scholarly journals Whole-exome sequencing in 16,511 individuals reveals a role of the HTRA1 protease and its substrate EGFL8 in brain white matter hyperintensities

2021 ◽  
Author(s):  
Rainer Malik ◽  
Nathalie Beaufort ◽  
Simon Frerich ◽  
Benno Gesierich ◽  
Marios K Georgakis ◽  
...  
Keyword(s):  
White Matter ◽  
General Population ◽  
White Matter Hyperintensities ◽  
Rare Variants ◽  
Uk Biobank ◽  
Protease Domain ◽  
Whole Exome ◽  
The Uk ◽  
Burden Tests

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on WMH volume, the contribution of rare variants to WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of WMH burden in the UK Biobank using publicly available whole-exome sequencing data (N=16,511) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level (c.691+2T>C, beta=-0.74, se=0.13, p=9.7E-9). Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 to associate with increased WMH volume (p=5.5E-6, FDR=0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204-364; beta=0.79, se=0.14, p=9.4E-8). The frequency of such variants in the UK Biobank population was 1 in 450. WMH volume was brought forward by approximately 11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (beta=0.26, se=0.02, p=2.9E-59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (beta=0.44, se=0.14, p=0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in a markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (p=1.5E-4, FDR=0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study (PheWAS) mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (OR=12.24, 95%CI [2.54-35.25], p=8.3E-5). Collectively, these findings highlight an important role of rare genetic variation and of the HTRA1 protease in determining WMH burden in the general population. 

scholarly journals Modelling the distribution of white matter hyperintensities due to ageing on MRI images using Bayesian inference

2018 ◽  
Author(s):  
Vaanathi Sundaresan ◽  
Ludovica Griffanti ◽  
Petya Kindalova ◽  
Fidel Alfaro-Almagro ◽  
Giovanna Zamboni ◽  
...  
Keyword(s):  
White Matter ◽  
Vascular Disease ◽  
White Matter Hyperintensities ◽  
Age Groups ◽  
Clinical Importance ◽  
Population Level ◽  
Distribution Model ◽  
Ageing Population ◽  
Uk Biobank ◽  
The Uk

AbstractWhite matter hyperintensities (WMH), also known as white matter lesions, are localised white matter areas that appear hyperintense on MRI scans. WMH commonly occur in the ageing population, and are often associated with several factors such as cognitive disorders, cardiovascular risk factors, cerebrovascular and neurodegenerative diseases. Despite the fact that some links between lesion location and parametric factors such as age have already been established, the relationship between voxel-wise spatial distribution of lesions and these factors is not yet well understood. Hence, it would be of clinical importance to model the distribution of lesions at the population-level and quantitatively analyse the effect of various factors on the lesion distribution model.In this work we compare various methods, including our proposed method, to generate voxel-wise distributions of WMH within a population with respect to various factors. Our proposed Bayesian spline method models the spatio-temporal distribution of WMH with respect to a parametric factor of interest, in this case age, within a population. Our probabilistic model takes as input the lesion segmentation binary maps of subjects belonging to various age groups and provides a population-level parametric lesion probability map as output. We used a spline representation to ensure a degree of smoothness in space and the dimension associated with the parameter, and formulated our model using a Bayesian framework.We tested our algorithm output on simulated data and compared our results with those obtained using various existing methods with different levels of algorithmic and computational complexity. We then compared the better performing methods on a real dataset, consisting of 1000 subjects of the UK Biobank, divided in two groups based on hypertension diagnosis. Finally, we applied our method on a clinical dataset of patients with vascular disease.On simulated dataset, the results from our algorithm showed a mean square error (MSE) value of 7.27 × 10−5, which was lower than the MSE value reported in the literature, with the advantage of being robust and computationally efficient. In the UK Biobank data, we found that the lesion probabilities are higher for the hypertension group compared to the non-hypertension group and further verified this finding using a statistical t-test. Finally, when applying our method on patients with vascular disease, we observed that the overall probability of lesions is significantly higher in later age groups, which is in line with the current literature.

