Alexander Guðjónsson

Icelandic Heart Association

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Vilmundur Guðnason

Icelandic Heart Association

Lenore J. Launer

National Institute on Aging

Valborg Guðmundsdóttir

Icelandic Heart Association

Thor Aspelund

University of Iceland

Valur Emilsson

Icelandic Heart Association

Lori L. Jennings

Novartis (United States)

Elías F. Guðmundsson

Icelandic Heart Association

Brynjolfur G. Jonsson

University of Iceland

Sudha Seshadri

Framingham Heart Study

John R. Lamb

Stanford University

Cooperative Institutions

University of Iceland

Icelandic Heart Association

Harvard University

Boston University

Alzheimer’s Disease Neuroimaging Initiative

The University of Texas Health Science Center at San Antonio

Inserm

Brigham and Women's Hospital

Fundació ACE

Karolinska Institutet

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Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer’s disease

Research Square (Research Square) (2024)

Valborg Guðmundsdóttir Elisabet A. Frick Valur Emilsson Þórarinn Jónmundsson Anna E. Steindorsdottir

Abstract The current demand for early intervention, prevention, and treatment of late onset Alzheimer’s disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n = 5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE-ε4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE-ε4 genotype adjustment, a finding which we replicate in an external cohort (n = 719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE-ε4. Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.

Apolipoprotein E

10.21203/rs.3.rs-3706206/v1

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Antihypertensive medication uses and serum ACE2 levels

medRxiv (Cold Spring Harbor Laboratory) (2020)

Valur Emilsson Elías F. Guðmundsson Thor Aspelund Brynjolfur G. Jonsson Alexander Guðjónsson

Abstract Importance Recent reports have shown that hypertension is the most common comorbidity associated with mortality in the current coronavirus disease 2019 (COVID-19). This has been related to the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) as animal studies indicate that these medications increase levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2. This has prompted clinicians to recommend discontinuing ACEIs and ARBs. Objective To examine the effect of ACEIs or ARBs treatment on serum levels of ACE2 and other key enzymes in the renin-angiotensin system (RAS). Design, Setting, and Participants A single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years) stratified by ACEIs (N = 699) or ARBs (N = 753) treatment. Main Outcomes and Measures The AGES-RS study population was stratified by ACEIs and ARBs medication use and compared for age, body mass index (BMI) (kg/m 2 ), hypertension and type 2 diabetes (T2D) as well as serum levels of renin, ACE and ACE2. Results While renin and ACE levels were significantly raised in serum of individuals on ACEIs or ARBs treatments, the ACE2 levels remained unaffected. Conclusions and Relevance Treatment with ACEIs or ARBs does not raise ACE2 levels in serum. Therefore, the present study does not support the proposed discontinuation of these medications among patients affected with COVID-19. Key Points Question Does treatment with the antihypertensive medications angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) result in elevated levels of the cellular receptor for the coronavirus SARS-CoV-2, ACE2? Findings In a single center population-based cohort (AGES-RS), 699 and 753 individuals were either on ACEIs or ARBs treatment, respectively. The serum levels of the key enzymes in the renin-angiotensin system (RAS), renin, ACE and ACE2 were measured in 5457 subjects of the AGES-RS and their serum levels in individuals on ACEIs or ARBs treatment compared to those not using these medications. While renin and ACE were significantly raised in serum of ACEIs and ARBs users, the levels of ACE2 remained unaffected. Meaning These results do not support the proposed routine discontinuation of ACEIs or ARBs among patients affected with COVID-19.

Discontinuation

Angiotensin-converting enzyme 2

10.1101/2020.05.21.20108738

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Citations (17)

Author Correction: Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease

Nature Aging (2024)

Elisabet A. Frick Valur Emilsson Þórarinn Jónmundsson Anna E. Steindorsdottir Erik C. B. Johnson

Apolipoprotein E

10.1038/s43587-024-00718-9

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The Proteomic Profile of Interstitial Lung Abnormalities

American Journal of Respiratory and Critical Care Medicine (2022)

G. Axelsson Gunnar Guðmundsson Katherine Pratte Thor Aspelund Rachel K. Putman

Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility–Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20–4.30]; P = 4.28 × 10−67), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13–2.77]; P = 8.01 × 10−40), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11–2.78]; P = 4.01 × 10−36) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning–based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.

