Cornelia M van Duijn

BackgroundUncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.MethodsWe performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta …

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism–. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases–. Here we present a genome-wide association study of 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 predominantly population-based cohorts. We discover over 400 independent loci and assign likely causal genes at two-thirds of these using detailed manual curation of highly plausible biological candidates. We highlight the importance of sample- and participant characteristics, such as fasting status and sample type, that can have significant impact on genetic associations, revealing direct and indirect associations on glucose and phenylalanine. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing for the first time the metabolic associations of an understudied phenotype, intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetoacetate and hypertension. Our publicly available results …

Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N= 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P< 5x10− 8) for BP traits, including 113 novel loci. These associations explain~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p= 9.08× 10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P= 9.71× 10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI= 0.781–0.801) to 0.814 (95% CI= 0.805–0.824,∆ AUC= 0.023, P= 2.27 x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.

Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) using large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization (MR) study by selecting instrumental variables for the abundance of over 2,700 proteins measured by either Olink or SomaScan platforms in plasma from UK Biobank and the deCODE Health Study. We also used the latest publicly-available GWAS for the diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 10,244 protein-disease associations, identifying 122 associations which were statistically significant (5% false discovery rate). Out of 57 associations (58%) tested using an instrumental variable from both Olink and SomaScan platforms, 33 (58%) were statistically significant in both platforms. Evidence of co-localisation between plasma protein abundance and disease risk (posterior probability >0.80) was identified for 46 protein-disease pairs. Twenty-three out of 46 protein-disease associations correspond to genetic loci not previously reported by genome-wide association studies. The newly-associated proteins for AD are involved in complement (C1S, C1R), microglia (SIRPA, PRSS8) and lysosomal functions (CLN5). A protein newly-associated with PD (CTF1) is involved in the interleukin-6 pathway, two proteins for …

Purpose: Glaucoma is an eye disease that is the most common cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro-inflammatory cytokines that may travel from the gastric mucosa to distal sites, for example, the optic nerve head or trabecular meshwork. There is evidence for a gut-eye axis, as microbial dysbiosis has been associated with retinal diseases. We investigated the microbial composition in patients with glaucoma and healthy controls. Moreover, we analyzed the association of the gut microbiome with intraocular pressure (IOP; risk factor of glaucoma) and vertical cup-to-disc ratio (VCDR; quantifying glaucoma severity).Methods: The discovery analyses included participants of the Rotterdam Study and the Erasmus Glaucoma Cohort. A total of 225 patients with glaucoma and 1247 age-and sex-matched participants without glaucoma were included in our analyses. Stool samples were used to generate 16S rRNA gene profiles. We assessed associations with 233 genera and species. We used data from the TwinsUK and the Study of Health in Pomerania (SHIP) to replicate our findings.Results: Several butyrate-producing taxa (eg Butyrivibrio, Caproiciproducens, Clostridium sensu stricto 1, Coprococcus 1, Ruminococcaceae UCG 007, and Shuttleworthia) were less abundant in people with glaucoma compared to healthy controls. The same taxa were also associated with lower IOP and smaller VCDR. The replication analyses confirmed the findings from the discovery analyses.Conclusions: Large human studies exploring the link between the gut microbiome and …

Objective: Whether or not Brain Care Score (BCS) components are associated with longitudinal changes in mood disorders is not clear. For this study, we tested the hypothesis that the BCS also significantly correlates to late-life depression incidence in the UKB. Background: The 21-point BCS, developed via a modified Delphi process with practitioners and patients, is a novel instrument designed to motivate behavioral and lifestyle changes, ultimately aiming to decrease incidence of dementia and stroke Design/Methods: The BCS was derived from UKB participants (using both the hospital and general practitioners cohort) aged 40–69 years, at baseline (2006–2010). After excluding patients with prevalent psychiatric disorders, we performed multivariable Cox proportional hazard regression models between the BCS and risk of incident late-life depression, adjusting for sex and stratified by age groups (< 50, 50–59,> …