scholarly journals Midlife blood pressure is associated with the severity of white matter hyperintensities: analysis of the UK Biobank cohort study

2020 ◽  
Author(s):  
Karolina Agnieszka Wartolowska ◽  
Alastair John Stewart Webb
Keyword(s):  
Blood Pressure ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Linear Models ◽  
Population Attributable Fraction ◽  
Relative Role ◽  
Uk Biobank ◽  
Assessment Centre ◽  
The Uk

Abstract Aims White matter hyperintensities (WMH) progress with age and hypertension, but the key period of exposure to elevated blood pressure (BP), and the relative role of systolic BP (SBP) vs. diastolic BP (DBP), remains unclear. This study aims to determine the relationship between WMH and concurrent vs. past BP.  Methods and results  UK Biobank is a prospective community-based cohort of 40–69-year olds from 22 centres, with magnetic resonance imaging in a subgroup of over 40 000 people at 4–12 years after baseline assessment. Standardized associations between WMH load (WMH volume normalized by total white matter volume and logit-transformed) and concurrent vs. past BP were determined using linear models, adjusted for age, sex, cardiovascular risk factors, BP source, assessment centre, and time since baseline. Associations adjusted for regression dilution bias were determined between median WMH and usual SBP or DBP, stratified by age and baseline BP. In 37 041 eligible participants with WMH data and BP measures, WMH were more strongly associated with concurrent SBP [DBP: β = 0.064, 95% confidence interval (CI) 0.050–0.078; SBP: β = 0.076, 95% CI 0.062–0.090], but the strongest association was for past DBP (DBP: β = 0.087, 95% CI 0.064–0.109; SBP: β = 0.045, 95% CI 0.022–0.069), particularly under the age of 50 (DBP: β = 0.103, 95% CI 0.055–0.152; SBP: β = 0.012, 95% CI −0.044 to 0.069). Due to the higher prevalence of elevated SBP, median WMH increased 1.126 (95% CI 1.107–1.146) per 10 mmHg usual SBP and 1.106 (95% CI 1.090–1.122) per 5 mmHg usual DBP, whilst the population attributable fraction of WMH in the top decile was greater for elevated SBP (19.1% for concurrent SBP; 24.4% for past SBP). Any increase in BP, even below 140 for SBP and below 90 mmHg for DBP, and especially if requiring antihypertensive medication, was associated with increased WMH. Conclusions WMH were strongly associated with concurrent and past elevated BP with the population burden of severe WMH greatest for SBP. However, before the age of 50, DBP was more strongly associated with WMH. Long-term prevention of WMH may require control of even mildly elevated midlife DBP.

scholarly journals Gene-level analysis of rare variants in 363,977 whole exome sequences reveals an association of GIGYF1 loss of function with diabetes

2021 ◽  
Author(s):  
Aimee M. Deaton ◽  
Margaret M. Parker ◽  
Lucas D. Ward ◽  
Alexander O. Flynn-Carroll ◽  
Lucas BonDurant ◽  
...  
Keyword(s):  
Rare Variants ◽  
Loss Of Function ◽  
Cholesterol Levels ◽  
Whole Exome ◽  
Increased Risk ◽  
Gene Level ◽  
Rare Genetic Variants ◽  
The Uk ◽  
Novel Associations

AbstractSequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and T2D diagnosis in 363,977 exome-sequenced participants in the UK Biobank. We identified known associations with diabetes including variants in GCK, HNF1A and PDX1, genes involved in Mendelian forms of diabetes. Novel associations were identified for GIGYF1 predicted loss of function (pLOF), TNRC6B pLOF and PFAS predicted damaging missense variants. Multiple rare variants contributed to these associations, including singleton variants. The most significant novel associations were seen for GIGYF1 pLOF which associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 × 10−12) and HbA1c (4.33 mmol/mol, p = 1.28 × 10−14) as well as T2D diagnosis (OR = 4.15, p= 6.14 x10−11). GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. An independent common variant association for glucose and T2D was identified at GIGYF1 which replicated in additional datasets. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.

