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Giedraitis, VilmantasORCID iD iconorcid.org/0000-0003-3423-2021
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Publications (10 of 61) Show all publications
Shah, S., Henry, A., Roselli, C., Lin, H., Sveinbjornsson, G., Fatemifar, G., . . . Ye, B. (2020). Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nature Communications, 11(1), Article ID 163.
Open this publication in new window or tab >>Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
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2020 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, no 1, article id 163Article in journal (Refereed) Published
Abstract [en]

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2020
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-407649 (URN)10.1038/s41467-019-13690-5 (DOI)000511898900014 ()31919418 (PubMedID)
Funder
AstraZenecaNovo Nordisk
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-03-30Bibliographically approved
Wuttke, M., Li, Y., Li, M., Sieber, K. B., Feitosa, M. F., Gorski, M., . . . Pattaro, C. (2019). A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics, 51(6), 957-972
Open this publication in new window or tab >>A catalog of genetic loci associated with kidney function from analyses of a million individuals
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 957-972Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-387933 (URN)10.1038/s41588-019-0407-x (DOI)000469996900008 ()31152163 (PubMedID)
Funder
AstraZenecaNovo NordiskNIH (National Institute of Health)
Note

Group Authors: Lifelines COHort Study

Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Gregson, J., Kaptoge, S., Bolton, T., Pennells, L., Willeit, P., Burgess, S., . . . Walker, M. (2019). Cardiovascular Risk Factors Associated With Venous Thromboembolism. JAMA cardiology, 4(2), 163-173
Open this publication in new window or tab >>Cardiovascular Risk Factors Associated With Venous Thromboembolism
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2019 (English)In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 4, no 2, p. 163-173Article in journal (Refereed) Published
Abstract [en]

IMPORTANCE: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). OBJECTIVE To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism.

DESIGN, SETTING, AND PARTICIPANTS: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018.

EXPOSURES: A panel of several established cardiovascular risk factors.

MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CND], 25131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI).

RESULTS: Of the 731728 participants from the ERFC. 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers.

CONCLUSIONS AND RELEVANCE: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

Place, publisher, year, edition, pages
AMER MEDICAL ASSOC, 2019
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-379278 (URN)10.1001/jamacardio.2018.4537 (DOI)000459481900014 ()30649175 (PubMedID)
Funder
EU, European Research Council, 268834EU, FP7, Seventh Framework Programme, HEALTH-F2-2012-279233
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-04-04Bibliographically approved
Åhman, H. B., Giedraitis, V., Cedervall, Y., Lennhed, B., Berglund, L., McKee, K., . . . Åberg, A. C. (2019). Dual-Task Performance and Neurodegeneration: Correlations Between Timed Up-and-Go Dual-Task Test Outcomes and Alzheimer's Disease Cerebrospinal Fluid Biomarkers. Journal of Alzheimer's Disease, 71, S75-S83
Open this publication in new window or tab >>Dual-Task Performance and Neurodegeneration: Correlations Between Timed Up-and-Go Dual-Task Test Outcomes and Alzheimer's Disease Cerebrospinal Fluid Biomarkers
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 71, p. S75-S83Article in journal (Refereed) Published
Abstract [en]

Background: Tools to identify individuals at preclinical stages of dementia disorders are needed to enable early interventions. Alterations in dual-task performance have been detected early in progressive neurodegenerative disorders. Hence, dual-task testing may have the potential to screen for cognitive impairment caused by neurodegeneration. Exploring correlations between dual-task performance and biomarkers of neurodegeneration is therefore of interest. Objective: To investigate correlations between Timed Up-and-Go dual-task (TUGdt) outcomes and Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-beta 42 (A beta(42)), total tau (t-tau), and phosphorylated tau (p-tau). Methods: This cross-sectional cohort study included 90 participants (age range 49-84 years) undergoing memory assessment, who were subsequently diagnosed with AD, other dementia disorders, mild cognitive impairment, or subjective cognitive impairment. TUG combined with "Naming Animals" (TUGdt NA) and "Months Backwards" (TUGdt MB), respectively, were used to assess dual-task performance. The number of correct words and time taken to complete the tests were measured. The CSF biomarkers were analysed by ELISA. Spearman's rank correlation was used for analyses between TUGdt outcomes (TUGdt NA and TUGdt MB), and CSF biomarkers, adjusted for age, gender, and educational level. Results: The number of correct words, as well as the number of correct words/10 s during TUGdt NA correlated negatively to CSF t-tau and p-tau. No correlations were found between any time scores and CSF biomarkers. Conclusion: The correlations between TUGdt NA and t-tau and p-tau may indicate that neurodegeneration affects dual-task performance. Longitudinal studies are needed to further explore dual-task testing in screening for cognitive impairment due to neurodegeneration.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, attention, biomarkers, cerebrospinal fluid, dementia, executive function, gait, mild cognitive impairment, subjective cognitive impairment
National Category
Geriatrics
Identifiers
urn:nbn:se:uu:diva-395565 (URN)10.3233/JAD-181265 (DOI)000487075000010 ()31104024 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved
Kunkle, B. W., Giedraitis, V., Kilander, L., Brundin, R., Lannfelt, L., Ingelsson, M. & Pericak-Vance, M. A. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature Genetics, 51(3), 414-430
Open this publication in new window or tab >>Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 414-430Article in journal (Refereed) Published
Abstract [en]