Aims/Purpose: Glaucoma is an eye disease that is the commonest cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro‐inflammatory cytokines that may travel from the gastric mucosa to distal sites, such as the optic nerve head or trabecular meshwork. There is evidence for a gut‐eye axis, as microbial dysbiosis has been associated with retinal diseases. Here, we investigated the association between glaucoma prevalence and the gut microbiome. Moreover, we analysed the association of the gut microbiome with intraocular pressure (IOP; risk factor of glaucoma) and vertical cup‐to‐disc ratio (VCDR; quantifying glaucoma severity). Methods: The discovery analyses included participants of the Rotterdam Study and the Erasmus Glaucoma Cohort. A total of 225 glaucoma patients were matched on age and sex with 1247 participants …

Introduction: The 21-point Brain Care Score (BCS), developed via a modified Delphi process with practitioners and patients, is a novel instrument designed to motivate behavioral and lifestyle changes, ultimately aiming to decrease incidence of dementia and stroke (Fig 1). Whether or not BCS components are associated with longitudinal changes in mood disorders is not clear. For this study, we tested the hypothesis that the BCS also significantly correlates to late-life depression incidence in the UK Biobank (UKB). Design / Methods: The BCS was derived from UKB participants (using both the hospital and general practitioners cohort) aged 40-69 years, at baseline (2006-2010). After excluding patients with prevalent psychiatric disorders, we performed multivariable Cox proportional hazard regression models between the BCS and risk of incident late-life depression, adjusting for sex and stratified by age groups …

Trimethylamine N‐oxide (TMAO) is a circulating microbiome‐derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO‐to‐precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in‐depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome‐wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3 …

The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by motivating lifestyle changes (Fig 1). In this study we aimed to assess if the BCS is also associated with brain changes on MRI in people who have not yet developed dementia or stroke. Methods: This study was conducted within the MRI substudy of the longitudinal cohort study UK Biobank. The assessed MRI neuroimaging markers included: brain volume, white matter hyperintensities (WMH) volume, fractional anisotropy (FA) and mean diffusivity (MD). FA/MD metrics were calculated as the average across 48 discrete brain regions. We used multivariable linear regression to test for association between the BCS computed using baseline data (2006-2010) and neuroimaging markers, measured both during first (2014+) and repeat (2019+) MRI assessments …

IntroductionBlood pressure (BP) is a highly heritable trait with over 2000 underlying genomic loci identified to date. Although the kidney plays a key role, little is known about specific cell types involved in the genetic regulation of BP.MethodsHere, we applied stratified linkage disequilibrium score (LDSC) regression to connect BP genome-wide association studies (GWAS) results to specific cell types of the mature human kidney. We used the largest single-stage BP genome-wide analysis to date, including up to 1,028,980 adults of European ancestry, and single-cell transcriptomic data from 14 mature human kidneys, with mean age of 41 years.ResultsOur analyses prioritized myofibroblasts and endothelial cells, among the total of 33 annotated cell type, as specifically involved in BP regulation (P < 0.05/33, i.e., 0.001515). Enrichment of heritability for systolic BP (SBP) was observed in myofibroblast cells in mature …

BackgroundSmoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS).MethodsWe meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina's EPIC array for current smoking (2560 exposed), quit < 1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C).FindingsUsing false discovery rate (FDR < 0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs …

The Brain Health crisis stands as one of humankind’s most pressing threats, with age-related noncommunicable brain diseases, particularly stroke, and dementia, affecting hundreds of millions annually and jeopardizing the economic well-being of populations worldwide. Epidemiological studies indicate that ≈40% of dementia and 60% of stroke cases are attributable to modifiable risk factors. In this Comments and Opinions article, we underscore the pivotal role of blood pressure (BP) control in reducing suffering, enhancing economic well-being, and promoting healthy longevity for populations worldwide. Emphasizing that BP control is crucial for both brain and heart health, it advocates for heightened awareness, positioning hypertension as a primary focus for preventing dementia and stroke with potential global impact. Despite its significance, BP control encounters global challenges, with proportions of the …

