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1. Saturated and Unsaturated Bone Marrow Lipids Have Distinct Effects on Bone Density and Fracture Risk in Older Adults

Author: Gina N. Woods, Susan K. Ewing, Anne L. Schafer, Vilmundur Gudnason, Sigurdur Sigurdsson, Thomas Lang, Trisha F. Hue, Deborah M. Kado, Eric Vittinghoff, Clifford Rosen, Xiaojuan Li, and Ann V. Schwartz
Subjects: Aged, 80 and over, Male, Endocrinology, Diabetes and Metabolism, Lipids, Article, Fractures, Bone, Absorptiometry, Photon, Bone Density, Bone Marrow, Humans, Spinal Fractures, Female, Orthopedics and Sports Medicine, Aged
Abstract: Greater bone marrow adiposity (BMAT) is associated with lower bone mineral density (BMD) and vertebral fractures; less is known about BMAT composition and bone. We studied BMAT composition and bone outcomes in 465 participants from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. BMAT saturation and unsaturation, measured with magnetic resonance spectroscopy, were defined as the ratio of saturated (1.3 ppm peak) or unsaturated (5.3 ppm peak) lipid to total marrow contents, respectively. At baseline and follow-up visits, spine and hip BMD were assessed with quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) and vertebral fractures were identified with DXA. Incident clinical fractures were identified through medical records for up to 8.8 years of follow-up. Associations between BMAT composition and BMD, bone loss, and fractures were evaluated in adjusted regression models. At baseline, mean ± standard deviation (SD) participant age was 81.7 ± 4.3 years, mean BMAT unsaturation was 3.5% ± 1.0%, and mean saturation was 46.3% ± 7.2% in the full cohort (47.7% women). Each SD increase in BMAT saturation was associated with lower trabecular BMD: -23.6% (spine) and -13.0% (total hip) (all p 0.0001). Conversely, BMAT unsaturation (per SD increase) was associated with higher trabecular BMD: +17.5% (spine) and +11.5% (total hip) (all p 0.001). BMAT saturation (per SD increase) was associated with greater risk for prevalent (odds ratio [OR] 1.46; 95% confidence interval [CI], 1.11-1.92) and incident (OR 1.55; 95% CI, 1.03-2.34) vertebral fracture. BMAT unsaturation (per SD increase) was associated with lower risk for incident vertebral fracture (OR 0.58; 95% CI, 0.38-0.89). In gender stratified analyses, BMAT saturation and unsaturation had opposite associations with incident clinical fracture among men. In general, saturated marrow lipids were associated with worse skeletal outcomes, whereas unsaturated lipids were associated with better outcomes. We recommend that future studies of marrow fat and skeletal health report measurements of saturated and unsaturated marrow lipids, rather than total marrow fat content alone. © 2022 American Society for Bone and Mineral Research (ASBMR).
Published: 2022

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

Author: Alexander Gudjonsson, Valborg Gudmundsdottir, Gisli T. Axelsson, Elias F. Gudmundsson, Brynjolfur G. Jonsson, Lenore J. Launer, John R. Lamb, Lori L. Jennings, Thor Aspelund, Valur Emilsson, and Vilmundur Gudnason
Subjects: Proteomics, Aged, 80 and over, Male, Multidisciplinary, Genome, Human, Science, Quantitative Trait Loci, Iceland, General Physics and Astronomy, General Chemistry, Genomics, Blood Proteins, Quantitative trait, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, Humans, Disease, Female, Genetic Predisposition to Disease, Aged, Genome-Wide Association Study
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 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% 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., Circulating proteins have been linked to many conditions, and understanding their genetic control can lead to understanding of disease. Here, the authors associate common genetic variants with protein levels, finding overlap of genetic associations with circulating proteins and complex disease.
Published: 2022