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A beta processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 x 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379343 (URN)10.1038/s41588-019-0358-2 (DOI)000459947200011 ()30820047 (PubMedID)
Note

For complete list of authors see http://dx.doi.org/10.1038/s41588-019-0358-2

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Teumer, A., Li, Y., Ghasemi, S., Prins, B. P., Wuttke, M., Hermle, T., . . . Koettgen, A. (2019). Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nature Communications, 10, Article ID 4130.
Open this publication in new window or tab >>Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 4130Article in journal (Refereed) Published
Abstract [en]

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n =192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-394955 (URN)10.1038/s41467-019-11576-0 (DOI)000485216900016 ()31511532 (PubMedID)
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved
Emami Khoonsari, P., Shevchenko, G., Herman, S., Remnestal, J., Giedraitis, V., Brundin, R., . . . Kultima, K. (2019). Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers. Journal of Alzheimer's Disease, 67(2), 639-651
Open this publication in new window or tab >>Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 2, p. 639-651Article in journal (Refereed) Published
Abstract [en]

Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable.

Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.

Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, cerebrospinal fluid, ELISA, mass spectrometry, mild cognitive impairment, proteomics
National Category
Neurology Geriatrics
Identifiers
urn:nbn:se:uu:diva-377711 (URN)10.3233/JAD-180855 (DOI)000457779300016 ()30614806 (PubMedID)
Funder
VINNOVAGun och Bertil Stohnes StiftelseÅke Wiberg FoundationStiftelsen Gamla Tjänarinnor
Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-04-29Bibliographically approved
Danielsson, M., Halvardson, J., Davies, H., Moghadam, B. T., Mattisson, J., Rychlicka-Buniowska, E., . . . Forsberg, L. A. (2019). Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals. European Journal of Human Genetics
Open this publication in new window or tab >>Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed) Epub ahead of print
Abstract [en]

Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.

National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397754 (URN)10.1038/s41431-019-0533-z (DOI)31654039 (PubMedID)
Note

These authors contributed equally: Jan P. Dumanski, Lars A. Forsberg

Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2019-11-25Bibliographically approved
Forsberg, L. A., Halvardson, J., Rychlicka-Buniowska, E., Danielsson, M., Moghadam, B. T., Mattisson, J., . . . Dumanski, J. P. (2019). Mosaic loss of chromosome Y in leukocytes matters [Letter to the editor]. Nature Genetics, 51(1), 4-7
Open this publication in new window or tab >>Mosaic loss of chromosome Y in leukocytes matters
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 4-7Article in journal, Letter (Other academic) Published
National Category
Medical Genetics Genetics
Identifiers
urn:nbn:se:uu:diva-373366 (URN)10.1038/s41588-018-0267-9 (DOI)000454108800004 ()30374072 (PubMedID)
Funder
EU, European Research CouncilSwedish Research Council
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Justice, A. E., Giedraitis, V., Gustafsson, S., Ingelsson, E., Lind, L., Wallentin, L. & Lindgren, C. M. (2019). Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics, 51(3), 452-469
Open this publication in new window or tab >>Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 452-469Article in journal (Refereed) Published
Abstract [en]

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379344 (URN)10.1038/s41588-018-0334-2 (DOI)000459947200014 ()30778226 (PubMedID)
Funder
NIH (National Institute of Health), 1K99HL130580NIH (National Institute of Health), R01-DK089256NIH (National Institute of Health), 2R01HD057194NIH (National Institute of Health), U01HG007416NIH (National Institute of Health), R01DK101855NIH (National Institute of Health), T32 HL007055NIH (National Institute of Health), KL2TR001109
Note

For complete list of authors see http://dx.doi.org/10.1038/s41588-018-0334-2

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-3423-2021

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