scholarly journals Obesity impairs cognitive function via metabolic syndrome and cerebrovascular disease: an SEM analysis in 15,000 adults from the UK Biobank

2020 ◽  
Author(s):  
Filip Morys ◽  
Mahsa Dadar ◽  
Alain Dagher
Keyword(s):  
Metabolic Syndrome ◽  
Cognitive Impairment ◽  
White Matter ◽  
Cerebrovascular Disease ◽  
Cortical Thickness ◽  
White Matter Hyperintensities ◽  
Uk Biobank ◽  
Central Nervous System Damage ◽  
The Uk ◽  
The Relationship

AbstractChronic obesity is associated with several complications, including cognitive impairment and dementia. However, we have piecemeal knowledge of the mechanisms linking obesity to central nervous system damage. Adiposity leads to the metabolic syndrome, consisting of inflammation, hypertension, dyslipidemia and insulin resistance. In turn, these metabolic abnormalities cause cerebrovascular dysfunction, which may cause white and grey matter tissue loss and consequent cognitive impairment. While there have been several neuroimaging studies linking adiposity to changes in brain morphometry, a comprehensive investigation of the relationship has so far not been done. Here we use structural equation modelling applied to over 15,000 individuals from the UK Biobank to identify the causal chain that links adiposity to cognitive dysfunction. We found that body mass index and waist-to-hip ratio were positively related to higher plasma C-reactive protein, dyslipidemia, occurrence of hypertension and diabetes, all of which were in turn related to cerebrovascular disease as measured by volume of white matter hyperintensities on magnetic resonance imaging. White mater hyperintensities were associated with lower cortical thickness and volume and higher subcortical volumes, which were associated with cognitive deficits on tests of visuospatial memory, fluid intelligence, and working memory among others. In follow-up analyses we found that inflammation, hypertension and diabetes mediated 20% of the relationship between obesity and cerebrovascular disease and that cerebrovascular disease mediated a significant proportion of the relationship between obesity and cortical thickness and volume. We also showed that volume of white matter hyperintensities was related to decreased fractional anisotropy and increased mean diffusivity in the majority of white matter tracts, pointing to white matter dysconnectivity as a major cause of impaired cognition. Our results have clinical implications, supporting a role for the management of adiposity in the prevention of late-life dementia and cognitive decline.

scholarly journals Is glycaemia associated with poorer brain health and risk of dementia? Cross sectional and follow-up analysis of the UK Biobank

2020 ◽  
Author(s):  
Victoria Garfield ◽  
Aliki-Eleni Farmaki ◽  
Sophie V. Eastwood ◽  
Rohini Mathur ◽  
Christopher T. Rentsch ◽  
...  
Keyword(s):  
Cognitive Function ◽  
White Matter ◽  
Cognitive Decline ◽  
Visual Memory ◽  
White Matter Hyperintensities ◽  
Undiagnosed Diabetes ◽  
Uk Biobank ◽  
Brain Health ◽  
Cross Sectional ◽  
The Uk

