Publications

Publication: BMJ Open Diabetes Research & Care

Fernández-Egea E, Walker R, Ziauddeen H, Cardinal RN, Bullmore ET

28 January 2020

The prevalence of diabetes in schizophrenia is twice that in the general population, but there are few reliable predictors of which individuals will develop glucose dysregulation.

This research tested if abnormal birth weight (either too low or too high) and parental diabetes, both variables that can be ascertained in the clinic, can predict diabetes onset in patients with schizophrenia.

Researchers looked at electronic records of a cohort of 190 clozapine-treated patients (37% treated for more than 20 years) and Cox regression survival analysis (with any type of glucose dysregulation as the event) to account for differences in length of treatment before the event and age at clozapine treatment initiation.

Age at clozapine initiation, family history of diabetes and birth weight were significant predictors of glucose dysregulation onset, while gender was not.

Among individuals with 10 years of follow-up, 80% of those with both abnormal birth weight and a family history of diabetes developed diabetes compared with 56% with only abnormal birth weight, 40% with only a family history of diabetes and 20% in those with neither.

Since 48% of cases had at least one risk factor and 6% had both risk factors, there is a substantial proportion of patients for whom preventive strategies could be implemented.

Publication: Nature Medicine

Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID-19 BioResource Collaboration, Sarah A. Teichmann, Menna R. Clatworthy et al

20 April 2021

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19).

The researchers looked at blood samples from a cross-sectional cohort of 130 patients in Newcastle, Cambridge and London with varying severities of COVID-19.

They found raised levels of specific immune cells in asymptomatic people to help fight infection – but that patients with more serious symptoms had lost these protective cell types and instead gained inflammatory cells. In severe cases this led to lung inflammation, blood clotting difficulties and hospitalisation.

While it is not yet understood how the infection stimulates these immune responses, the study gives a molecular explanation for how COVID-19 could cause an increased risk of blood clotting and inflammation in the lungs, which can lead to the patient needing a ventilator.

This also uncovers potential new therapeutic targets to help protect patients against inflammation and severe disease.

Read the news article on our website.

Publication:

Margaret L. Westwater, Flavia Mancini, Adam X. Gorka, Jane Shapleske, Jaco Serfontein, Christian Grillon, Monique Ernst , Hisham Ziauddeen  and Paul C. Fletcher

12 April 2021

Summary

Stress does not trigger binge eating in people with eating disorders Cambridge researchers found. Researchers invited women with anorexia nervosa,  bulimia nervosa and healthy controls – to attend a two-day stay at Wellcome-MRC Institute of Metabolic Science Translational Research Facility (TRF) where they performed tasks while their brain activity was monitored using a functional MRI scanner.

Read the full story

Publication: Revista de Psiquiatría y Salud Mental

Alabaf S, Kirkpatrick B, Chen S, Cardinal RN, Fernández-Egea E

10 April 2021

Schizophrenia typically involves so-called “positive” or psychotic symptoms (symptoms that are present but are unwanted), but sometimes also so-called “negative” or deficit symptoms (aspects of normal behaviour that are absent).

In a group of 167 patients with schizophrenia and being treated with clozapine, those patients with “non-deficit” schizophrenia were more likely than those with “deficit” schizophrenia to have reported cannabis use by the time of their first-episode psychosis, or trauma (related to crime or abuse) prior to that first episode of psychosis.

Patients with “deficit” schizophrenia were more likely to have been born in summer months. The timing of stressors during brain development may influence the pattern of symptoms that emerge.

Publication: Journal of Neurology, Neurosurgery and Psychiatry

Maura Malpetti, Luca Passamonti, P Simon Jones, Duncan Street, Timothy Rittman, Timothy D Fryer, Young T Hong, Patricia Vàsquez Rodriguez,  W Richard Bevan-Jones, Franklin I Aigbirhio, John T O’Brien, James B Rowe

17 March 2021

Summary:

Progressive supranuclear palsy (PSP) causes dementia and movement disorders. Researchers show that it is associated with brain inflammation, in addition to tau protein build-up. Using a PET (Positron Emission Tomography ) brain scan they were able to map the presence of inflammation in the brain of living volunteers with PSP, who were followed up for several years.

