The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease.

We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer's disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in cardiovascular deaths, schizophrenia, Alzheimer's and Parkinson's disease, and with the two antigens of the XG blood group located in the pseudoautosomal region of the sex chromosomes. We further reveal that the most deleterious modifiable risk factors for this vulnerable brain network are diabetes, nitrogen dioxide - a proxy for traffic-related air pollution - and alcohol intake frequency. The extent of these associations was uncovered by examining these modifiable risk factors in a single model to assess the unique contribution of each on the vulnerable brain network, above and beyond the dominating effects of age and sex. These results provide a comprehensive picture of the role played by genetic and modifiable risk factors on these fragile parts of the brain.

Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.

Physiological phenotypes have optimal values relevant to healthy aging: sweet spots deduced from the Canadian Longitudinal Study on Aging.

Previous observations on a group of exceptionally healthy "Super-Seniors" showed a lower variance of multiple physiological measures relevant for health than did a less healthy group of the same age. The finding was interpreted as the healthier individuals having physiological measurement values closer to an optimal level, or "sweet spot." Here, we tested the generalizability of the sweet-spot hypothesis in a larger community sample, comparing differences in the variance between healthier and less healthy groups. We apply this method to the Canadian Longitudinal Study on Aging (CLSA) comprehensive cohort of 30,097 participants aged 45 to 85 years with deep phenotype data. Data from both sexes and four age ranges were analyzed. Five instruments were used to represent different aspects of health, physical, and cognitive functioning. We tested 231 phenotypic measures for lower variance in the most healthy vs. least healthy quartile of each sex and age group, as classified by the five instruments. Segmented regression was used to determine sex-specific optimal values. One hundred forty-two physiological measures (61%) showed lower variance in the healthiest than in the least healthy group, in at least one sex and age group. The difference in variance was most significant for hemoglobin A1c and was also significant for many body composition measurements, but not for bone mineral density. Ninety-four phenotypes showed a nonmonotonic relationship with health, consistent with the idea of a sweet spot; for these, we determined optimal values and 95% confidence intervals that were generally narrower than the ranges of current clinical reference intervals. These findings for sweet spot discovery validate the proposed approach for identifying traits important for healthy aging.

Amplitudes of resting-state functional networks - investigation into their correlates and biophysical properties.

Resting-state fMRI studies have shown that multiple functional networks, which consist of distributed brain regions that share synchronised spontaneous activity, co-exist in the brain. As these resting-state networks (RSNs) have been thought to reflect the brain's intrinsic functional organization, intersubject variability in the networks' spontaneous fluctuations may be associated with individuals' clinical, physiological, cognitive, and genetic traits. Here, we investigated resting-state fMRI data along with extensive clinical, lifestyle, and genetic data collected from 37,842 UK Biobank participants, with the object of elucidating intersubject variability in the fluctuation amplitudes of RSNs. Functional properties of the RSN amplitudes were first examined by analyzing correlations with the well-established between-network functional connectivity. It was found that a network amplitude is highly correlated with the mean strength of the functional connectivity that the network has with the other networks. Intersubject clustering analysis showed the amplitudes are most strongly correlated with age, cardiovascular factors, body composition, blood cell counts, lung function, and sex, with some differences in the correlation strengths between sensory and cognitive RSNs. Genome-wide association studies (GWASs) of RSN amplitudes identified several significant genetic variants reported in previous GWASs for their implications in sleep duration. We provide insight into key factors determining RSN amplitudes and demonstrate that intersubject variability of the amplitudes primarily originates from differences in temporal synchrony between functionally linked brain regions, rather than differences in the magnitude of raw voxelwise BOLD signal changes. This finding additionally revealed intriguing differences between sensory and cognitive RSNs with respect to sex effects on temporal synchrony and provided evidence suggesting that synchronous coactivations of functionally linked brain regions, and magnitudes of BOLD signal changes, may be related to different genetic mechanisms. These results underscore that intersubject variability of the amplitudes in health and disease need to be interpreted largely as a measure of the sum of within-network temporal synchrony and amplitudes of BOLD signals, with a dominant contribution from the former.

Genome-Wide Association with Uncertainty in the Genetic Similarity Matrix.

Genome-wide association studies (GWASs) are often confounded by population stratification and structure. Linear mixed models (LMMs) are a powerful class of methods for uncovering genetic effects, while controlling for such confounding. LMMs include random effects for a genetic similarity matrix, and they assume that a true genetic similarity matrix is known. However, uncertainty about the phylogenetic structure of a study population may degrade the quality of LMM results. This may happen in bacterial studies in which the number of samples or loci is small, or in studies with low-quality genotyping. In this study, we develop methods for linear mixed models in which the genetic similarity matrix is unknown and is derived from Markov chain Monte Carlo estimates of the phylogeny. We apply our model to a GWAS of multidrug resistance in tuberculosis, and illustrate our methods on simulated data.