ABSTRACTObjectiveTo understand the relationship across the glycaemic spectrum with incident dementia, brain structure, and cognitive decline.Research Design and Methods: UK Biobank participants, aged 40-69 at recruitment. HbA1c and diabetes diagnosis define baseline glycaemic categories. Outcomes included incident vascular dementia (VD), Alzheimer’s dementia (AD), hippocampal volume (HV), white matter hyperintensity (WMH) volume, cognitive function and decline. All results are in reference to normoglycaemic individuals (HbA1c 35-<42 mmol/mol).Results210433 (47%), 15246 (3%), 3280 (0.7%), 20793 (5%) individuals had low HbA1c, pre-diabetes, undiagnosed diabetes, and known diabetes, respectively. Pre- and known diabetes markedly increased incident VD, (hazard ratios (HR) 1.51, 95%CI=1.01;2.25 and 1.96, 95%CI=1.49;2.58, respectively), less so AD (1.18, 0.92;1.52 and 1.13 0.95,1.33), adjusting for demographic and socioeconomic variables. For VD, multivariate adjustment, driven by antihypertensives, attenuated associations, HR 1.27, 0.84;1.91 and 1.45,1.07;1.97. Pre- and known diabetes conferred elevated risks of cognitive decline (odds ratio OR 1.53, 1.02;2.29 and 1.49, 1.02;2.18, respectively). People with pre-diabetes, undiagnosed and known diabetes had higher WMH volumes (4%, 30%, 3%, respectively), and lower HV (34.51 mm3, 11.73 mm3 and 61.13 mm3 respectively). People with low-normal HbA1c (<35 mmol/mol) had 5% lower WMH volume and 13.6 mm3 greater HV than normoglycaemic individuals.ConclusionsPre and known diabetes increase VD risks, less so AD. Excess VD risks were largely accounted for by treated hypertension. Hyperglycaemic states were associated with adverse, whereas low normal HbA1c was associated with favourable brain structure compared to normoglycaemic individuals. Our findings have implications for cardiovascular medication in hyperglycaemia for brain health.Type-2 diabetes and, more generally, hyperglycaemic states, have been associated with poorer cognitive function (such as learning and memory)(1), increased risk of dementia(2) and alterations in key brain structures, particularly the hippocampus(3). In contrast, recent evidence from a randomised crossover trial also suggests that, in people with diabetes, even modest hypoglycaemia has a detrimental effect on cognitive function(4). Thus, it is also important to explore how low levels of glycated haemoglobin (HbA1c) relate to these outcomes. A previous paper explored the cross sectional association between baseline diabetes and two cognition measures in the UK Biobank (reaction time and visual memory)(5). The authors found that diabetes was associated with poorer scores on the reaction time test, but paradoxically, better scores on the visual memory test. They did not explore other outcomes or lesser glycaemic states.Memory loss is the most conclusively reported adverse effect of hyperglycaemia on cognitive function(6). Hippocampal atrophy is a crucial feature of age-related memory loss and the hippocampus is particularly vulnerable to the neurotoxic consequences of diabetes(7). Evidence relating diabetes to the presence and progression of white matter hyperintensities is equivocal(8), but some research suggests that those with diabetes have greater volumes of white matter hyperintensities(9,10). Although there have been numerous studies in this area, the role of glycaemia in brain health across the entire glycaemic spectrum remains unclear, in particular no studies have investigated how lesser hyperglycaemic states relate to these outcomes, as most studies have focused on diagnosed diabetes only.Thus, the aim of this study was to investigate the associations between five glycaemic states across the entire spectrum (low HbA1c, normoglycaemia, pre-diabetes, undiagnosed diabetes and known diabetes) and Alzheimer’s dementia (AD) risk, vascular dementia (VD) risk, baseline cognitive function and cognitive decline, hippocampal volume, and white matter hyperintensities volume in the UK Biobank. We hypothesised that there would be a U-shaped association between glycaemia and our outcomes of interest, such that those with lower and higher HbA1c would have worse outcomes than those with normal glycaemic levels.

scholarly journals Socioeconomic Inequalities and Ethnicity Are Associated with a Positive COVID-19 Test among Cancer Patients in the UK Biobank Cohort

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1514
Author(s):  
Shing Fung Lee ◽  
Maja Nikšić ◽  
Bernard Rachet ◽  
Maria-Jose Sanchez ◽  
Miguel Angel Luque-Fernandez
Keyword(s):  
Cancer Patients ◽  
Socioeconomic Inequalities ◽  
Uk Biobank ◽  
Incident Cancer ◽  
Increased Risk ◽  
Exposure Variable ◽  
Independent Risk Factors ◽  
The Uk ◽  
Deprived Areas