Publication: The American Journal of Clinical Nutrition

Gallant, J., Chan, K., Green, T., Wieringa, F., Leemaqz, S., Ngik, R., Measelle, J., Baldwin, D., Borath, M., Sophonneary, P., Yelland, L., Hampel, D., Shahab-Ferdows, S., Allen, L., Jones, K., Koulman, A., Parkington, D., Meadows, S., Kroeun, H. and Whitfield, K.

7 April 2021

Publication: Acta Neuropathologica

Mayen Briggs, Kieren Allinson, Maura Malpetti, Maria G. Spillantini, James B. Rowe, Sanne S. Kaalund

16 March 2021

Summary:

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder. Researchers test the new PSP pathology staging system in an independent series of PSP, and test the potential association between pathology stage and clinical severity at death.

Researchers show that those with a higher pathology stage – more widespread pathology, at post mortem also scored higher on disease severity scales in life.

Publication: Nutrients

Danielle Jones, Emanuella De Lucia Rolfe, Kirsten L. Rennie, Linda M. Oude Griep, Laura C. Kusinski, Deborah J. Hughes, Soren Brage, Ken K. Ong, Kathryn Beardsall, Claire L. Meek

31 March 2021

Summary

Around 5-10% of pregnant women in the UK develop gestational diabetes, which arises during pregnancy and typically resolves after delivery. Mothers with gestational diabetes are at greater risk of diabetes in later life, and their babies are also more likely to develop short-term and long-term health complications.

Preventing childhood obesity is really important, and yet, we still have an incomplete understanding about why and how obesity develops in early life.  The aim of this study is to assess pregnancy and early postnatal factors which contribute to maternal and child obesity after gestational diabetes, and to identify if a reduced-calorie diet in pregnancy can reduced these risks.

This paper outlines our plans to follow-up mothers and babies after gestational diabetes, who participated in our DiGest trial. Researchers will collect information about changes in weight in mothers and babies for 3 years following birth and will also assess the importance of infant feeding, early life growth, maternal diet and physical activity upon weight and glucose tolerance.

Publication: Brain

Claire O’Callaghan, Frank H Hezemans, Rong Ye, Catarina Rua, P Simon Jones, Alexander G Murley, Negin Holland, Ralf Regenthal, Kamen A Tsvetanov, Noham Wolpe, Roger A Barker, Caroline H Williams-Gray, Trevor W Robbins, Luca Passamonti, James B Rowe

30 March 2021

Summary:

Drugs that increase the brain’s noradrenaline can improve cognition in Parkinson’s disease. A challenge remains to identify those who will most benefit from noradrenergic drugs. We show that drug response depends on integrity of the locus coeruleus nucleus. This will inform clinical trial patient selection and treatment.

Publication: Acta Neuropathologica

Mayen Briggs, Kieren Allinson, Maura Malpetti, Maria G. Spillantini, James B. Rowe, Sanne S. Kaalund

28 March 2021

The research team validated a new system for staging brain pathology at post mortem in a devastating neurodegenerative diseases called progressive supranuclear palsy (PSP).

They show that those with a higher pathology stage, i.e. more widespread pathology, at post mortem also scored higher on disease severity scales in life.

Standardised staging systems provides a common language for neuropathologists on what is considered mild, moderate and severe pathology. They can be used to test if treatments impact the severity of pathology, and make it easier to compare results between studies.

Showing that the pathology stage is associated with clinical severity, the next step will be to try and replicate the pathology staging in vivo using brain imaging, e.g. PET, to test if researchers can track pathogenesis alongside clinical disease progression.

