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 …