We explored the role of socioeconomic inequalities in COVID-19 incidence among cancer patients during the first wave of the pandemic. We conducted a case-control study within the UK Biobank cohort linked to the COVID-19 tests results available from 16 March 2020 until 23 August 2020. The main exposure variable was socioeconomic status, assessed using the Townsend Deprivation Index. Among 18,917 participants with an incident malignancy in the UK Biobank cohort, 89 tested positive for COVID-19. The overall COVID-19 incidence was 4.7 cases per 1000 incident cancer patients (95%CI 3.8–5.8). Compared with the least deprived cancer patients, those living in the most deprived areas had an almost three times higher risk of testing positive (RR 2.6, 95%CI 1.1–5.8). Other independent risk factors were ethnic minority background, obesity, unemployment, smoking, and being diagnosed with a haematological cancer for less than five years. A consistent pattern of socioeconomic inequalities in COVID-19 among incident cancer patients in the UK highlights the need to prioritise the cancer patients living in the most deprived areas in vaccination planning. This socio-demographic profiling of vulnerable cancer patients at increased risk of infection can inform prevention strategies and policy improvements for the coming pandemic waves.

scholarly journals Rare variants in axonogenesis genes connect three families with sound–color synesthesia

2018 ◽  
Vol 115 (12) ◽  
pp. 3168-3173 ◽  
Author(s):  
Amanda K. Tilot ◽  
Katerina S. Kucera ◽  
Arianna Vino ◽  
Julian E. Asher ◽  
Simon Baron-Cohen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rare Variants ◽  
Autism Spectrum ◽  
Sensory Experiences ◽  
Limited Success ◽  
Whole Exome ◽  
Rare Genetic Variants ◽  
Sound Color ◽  
Stimulation Of

Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound–color (auditory–visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2—associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.

scholarly journals Role of white matter hyperintensities, hemoglobin and vitamin B‐12 on cognitive decline: Two‐year follow‐up data from the Tata Longitudinal Study of Ageing (TLSA)

2020 ◽  
Vol 16 (S6) ◽  
Author(s):  
Aditi Balakrishnan ◽  
Vivek Tiwari ◽  
M.L. Abhishek ◽  
Naren P. Rao ◽  
Vijayalakshmi Ravindranath ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
White Matter ◽  
Cognitive Decline ◽  
White Matter Hyperintensities ◽  
Vitamin B ◽  
Vitamin B 12

scholarly journals Assessing the contribution of rare-to-common protein-coding variants to circulating metabolic biomarker levels via 412,394 UK Biobank exome sequences

2021 ◽  
Author(s):  
Abhishek Nag ◽  
Lawrence Middleton ◽  
Ryan S Dhindsa ◽  
Dimitrios Vitsios ◽  
Eleanor M Wigmore ◽  
...  
Keyword(s):  
Gene Networks ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Protein Coding ◽  
The Uk ◽  
Metabolic Biomarkers ◽  
Coding Variants

Genome-wide association studies have established the contribution of common and low frequency variants to metabolic biomarkers in the UK Biobank (UKB); however, the role of rare variants remains to be assessed systematically. We evaluated rare coding variants for 198 metabolic biomarkers, including metabolites assayed by Nightingale Health, using exome sequencing in participants from four genetically diverse ancestries in the UKB (N=412,394). Gene-level collapsing analysis, that evaluated a range of genetic architectures, identified a total of 1,303 significant relationships between genes and metabolic biomarkers (p<1x10-8), encompassing 207 distinct genes. These include associations between rare non-synonymous variants in GIGYF1 and glucose and lipid biomarkers, SYT7 and creatinine, and others, which may provide insights into novel disease biology. Comparing to a previous microarray-based genotyping study in the same cohort, we observed that 40% of gene-biomarker relationships identified in the collapsing analysis were novel. Finally, we applied Gene-SCOUT, a novel tool that utilises the gene-biomarker association statistics from the collapsing analysis to identify genes having similar biomarker fingerprints and thus expand our understanding of gene networks.

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