Publication: Journal of Medical Ethics

Publication: European Journal of Sport Science,

Eero A. Haapala ,Juuso Väistö ,Johanna K. Ihalainen ,Claudia Tomaselli González,Marja H. Leppänen ,Aapo Veijalainen ,Taisa Sallinen ,Aino-Maija Eloranta ,Ulf Ekelund ,Ursula Schwab ,Soren Brage ,Mustafa Atalay &Timo A. Lakka

14 March 2021

Summary

We investigated the associations of ST, screen time, PA at different intensities, and diet quality with biomarkers for inflammation, including hs-CRP, leptin, IL-6, adiponectin, TNF-α, and glycoprotein acetyls, in a population sample of children. We also investigated the modifying effect of BF% on these associations. Finally, we studied the modifying effect of diet quality on the associations of ST, screen time, and PA at different intensities with these biomarkers of inflammation.

Publication: The Lancet Psychiatry

Varun Warrier, Alex S F Kwong, Mannan Luo, Shareefa Dalvie, Jazz Croft, Hannah M Sallis, et al.

16 March 2021

Childhood maltreatment is associated with poor mental and physical health. However, the mechanisms of gene–environment correlations and the potential causal effects of childhood maltreatment on health are unknown. Using genetics, the researchers aimed to delineate the sources of gene–environment correlation for childhood maltreatment and the causal relationship between childhood maltreatment and health.

They did a genome-wide association study meta-analysis of childhood maltreatment using data from the UK Biobank, Psychiatric Genomics Consortium, Avon Longitudinal Study of Parents and Children, Adolescent Brain Cognitive Development Study and Generation R.

Family-based and population-based polygenic score analyses were done to elucidate gene–environment correlation mechanisms. The team used genetic correlation and Mendelian randomisation analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions.

This meta-analysis of genome-wide association studies identified 14 independent loci associated with childhood maltreatment. The researchers identified high genetic overlap among different maltreatment operationalisations, subtypes, and reporting methods.

Within-family analyses provided some support for active and reactive gene–environment correlation but did not show the absence of passive gene–environment correlation. Robust Mendelian randomisation suggested a potential causal role of childhood maltreatment in depression (unidirectional), as well as both schizophrenia and ADHD (bidirectional), but not in physical health conditions (coronary artery disease, type 2 diabetes) or inflammation (C-reactive protein concentration).

Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalisations, subtypes, and retrospective and prospective reports of childhood maltreatment.

Family-based analyses point to a role of active and reactive gene–environment correlation, with equivocal support for passive correlation. Mendelian randomisation supports a (primarily bidirectional) causal role of childhood maltreatment on mental health, but not on physical health conditions. This study identifies research avenues to inform the prevention of childhood maltreatment and its long-term effects.

Publication: Journal of Neurology, Neurosurgery and Psychiatry

Bernard P H Cho, Stefania Nannoni, Eric L Harshfield, Daniel Tozer, Stefan Gräf, Steven Bell, Hugh S Markus

12 March 2021

Researchers in Cambridge have discovered that people with a small change in a gene known as NOTCH3 could be at greater risk of having a stroke and developing vascular dementia.

Their research looked at the clinical records (medical notes) and genetic data of more than 200,000 healthy volunteers from the UK BioBank between 2006-10.

They found that around 1 in 450 carried a variant (a small difference) in the NOTCH3 gene, which provides instructions for making a protein essential for the maintenance of blood vessels, including those that supply blood to the brain.

The researchers then looked at how many people with and without changes in NOTCH3 had had a stroke, vascular dementia or other related conditions and discovered that variant carriers had more than a two-fold increase in the odds of stroke.

Vascular dementia was also more frequent in people who have the NOTCH3 variant. There was also an increased association with cerebral small vessel disease (SVD), which is a major cause of stroke and dementia.

This study shows that NOTCH3 variants are common in the general population and these variants are associated with increased risk of both stroke and vascular dementia, and with MRI markers of SVD. This demonstrates that genetic variation in the NOTCH3 gene accounts for a much greater proportion of stroke in the general population than previously thought.