Anthropometric traits, measuring body size and shape, are highly heritable and significant clinical risk factors for cardiometabolic disorders. These traits have been extensively studied in genome-wide association studies (GWASs), with hundreds of genome-wide significant loci identified. We performed a whole-exome sequence analysis of the genetics of height, body mass index (BMI) and waist/hip ratio (WHR). We meta-analyzed single-variant and gene-based associations of whole-exome sequence variation with height, BMI, and WHR in up to 22,004 individuals, and we assessed replication of our findings in up to 16,418 individuals from 10 independent cohorts from Trans-Omics for Precision Medicine (TOPMed). We identified four trait associations with single-nucleotide variants (SNVs; two for height and two for BMI) and replicated the LECT2 gene association with height. Our expression quantitative trait locus …

BackgroundIn a substantial subgroup of depressed patients, atypical, energy-related depression symptoms (e.g. increased appetite/weight, hypersomnia, loss of energy) tend to cluster with immuno-metabolic dysregulations (e.g. increased BMI and inflammatory markers). This clustering is proposed to reflect a more homogeneous depression pathology. This study examines to what extent energy-related symptoms are associated and share demographic, lifestyle and clinical characteristics.MethodsData were available from 13,965 participants from eight Dutch cohorts with DSM-5 lifetime major depression assessed by the Lifetime Depression Assessment Self-report (LIDAS) questionnaire. Information on four energy-related depression symptoms were extracted: energy loss, increased appetite, increased weight, and hypersomnia. Tetrachoric correlations between these symptoms, and associations of these …

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein’s heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting …

Radford-Smith and Anthony have raised questions about the validity of the associations we have identified in our study based on 2 main concerns:(1) the time difference between blood sampling and the date of diagnosis of MDD and (2) confounding due to and underlying somatic disease or physical activity. The authors have further raised concerns about including incident cases in the analysis. Regarding the first concern, Radford-Smith and Anthony have incorrectly assumed that we used only hospital-based records to identify MDD cases in our study. We have mentioned very clearly that we used both self-reported depression (field:20126) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision–derived MDD excluding incident cases. Field 20126 is a derived variable from fields 4598, 4609, 4620, 4631, 5375, 5386, 2090, and 2100, 4 which are nearly all questions …

The power of genetic diversity in genome-wide association studies of lipids (vol 600, pg 675, 2021) | Scholarly Publications Skip to main content Universiteit Leiden Leiden University Scholarly Publications Home Submit About Select Collection Search box Graham, SE; Clarke, SL; Wu, KHH; Kanoni, S.; Zajac, GJM; Ramdas, S.; ... ; Stark, K. (2023) The power of genetic diversity in genome-wide association studies of lipids (vol 600, pg 675, 2021) Article / Letter to editor All authors Graham, SE; Clarke, SL; Wu, KHH; Kanoni, S.; Zajac, GJM; Ramdas, S.; Surakka, I.; Ntalla, I.; Vedantam, S.; Winkler, TW; Locke, AE; Marouli, E.; Hwang, MY; Han, S.; Narita, A.; Choudhury, A.; Bentley, AR; Ekoru, K.; Verma, A.; Trivedi, B.; Martin, HC; Hunt, KA; Hui, Q.; Klarin, D.; Zhu, X.; Thorleifsson, G.; Helgadottir, A.; Gudbjartsson, DF; Holm, H.; Olafsson, I.; Akiyama, M.; Sakaue, S.; Terao, C.; Kanai, M.; Zhou, W.; Brumpton, BM; Rasheed, H.; …

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth …

Background Although the pivotal role of apolipoprotein E () in AD has been recognized for three decades, its function in different brain cells is far from understood. Knockout studies of the APOE gene may shed light of the function of ApoE. The aim of the present study was to unravel its function in induced pluripotent stem cell (iPSC) derived microglia. Method We studied two human iPSC‐derived microglia cell cultures, one derived from a healthy control (Bioni010‐C – endogenous genotype apolipoprotein E34 (APOE34)) and one from an AD patient (UKBi011‐A – endogenous genotype APOE44) and their edited isogenic cell‐lines (for UKBi011‐A, APOE22 and APOE33 and for Bioni010‐C, hemizygous due to gene editing, APOE2‐ and APOE3‐ (32971461, 29753274)). Additionally, APOE KO lines were generated from both backgrounds. We performed whole genome transcriptomic (IlluminaTruSequencing) and …