Relationship between inherited genetic variation and survival from colorectal cancer stratified by tumour location.

The location of a patient's colorectal cancer (CRC) influences their outcome but inherited factors may also be involved. We studied 1899 patients with advanced CRC (514 had proximal colonic, 493 distal colonic and 892 rectal tumours) and carried out genome-wide association studies for survival. Single nucleotide polymorphisms (SNPs) suggestive of association (P < 1.

Polygenic scores stratify neurodevelopmental copy number variant carrier cognitive outcomes in the UK Biobank.

Rare copy-number variants associated with neurodevelopmental conditions (ND-CNVs) exhibit variable expressivity of clinical, physical, behavioural outcomes. Findings from clinically ascertained cohorts suggest this variability may be partly due to additional genetic variation. Here, we assessed the impact of polygenic scores (PGS) and rare variants on ND-CNV carrier fluid intelligence (FI) scores in the UK Biobank.

Epilepsy and the risk of COVID-19-related hospitalization and death: A population study.

Objective: People with epilepsy (PWE) may be at an increased risk of severe COVID-19. It is important to characterize this risk to inform PWE and for future health and care planning. We assessed whether PWE were at higher risk of being hospitalized with, or dying from, COVID-19.

Health care utilization and mortality for people with epilepsy during COVID-19: A population study.

Objective: This study was undertaken to characterize changes in health care utilization and mortality for people with epilepsy (PWE) during the COVID-19 pandemic.

Methods: We performed a retrospective study using linked, individual-level, population-scale anonymized health data from the Secure Anonymised Information Linkage databank. We identified PWE living in Wales during the study "pandemic period" (January 1, 2020-June 30, 2021) and during a "prepandemic" period (January 1, 2016-December 31, 2019).

Pathway-specific polygenic scores for Alzheimer's disease are associated with changes in brain structure in younger and older adults.

Genome-wide association studies have identified multiple Alzheimer's disease risk loci with small effect sizes. Polygenic risk scores, which aggregate these variants, are associated with grey matter structural changes. However, genome-wide scores do not allow mechanistic interpretations.

Genome-wide Analysis of Motor Progression in Parkinson Disease.

Background And Objectives: The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets.

Genetic meta-analysis of levodopa induced dyskinesia in Parkinson's disease.

Importance: Forty percent of Parkinson's disease patients develop levodopa-induced-dyskinesia (LiD) within 4 years of starting levodopa. The genetic basis of LiD remains poorly understood, and there have been few well powered studies.

Objective: To discover common genetic variants in the PD population that increase the probability of developing LiD.

Identifying the neurodevelopmental and psychiatric signatures of genomic disorders associated with intellectual disability: a machine learning approach.

Background: Genomic conditions can be associated with developmental delay, intellectual disability, autism spectrum disorder, and physical and mental health symptoms. They are individually rare and highly variable in presentation, which limits the use of standard clinical guidelines for diagnosis and treatment. A simple screening tool to identify young people with genomic conditions associated with neurodevelopmental disorders (ND-GCs) who could benefit from further support would be of considerable value.

COVID-19 vaccination uptake in people with epilepsy in wales.

Purpose: People with epilepsy (PWE) are at increased risk of severe COVID-19. Assessing COVID-19 vaccine uptake is therefore important. We compared COVID-19 vaccination uptake for PWE in Wales with a matched control cohort.

Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer.

Background: Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations.

Methods: In total, 694 patients from the clinical trials COIN and COIN-B had MAPK-activated CRCs (assigned as KRAS, NRAS, or BRAF mutant).

Universal clinical Parkinson's disease axes identify a major influence of neuroinflammation.

Background: There is large individual variation in both clinical presentation and progression between Parkinson's disease patients. Generation of deeply and longitudinally phenotyped patient cohorts has enormous potential to identify disease subtypes for prognosis and therapeutic targeting.

Methods: Replicating across three large Parkinson's cohorts (Oxford Discovery cohort (n = 842)/Tracking UK Parkinson's study (n = 1807) and Parkinson's Progression Markers Initiative (n = 472)) with clinical observational measures collected longitudinally over 5-10 years, we developed a Bayesian multiple phenotypes mixed model incorporating genetic relationships between individuals able to explain many diverse clinical measurements as a smaller number of continuous underlying factors ("phenotypic axes").

Association between the LRP1B and APOE loci and the development of Parkinson's disease dementia.

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood.

Combining biomarkers for prognostic modelling of Parkinson's disease.

Background: Patients with Parkinson's disease (PD) have variable rates of progression. More accurate prediction of progression could improve selection for clinical trials. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be further improved by blood biomarkers.

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand-foot syndrome.

Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand-foot syndrome (HFS) or palmar-plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type-2 diabetes (T2D), a disease also associated with HFS. We analysed genome-wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN-B trials.

Pre-operative dosing of dexamethasone for the management of children with posterior fossa tumours: are we getting it right?

Introduction: Posterior fossa (PF) tumours are associated with vasogenic oedema causing symptoms of raised intracranial pressure. Preoperatively this is managed with dexamethasone. To minimise steroid related complications, the lowest effective dose should be administered.

Measuring heritable contributions to Alzheimer's disease: polygenic risk score analysis with twins.

The heritability of Alzheimer's disease estimated from twin studies is greater than the heritability derived from genome-based studies, for reasons that remain unclear. We apply both approaches to the same twin sample, considering both Alzheimer's disease polygenic risk scores and heritability from twin models, to provide insight into the role of measured genetic variants and to quantify uncaptured genetic risk. A population-based heritability and polygenic association study of Alzheimer's disease was conducted between 1986 and 2016 and is the first study to incorporate polygenic risk scores into biometrical twin models of Alzheimer's disease.

A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO) with single gas calibrated fMRI.

One promising approach for mapping CMRO is dual-calibrated functional MRI (dc-fMRI). This method exploits the Fick Principle to combine estimates of CBF from ASL, and OEF derived from BOLD-ASL measurements during arterial O and CO modulations. Multiple gas modulations are required to decouple OEF and deoxyhemoglobin-sensitive blood volume.