Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Infectious mononucleosis in university students in the United Kingdom: evaluation of the clinical features and consequences of the disease

Infectious mononucleosis (IM) resulted in marked reductions in student study time, social activities, and physical exercise, and sustained hypersomnia. Females were more likely to discontinue their studies following IM and reported more-prolonged fatigue. Elevated levels of γΔ T cells persisted into the convalescent period. &lt;br/&gt; &lt;br/&gt; Background. Infectious mononucleosis (IM) is common among university students. We undertook to analyze the clinical features and sequelae of the disease in a cohort of students at Edinburgh University. &lt;br/&gt; &lt;br/&gt; Methods. Consecutive IM case patients were recruited from 2000 through 2002 at the University Health Service after diagnosis of IM. &lt;br/&gt; &lt;br/&gt; Results. IM resulted in marked reductions in student study time, physical exercise, and non–exercise-related social activities, and sustained increases in reported number of hours of sleep. The disease profile differed between the sexes, with significantly more females reporting fatigue, which was more likely to be prolonged (P=.003) and to lead to loss of study time (P=.013). Female case patients were more likely to discontinue their studies following IM (16% vs 0%; P=.056). Within the typically elevated lymphocyte counts in IM, we identified an elevated γΔ T cell component that may contribute to the disease pathogenesis. &lt;br/&gt; &lt;br/&gt; Conclusions. IM results in substantial morbidity among university students, reported as more profound in females, and affecting academic studies, physical exercise, and social activities. Immunization to prevent IM and strategies to reduce post-IM disability would be beneficial in this population

A study of risk factors for acquisition of Epstein‐Barr virus and its subtypes

Background. Risk factors for primary infection with Epstein-Barr virus (EBV) and its subtypes have not been fully investigated. &lt;br/&gt; Methods. Questionnaires and serum samples from a total of 2006 students who entered Edinburgh University in 1999–2000 were analyzed to examine risk factors for EBV seropositivity, both overall and by EBV type. &lt;br/&gt; Results. The prevalence of EBV seropositivity was significantly increased among females, older students, those who had lived in tropical countries, those with siblings, and those who were sexually active, particularly if they had had numerous sex partners. Risk was lower (1) among students who always used a condom than among those who had sexual intercourse without one and (2) among female oral-contraceptive users than among sexually active nonusers. Risk factors for type 1 EBV infection were similar to those for EBV overall. No associations were found between nonsexual risk factors and type 2 infection. Sexual activity increased the risk of type 2 infection, but the increase in risk with number of sex partners was less consistent than for type 1 infections. Dual infection was uncommon, but the patterns of risk appeared to be similar to those of type 1 infection. &lt;br/&gt; Conclusion. This study provides further evidence that EBV may be sexually transmitted and some suggestion that the risk factors for type 1 and type 2 infection differ