Computational Efficiency and Precision for Replicated-Count and Batch-Marked Hidden Population Models.

We address two computational issues common to open-population N-mixture models, hidden integer-valued autoregressive models, and some hidden Markov models. The first issue is computation time, which can be dramatically improved through the use of a fast Fourier transform. The second issue is tractability of the model likelihood function for large numbers of hidden states, which can be solved by improving numerical stability of calculations. As an illustrative example, we detail the application of these methods to the open-population N-mixture models. We compare computational efficiency and precision between these methods and standard methods employed by state-of-the-art ecological software. We show faster computing times (a ∼ 6 to ∼ 30 times speed improvement for population size upper bounds of 500 and 1000, respectively) over state-of-the-art ecological software for N-mixture models. We also apply our methods to compute the size of a large elk population using an N-mixture model and show that while our methods converge, previous software cannot produce estimates due to numerical issues. These solutions can be applied to many ecological models to improve precision when logs of sums exist in the likelihood function and to improve computational efficiency when convolutions are present in the likelihood function. Supplementary materials accompanying this paper appear online. Supplementary materials for this article are available at 10.1007/s13253-022-00509-y.

Estimation of SARS-CoV-2 antibody prevalence through serological uncertainty and daily incidence.

Serology tests for SARS-CoV-2 provide a paradigm for estimating the number of individuals who have had an infection in the past (including cases that are not detected by routine testing, which has varied over the course of the pandemic and between jurisdictions). Such estimation is challenging in cases for which we only have limited serological data and do not take into account the uncertainty of the serology test. In this work, we provide a joint Bayesian model to improve the estimation of the sero-prevalence (the proportion of the population with SARS-CoV-2 antibodies) through integrating multiple sources of data, priors on the sensitivity and specificity of the serological test, and an effective epidemiological dynamics model. We apply our model to the Greater Vancouver area, British Columbia, Canada, with data acquired during the pandemic from the end of January to May 2020. Our estimated sero-prevalence is consistent with previous literature but with a tighter credible interval.

Le dépistage sérologique du SRAS­CoV­2 permet d'estimer le nombre de personnes qui ont déjà été infectées (y compris les cas qui ne sont pas détectés au moyen de tests de dépistage réguliers, qui ont varié au cours de la pandémie et d'une province ou d'un territoire à l'autre). Une telle estimation est difficile lorsqu'il existe peu de données sérologiques et que l'incertitude du test sérologique n'est pas prise en compte. Nous proposons dans ce travail un modèle bayésien conjoint visant à améliorer l'estimation de la séroprévalence (la proportion de la population avec des anticorps SRAS­CoV­2) en intégrant de multiples sources de données, des lois a priori sur la sensibilité et la spécificité du test sérologique, et un modèle efficace des dynamiques épidémiologiques. Nous appliquons ce modèle à des données recueillies dans la région métropolitaine de Vancouver (Colombie­Britannique, Canada) pendant la pandémie de fin janvier à mai 2020. Notre estimation de la séroprévalence est cohérente avec la littérature antérieure tout en ayant un intervalle de crédibilité plus précis.

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging.

A key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging magnetic resonance imaging technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We present an open resource of QSM-based imaging measures of multiple brain structures in 35,273 individuals from the UK Biobank prospective epidemiological study. We identify statistically significant associations of 251 phenotypes with magnetic susceptibility that include body iron, disease, diet and alcohol consumption. Genome-wide associations relate magnetic susceptibility to 76 replicating clusters of genetic variants with biological functions involving iron, calcium, myelin and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* signal decay time measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers worldwide, creating the potential to discover new, non-invasive markers of brain health.

Under-reporting of COVID-19 in the Northern Health Authority region of British Columbia.

Asymptomatic and pauci-symptomatic presentations of COVID-19 along with restrictive testing protocols result in undetected COVID-19 cases. Estimating undetected cases is crucial to understanding the true severity of the outbreak. We introduce a new hierarchical disease dynamics model based on the N-mixtures hidden population framework. The new models make use of three sets of disease count data per region: reported cases, recoveries and deaths. Treating the first two as under-counted through binomial thinning, we model the true population state at each time point by partitioning the diseased population into the active, recovered and died categories. Both domestic spread and imported cases are considered. These models are applied to estimate the level of under-reporting of COVID-19 in the Northern Health Authority region of British Columbia, Canada, during 30 weeks of the provincial recovery plan. Parameter covariates are easily implemented and used to improve model estimates. We compare two distinct methods of model-fitting for this case study: (1) maximum likelihood estimation, and (2) Bayesian Markov chain Monte Carlo. The two methods agreed exactly in their estimates of under-reporting rate. When accounting for changes in weekly testing volumes, we found under-reporting rates varying from 60.2% to 84.2%.

Le recours à des protocoles de tests restrictifs et l'existence de formes asymptomatiques et paucisymptomatiques de la COVID­19 contribuent à la non détection de cas COVID­19. Pour comprendre la véritable gravité de l'épidémie, il est primordial d'estimer correctement le nombre de cas non détectés. A cette fin, les auteurs de ce travail proposent un nouveau modèle hiérarchique des dynamiques de la maladie basé sur l'approche de N­mélanges de population cachée. Ces modèles utilisent trois types de données régionales, à savoir, les nombres de cas déclarés, guéris et décédés. En faisant appel à l'amincissement binomial (binomial thinning) et en traitant les nombres de cas déclarés et guéris comme étant sous­évalués, les auteurs proposent une modélisation de l'état réel de l'épidémie basée sur une partition de la population malade en trois catégories : cas actifs, cas guéris et cas décédés. Cette partition tient compte des cas de propagation intérieure et des cas importés. Les auteurs ont utilisé les données recueillies durant les trente semaines du plan de rétablissement provincial de la région de l'Autorité sanitaire du Nord de la Colombie­Britannique, Canada pour illustrer leur approche et estimer le niveau de sous­déclaration COVID­19 associé. Des covariables peuvent être facilement incorporées au modèle proposé et améliorer la qualité des estimations. Deux méthodes d'ajustement sont retenues: (1) l'estimation par maximum de vraisemblance, et (2) la méthode de Monte Carlo par chaînes de Markov. Les estimations du taux de sous­déclaration obtenues par ces deux méthodes concordent exactement et varient entre 60,2% et 84,2% après ajustement des variations des volumes de tests hebdomadaires.

Long time frames to detect the impact of changing COVID-19 measures, Canada, March to July 2020.

BackgroundMany countries have implemented population-wide interventions to control COVID-19, with varying extent and success. Many jurisdictions have moved to relax measures, while others have intensified efforts to reduce transmission.AimWe aimed to determine the time frame between a population-level change in COVID-19 measures and its impact on the number of cases.MethodsWe examined how long it takes for there to be a substantial difference between the number of cases that occur following a change in COVID-19 physical distancing measures and those that would have occurred at baseline. We then examined how long it takes to observe this difference, given delays and noise in reported cases. We used a susceptible-exposed-infectious-removed (SEIR)-type model and publicly available data from British Columbia, Canada, collected between March and July 2020.ResultsIt takes 10 days or more before we expect a substantial difference in the number of cases following a change in COVID-19 control measures, but 20-26 days to detect the impact of the change in reported data. The time frames are longer for smaller changes in control measures and are impacted by testing and reporting processes, with delays reaching ≥ 30 days.ConclusionThe time until a change in control measures has an observed impact is longer than the mean incubation period of COVID-19 and the commonly used 14-day time period. Policymakers and practitioners should consider this when assessing the impact of policy changes. Rapid, consistent and real-time COVID-19 surveillance is important to minimise these time frames.

Compression for population genetic data through finite-state entropy.

We improve the efficiency of population genetic file formats and GWAS computation by leveraging the distribution of samples in population-level genetic data. We identify conditional exchangeability of these data, recommending finite state entropy algorithms as an arithmetic code naturally suited for compression of population genetic data. We show between [Formula: see text] and [Formula: see text] speed and size improvements over modern dictionary compression methods that are often used for population genetic data such as Zstd and Zlib in computation and decompression tasks. We provide open source prototype software for multi-phenotype GWAS with finite state entropy compression demonstrating significant space saving and speed comparable to the state-of-the-art.

Estimating Genetic Similarity Matrices Using Phylogenies.

Genetic similarity is a measure of the genetic relatedness among individuals. The standard method for computing these matrices involves the inner product of observed genetic variants. Such an approach is inaccurate or impossible if genotypes are not available, or not densely sampled, or of poor quality (e.g., genetic analysis of extinct species). We provide a new method for computing genetic similarities among individuals using phylogenetic trees. Our method can supplement (or stand in for) computations based on genotypes. We provide simulations suggesting that the genetic similarity matrices computed from trees are consistent with those computed from genotypes. With our methods, quantitative analysis on genetic traits and analysis of heritability and coheritability can be conducted directly using genetic similarity matrices and so in the absence of genotype data, or under uncertainty in the phylogenetic tree. We use simulation studies to demonstrate the advantages of our method, and we provide applications to data.

An expanded set of genome-wide association studies of brain imaging phenotypes in UK Biobank.

UK Biobank is a major prospective epidemiological study, including multimodal brain imaging, genetics and ongoing health outcomes. Previously, we published genome-wide associations of 3,144 brain imaging-derived phenotypes, with a discovery sample of 8,428 individuals. Here we present a new open resource of genome-wide association study summary statistics, using the 2020 data release, almost tripling the discovery sample size. We now include the X chromosome and new classes of imaging-derived phenotypes (subcortical volumes and tissue contrast). Previously, we found 148 replicated clusters of associations between genetic variants and imaging phenotypes; in this study, we found 692, including 12 on the X chromosome. We describe some of the newly found associations, focusing on the X chromosome and autosomal associations involving the new classes of imaging-derived phenotypes. Our novel associations implicate, for example, pathways involved in the rare X-linked STAR (syndactyly, telecanthus and anogenital and renal malformations) syndrome, Alzheimer's disease and mitochondrial disorders.

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

BACKGROUND AND PURPOSE: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Brain aging comprises many modes of structural and functional change with distinct genetic and biophysical associations.

Brain imaging can be used to study how individuals' brains are aging, compared against population norms. This can inform on aspects of brain health; for example, smoking and blood pressure can be seen to accelerate brain aging. Typically, a single 'brain age' is estimated per subject, whereas here we identified 62 modes of subject variability, from 21,407 subjects' multimodal brain imaging data in UK Biobank. The modes represent different aspects of brain aging, showing distinct patterns of functional and structural brain change, and distinct patterns of association with genetics, lifestyle, cognition, physical measures and disease. While conventional brain-age modelling found no genetic associations, 34 modes had genetic associations. We suggest that it is important not to treat brain aging as a single homogeneous process, and that modelling of distinct patterns of structural and functional change will reveal more biologically meaningful markers of brain aging in health and disease.

Kinship Solutions for Partially Observed Multiphenotype Data.

Current work for multivariate analysis of phenotypes in genome-wide association studies often requires that genetic similarity matrices be inverted or decomposed. This can be a computational bottleneck when many phenotypes are presented, each with a different missingness pattern. A usual method in this case is to perform decompositions on subsets of the kinship matrix for each phenotype, with each subset corresponding to the set of observed samples for that phenotype. We provide a new method for decomposing these kinship matrices that can reduce the computational complexity by an order of magnitude by propagating low-rank modifications along a tree spanning the phenotypes. We demonstrate that our method provides speed improvements of around 40% under reasonable conditions.

The spatial correspondence and genetic influence of interhemispheric connectivity with white matter microstructure.

Microscopic features (that is, microstructure) of axons affect neural circuit activity through characteristics such as conduction speed. To what extent axonal microstructure in white matter relates to functional connectivity (synchrony) between brain regions is largely unknown. Using MRI data in 11,354 subjects, we constructed multivariate models that predict functional connectivity of pairs of brain regions from the microstructural signature of white matter pathways that connect them. Microstructure-derived models provided predictions of functional connectivity that explained 3.5% of cross-subject variance on average (ranging from 1-13%, or r = 0.1-0.36) and reached statistical significance in 90% of the brain regions considered. The microstructure-function relationships were associated with genetic variants, co-located with genes DAAM1 and LPAR1, that have previously been linked to neural development. Our results demonstrate that variation in white matter microstructure predicts a fraction of functional connectivity across individuals, and that this relationship is underpinned by genetic variability in certain brain areas.

Genome-wide association studies of brain imaging phenotypes in UK Biobank.

The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid-line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing.

The UK Biobank resource with deep phenotyping and genomic data.

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

Directed functional connectivity using dynamic graphical models.

There are a growing number of neuroimaging methods that model spatio-temporal patterns of brain activity to allow more meaningful characterizations of brain networks. This paper proposes dynamic graphical models (DGMs) for dynamic, directed functional connectivity. DGMs are a multivariate graphical model with time-varying coefficients that describe instantaneous directed relationships between nodes. A further benefit of DGMs is that networks may contain loops and that large networks can be estimated. We use network simulations and human resting-state fMRI (N = 500) to investigate the validity and reliability of the estimated networks. We simulate systematic lags of the hemodynamic response at different brain regions to investigate how these lags potentially bias directionality estimates. In the presence of such lag confounds (0.4-0.8 s offset between connected nodes), our method has a sensitivity of 72%-77% to detect the true direction. Stronger lag confounds have reduced sensitivity, but do not increase false positives (i.e., directionality estimates of the opposite direction). In human resting-state fMRI, the default mode network has consistent influence on the cerebellar, the limbic and the auditory/temporal networks. We also show a consistent reciprocal relationship between the visual medial and visual lateral network. Finally, we apply the method in a small mouse fMRI sample and discover a highly plausible relationship between areas in the hippocampus feeding into the cingulate cortex. We provide a computationally efficient implementation of DGM as a free software package for R.