from gene-based association analyses. Of the 27 loci, 21 (78%) had greater effect sizes in stage III/IV disease compared to stage I/II, 1 (4%) had greater effect size in stage I/II compared to stage III/IV and 17 (63%) had greater effect sizes when restricted to infertility-associated endometriosis cases compared to overall endometriosis. These results suggest that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Analyses of genetic variants underlying different pain symptoms reported in the UK Biobank showed that 7/9 had positive significant (p<1.28x103) positive genetic correlations with endometriosis, suggesting a genetic basis for sensitivity to pain in general. Additional conditions with significant positive genetic correlations with endometriosis included uterine fibroids, excessive and irregular menstrual bleeding, osteoarthritis, diabetes as well as menstrual cycle length and age at menarche. These results provide a basis for fine-mapping of the causal variants at these 27 loci, and for functional follow-up to understand their contribution to endometriosis and its potential subtypes.

genomics↗