10.1164/rccm.202110-2296oc

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A genome-wide association study of serum proteins reveals shared loci with common diseases

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Alexander Guðjónsson Valborg Guðmundsdóttir G. Axelsson Elías F. Guðmundsson Brynjolfur G. Jonsson

Abstract With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,113 independent associations between genetic variants and 2,099 serum proteins, of which 37% are previously unreported. The majority of both cis - and trans -acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein’s genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.

Genome-wide Association Study

Genetic Association

10.1101/2021.07.02.450858

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Citations (1)

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

The American Journal of Human Genetics (2022)

Natalia Trpchevska Maxim B. Freidin Linda Broer Berthe C. Oosterloo Shuyang Yao

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.

Presbycusis

Genome-wide Association Study

10.1016/j.ajhg.2022.04.010

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Citations (44)

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2022)

Natalia Trpchevska Freidin M.B Linda Broer Oosterloo B.C Shaohua Yao

Genome-wide Association Study

Association (psychology)

Genetic Association

10.17615/fg4z-2k83

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A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia.

PubMed (2021)

Bernard Fongang Galit Weinstein Alexander Guðjónsson Aniket Mishra Josh Bis

Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. There have been over 40 genetic loci associated with AD but genome-wide associations (GWA) underlying VaD remain incompletely identified. The proportion of VaD differs across studies based on study-specific definitions. We hypothesize that common forms of dementia (AD, VaD) will share genetic risk factors. We conducted the largest GWAS to date of VaD and examined the genetic overlap with "all-cause dementia" (ACD).A total of 293,544 participants from 9 population-based CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) cohorts, 2 national case-control consortia (ADGC, MEMENTO) and the UKBB contributed 23,986 and 2,935 cases of ACD and VaD, respectively. We ran study-specific analyses adjusting for age, sex, and population structure and meta-analyzed summary statistics using the sample size weighted method implemented in METAL, followed by conditional analyses, fine-mapping and bioinformatic exploration of loci.Genome-wide associations with VaD were identified at the APOE locus and at 5 additional loci. One locus has been previously associated with hippocampal volume, verbal memory and CSF amyloid levels (ASTN2); others were near genes associated with hypertension, diabetes and hyperlipidemia (Figures 1 and 2). In addition to previously identified AD loci, we identified novel variants associated with ACD. VaD-related loci also showed sub-threshold associations with ACD that were congruent in direction of effect, thus suggesting additional biological targets underlying ACD. We will additionally present results of an ongoing multiethnic GWAS and insights from pathway analyses and bioinformatic parsing of the identified loci.Although VaD is the second most common cause of dementia, the identification of associated genetic loci has been hindered by the heterogeneity of its definition, which necessitates a large sample size to reach genome-wide significance. The newly identified loci could provide novel insights into the pathophysiological mechanisms of dementia and point to new prevention and treatment strategies.

Genome-wide Association Study

Genetic Association

Genetic architecture

Vascular dementia

Genetic epidemiology

10.1002/alz.056081

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Coding and regulatory variants are associated with serum protein levels and disease

Nature Communications (2022)

Valur Emilsson Valborg Guðmundsdóttir Alexander Guðjónsson Þórarinn Jónmundsson Brynjolfur G. Jonsson

Abstract Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins’ emerging role as biomarkers and potential causative agents of a wide range of diseases.

Exome

Proteome

10.1038/s41467-022-28081-6

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Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia

JAMA Network Open (2024)

Muralidharan Sargurupremraj Aïcha Soumaré Joshua C. Bis Ida Surakka Tuuli Jürgenson

Importance Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results In 2SMR (summary statistics–based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10 −14 ), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. Conclusions These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

Mendelian Randomization

Stroke

Genome-wide Association Study

Genetic Association

Vascular dementia

10.1001/jamanetworkopen.2024.12824

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Citations (6)