Publication: Nature

Tim H. H. Coorens, Thomas R. W. Oliver, Rashesh Sanghvi, Ulla Sovio, Emma Cook, Roser Vento-Tormo, Muzlifah Haniffa, Matthew D. Young, Raheleh Rahbari, Neil Sebire, Peter J. Campbell, D. Stephen Charnock-Jones, Gordon C. S. Smith & Sam Behjati

10 March 2020

Summary

Researchers found evidence to support the theory of the placenta as a ‘dumping ground’ for genetic defects, whereas the fetus corrects or avoids these errors. The findings provide a clear rationale for studying the association between genetic aberrations and birth outcomes, in order to better understand problems such as premature birth and stillbirth. Read the full story.

Publication: Nature Communications

Robert C. Will, Thandavarayan Ramamurthy, Naresh Chand Sharma, Balaji Veeraraghavan, Lucky Sangal, Pradeep Haldar, Agila Kumari Pragasam, Karthick Vasudevan, Dhirendra Kumar, Bhabatosh Das, Eva Heinz, Vyacheslav Melnikov, Stephen Baker, Vartul Sangal, Gordon Dougan & Ankur Mutreja

8 March 2021

Summary

Diphtheria is a highly contagious infection that can affect the nose and throat, and sometimes the skin.

In a study published in Nature Communications,  an international team of researchers analysed the genomes of 61 bacteria isolated from patients and combining these with 441 publicly available genomes. They used this information to assess the presence of antimicrobial resistance (AMR) genes and assess toxin variation. Read the full story.

Publication: Gut

Daniele Biasci, James C Lee Nurulamin M Noor, Diana R Pombal, Monica Hou, Nina Lewis, Tariq Ahmad, Ailsa Hart, Miles Parkes, Eoin F McKinney, Paul A Lyons, Kenneth G C Smith

1 October 2019

Summary:

Researchers have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. They sought to develop a blood-based test that could identify these subgroups without cell separation, and would be suitable for clinical use in Crohn’s disease (CD) and ulcerative colitis (UC).

Publication: Nature

Simon F Brunner, Nicola D Roberts, Luke A Wylie, Luiza Moore, Sarah J Aitken, Susan E Davies, Mathijs A Sanders , Pete Ellis, Chris Alder, Yvette Hooks, Federico Abascal, Michael R Stratton, Inigo Martincorena, Matthew Hoare, Peter J Campbell

23 October 2019

Summary:

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease.

The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes. Stem cells from normal livers have a low mutational burden and limited diversity of signatures, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation.

Publication: Nature

Hannah Wand, Samuel A. Lambert, Cecelia Tamburro, Michael A. Iacocca, Jack W. O’Sullivan, Catherine Sillari, Iftikhar J. Kullo, Robb Rowley, Jacqueline S. Dron, Deanna Brockman, Eric Venner, Mark I. McCarthy, Antonis C. Antoniou, Douglas F. Easton, Robert A. Hegele, Amit V. Khera, Nilanjan Chatterjee, Charles Kooperberg, Karen Edwards, Katherine Vlessis, Kim Kinnear, John N. Danesh, et al

10 March 2021

Summary

This research is a perspective piece that provides a framework to promote the validity, transparency, and reproducibility of polygenic risk scores (PRS) by encouraging authors to detail the study population, statistical methods, and potential clinical utility of a published score.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics.

However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, the researchers present the Polygenic Risk Score Reporting Standards (PRS-RS), in which they update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field.

Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications.

The researchers encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.

Publication: Cell

M. Zaeem Cader, Rodrigo Pereira de Almeida Rodrigues, James A. West, Gavin W. Sewell, Muhammad N. Md-Ibrahim, Stephanie Reikine, Giuseppe Sirago, Lukas W. Unger, Ana Belén Iglesias-Romero, Katharina Ramshorn, Lea-Maxie Haag, Svetlana Saveljeva, Jana-Fabienne Ebel, Philip Rosenstiel, Nicole C. Kaneider, James C. Lee, Trevor D. Lawley, Allan Bradley, Gordon Dougan, Yorgo Modis, Julian L. Griffin, Arthur Kaser

23 January 2020

Summary

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn’s disease and leprosy. Researchers developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein.