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Lehtimäki, T.

Publications and source records attributed to Lehtimäki, T..

8 recordsLinked to original sources
bioRxiv2026

Traditional disease risk factors outperform epigenetic clocks as predictors of non-communicable disease morbidity in a middle-aged cohort

DNA methylation-based epigenetic clocks have been highlighted as promising biomarkers of ageing, and they have been shown to robustly predict morbidity and mortality. However, current literature is lacking a formal analysis of the increased prediction accuracy, or the added value, of the epigenetic clocks over traditional risk factors of common chronic diseases. Here, we have compared the most commonly used epigenetic clocks and traditional risk factors as predictors of incidence of ageing-associated non-communicable chronic disease in a 7-to-9-year follow-up in a middle-aged population cohort (n=1108, aged 34 to 49 years at baseline). In our cohort, a statistical model consisting of a combination of traditional risk factors outperforms any model including an epigenetic clock. The added value of epigenetic clock measurements over simple and affordable traditional risk factors should be clearly established, if epigenetic clocks are to be used in clinical settings or as tools of personal health monitoring.

molecular biology↗
bioRxiv2025

Multi-modal choroid plexus pathology in aging and Alzheimer's disease

Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimers disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.

neuroscience↗
bioRxiv2025

Suppression of non-canonical autophagy induces endothelial and cardiac dysfunction

BackgroundWhile roles for canonical autophagy in the pathophysiology of cardiovascular disease have been established, we have limited understanding of the non-canonical functions of autophagy proteins in this context. LC3-asssociated endocytosis (LANDO) is a novel non-canonical function of autophagy proteins, in which LC3 (microtubule-associated protein light chain 3) is conjugated to early endosome membranes using a portion of the canonical autophagy machinery, and functions in the endocytic recycling of several plasma membrane proteins. Here we ask whether perturbation of LANDO can promote cardiovascular pathogenesis. MethodsCardiac and endothelial functions were assessed by echocardiography and flow-mediated dilatation in mice lacking Rubicon (Rubcn-/-) or the WD domain of ATG16L1 (Atg16l1{Delta}WDki), two known effectors of LANDO. Mice with conditional depletion of Rubicon in the endothelial, myeloid and cardiomyocyte compartments were used as well. Three-dimensional murine cardiac vasculature leakiness was investigated by light sheet fluorescence microcopy. Endothelial activation induced by shear stress was characterized in vitro in primary endothelial cells isolated from murine lungs and human aortic endothelial cells. Associations between genetically predicted expression of candidate genes involved in LANDO and human cardiovascular parameters were studied in the Young Finns Study and the UK Biobank. ResultsCompared to littermate controls, young Rubcn-/- and Atg16l1{Delta}WDki mice showed a decrease in cardiac and endothelial functions, as did mice with endothelium-specific deficiency. VEGFR2 recycling to the plasma membrane and nitric oxide pathway during shear stress were disrupted in LANDO-deficient primary murine and human endothelial cells. Proteomic analysis in primary human aortic endothelial cells revealed an upregulation of intracellular hemoglobin subunit alpha (Hb-) upon shear stress, which was blunted when RUBCN was ablated. Genetic expression studies uncovered several candidate genes related to LANDO that correlated with cardiovascular parameters. These included the retromer complex subunit VPS29, disruption of which decreased Hb- expression levels in human endothelial cells. ConclusionsOur data support a pivotal role of non-canonical functions of autophagy proteins in recycling VEGFR2 upon shear stress activation in endothelial cells together with Hb- expression that may contribute to the etiology of cardiovascular diseases.

physiology↗
bioRxiv2022

Methylation status of VTRNA2-1/nc886 is stable across human populations, monozygotic twin pairs and in majority of somatic tissues

Aims and methodsOur aim was to characterise the methylation level of a polymorphically imprinted gene, VTRNA2-1/nc886, in human populations and somatic tissues. We utilised 48 datasets, consisting of >30 different tissues and >30 000 individuals. ResultsWe show that the nc886 methylation status is associated with twin status and ethnic background, but the variation between populations is limited. Monozygotic twin pairs present concordant methylation, while [~]30% of dizygotic twin pairs present discordant methylation in the nc886 locus. The methylation levels of nc886 are uniform across somatic tissues, except in cerebellum and skeletal muscle. ConclusionWe hypothesize that the nc886 imprint is established in the oocyte and that after implantation, the methylation status is stable, excluding a few specific tissues.

molecular biology↗
bioRxiv2019

Multivariate genome-wide association analysis of a cytokine network reveals variants with widespread immune, haematological and cardiometabolic pleiotropy

Cytokines are essential regulatory components of the immune system and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlie them, remain unknown. Here we aimed to identify and characterise genetic variants with pleiotropic effects on cytokines - to do this we performed a multivariate genome-wide association study on a correlation network of 11 circulating cytokines measured in 9,263 individuals. Meta-analysis identified a total of 8 loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. Bayesian colocalisation analysis revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins; on metabolic traits such as lipoprotein and lipid levels; on blood-cell related traits such as platelet count; and on disease traits such as coronary artery disease and type 2 diabetes.

genomics↗
bioRxiv2018

Genetic and environmental perturbations lead to regulatory decoherence

Correlation among traits is a fundamental feature of biological systems. From morphological characters, to transcriptional or metabolic networks, the correlations we routinely observe between traits reflect a shared regulation that remains poorly understood and difficult to study. To address this problem, we developed a new and flexible approach that allows us to identify factors associated with variation in correlation between individuals. Here, we use data from three large human cohorts to study the effects of genetic variation and environmental perturbation on correlations among mRNA transcripts and among NMR metabolites. We first show that environmental exposures (namely, infection and disease) lead to a systematic loss of correlation, which we define as decoherence. Using longitudinal data, we show that decoherent metabolites are better predictors of whether someone will develop metabolic syndrome than metabolites commonly used as biomarkers of this disease. Finally, we show that correlation itself is a trait under genetic control: specifically, we mapped and replicated hundreds of correlation QTLs, which often involve transcription factors or their known target genes. Together, this work furthers our understanding of how and why coordinated biological processes break down, and highlights the role of decoherence in disease emergence.

genomics↗
bioRxiv2018

New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

genomics↗
bioRxiv2017

Consortium genome-wide meta-analysis for childhood dental caries traits

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from 9 contributing centers. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage (imputed to Haplotype Reference Consortium or 1000 Genomes phase 1 version 3 panels) accounting for population stratification. Fixed-effects meta-analysis was performed weighted by inverse standard error. Analysis included up to 19,003 individuals (7,530 affected) for primary teeth and 13,353 individuals (5,875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth (intronic within ALLC, Odds Ratio (OR) 0.85, Effect Allele Frequency (EAF) 0.60, p 4.13e-8) and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, p 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low (h2 of 1% [95% CI: 0%:7%] and 6% [95% CI 0%:13%] for primary and permanent dentitions, respectively) compared to corresponding within-study estimates (h2 of 28%, [95% CI: 9%:48%] and 17% [95% CI:2%:31%]) or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.\n\nAuthor summaryDental caries (tooth decay) is a common disease in children. Previous studies suggest genetic factors alter caries risk, but to date there is a gap of knowledge in identifying which specific genetic variants are responsible. We undertook analysis in a consortium including around 19,000 children and investigated whether any of 8 million common genetic variants were associated with risk of caries in primary (milk) or permanent teeth. If identified, these variants are used as tags to highlight genes which may be involved in a disease. We identified variants in two loci associated with caries status; in the primary (rs1594318) and permanent dentition (rs7738851). The former is intronic in ALLC, a gene with poorly understood function. The latter is an intronic variant within NEDD9, a gene which has several known functions including a role in development of craniofacial structures. To gain a more comprehensive understanding of genetic effects which influence caries larger studies and a better understanding of environmental modifiers or interactions with genetic effects are required.

genetics↗