3. New creatinine- And cystatin C-based equations to estimate GFR without race

Author: Lesley A, Inker, Nwamaka D, Eneanya, Josef, Coresh, Hocine, Tighiouart, Dan, Wang, Yingying, Sang, Deidra C, Crews, Alessandro, Doria, Michelle M, Estrella, Marc, Froissart, Morgan E, Grams, Tom, Greene, Anders, Grubb, Vilmundur, Gudnason, Orlando M, Gutiérrez, Roberto, Kalil, Amy B, Karger, Michael, Mauer, Gerjan, Navis, Robert G, Nelson, Emilio D, Poggio, Roger, Rodby, Peter, Rossing, Andrew D, Rule, Elizabeth, Selvin, Jesse C, Seegmiller, Michael G, Shlipak, Vicente E, Torres, Wei, Yang, Shoshana H, Ballew, Sara J, Couture, Neil R, Powe, Andrew S, Levey, Chronic Kidney Disease Epidemiology Collaboration, Andresdottir, M.B., Gudmundsdottir, H., Indridason, O.S., Palsson, R., Kasiske, B., Weir, M., Pesavento, T., Kalil, R., Feldman, H., Anderson, A., Go, A., Hsu, C.Y., Chapman, A.B., Landsittel, D.P., Mrug, M., Yu, ASL, Steffes, M., Braffett, B.H., Wyatt, C., Krishnasami, Z., Hellinger, J., Abraham, A., Lieske, J.C., Shafi, T., Post, W., Rossing, P., Rossert, J., Stengel, B., Galecki, A., Spino, C., Mauer, M., Karger, A., Zinman, B., Klein, R., Parving, H.H., Looker, H.C., Knowler, W.C., Klintmalm, G.B., Velez, R., Selvin, E., Wang, D., Value, Affordability and Sustainability (VALUE), and Groningen Kidney Center (GKC)
Subjects: Male, Kidney Disease, 030232 urology & nephrology, Datasets as Topic, urologic and male genital diseases, Medical and Health Sciences, GLOMERULAR-FILTRATION-RATE, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, Renal Insufficiency, Chronic, Adult, African Continental Ancestry Group, Aged, Algorithms, Continental Population Groups, Creatinine/blood, Cystatin C/blood, Female, Glomerular Filtration Rate, Humans, Middle Aged, Renal Insufficiency, Chronic/blood, Renal Insufficiency, Chronic/epidemiology, Renal Insufficiency, Chronic/ethnology, Renal Insufficiency, Chronic/physiopathology, United States/epidemiology, CALIBRATION, biology, General Medicine, female genital diseases and pregnancy complications, PREVALENCE, Background current, Creatinine, Lower prevalence, NATIONAL-HEALTH, medicine.medical_specialty, Urology, Renal and urogenital, Renal function, Black People, 03 medical and health sciences, Clinical Research, Diabetes mellitus, General & Internal Medicine, medicine, Cystatin C, Renal Insufficiency, Chronic, SERUM CREATININE, business.industry, Prevention, Racial Groups, Chronic Kidney Disease Epidemiology Collaboration, medicine.disease, Confidence interval, United States, chemistry, biology.protein, business, Kidney disease
Abstract: New Equations for Estimating GFR without Race Equations for estimating GFR with serum creatinine overestimate measured GFR in Blacks. The authors report new equations, without race as an inflation factor, using cystatin C and creatinine that reduced errors in estimation between Black participants and non-Black participants.Background Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct. Methods We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations. Results In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m(2) of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m(2); 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m(2); 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m(2); 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m(2); 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks. Conclusions New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
Published: 2021

4. Soft tissue radiodensity parameters mediate the relationship between self-reported physical activity and lower extremity function in AGES-Reykjavík participants

Author: Sigurdur Sigurdsson, Ugo Carraro, Paolo Gargiulo, Kyle Edmunds, Sarah Lose, Ozioma C. Okonkwo, and Vilmundur Gudnason
Subjects: Male, medicine.medical_specialty, Multivariate statistics, Aging, Sarcopenia, Science, Population, Isometric exercise, Article, Physical medicine and rehabilitation, Risk Factors, Linear regression, medicine, Humans, Computational models, Longitudinal Studies, Prospective Studies, education, Muscle, Skeletal, Exercise, Aged, Aged, 80 and over, education.field_of_study, Multidisciplinary, business.industry, Regression analysis, medicine.disease, Healthy Volunteers, Walking Speed, Ageing, Lower Extremity, Cohort, Medicine, Female, Self Report, business, Tomography, X-Ray Computed, Biomedical engineering
Abstract: Although previous studies have highlighted the association between physical activity and lower extremity function (LEF) in elderly individuals, the mechanisms underlying this relationship remain debated. Our recent work has recognized the utility of nonlinear trimodal regression analysis (NTRA) parameters in characterizing changes in soft tissue radiodensity as a quantitative construct for sarcopenia in the longitudinal, population-based cohort of the AGES-Reykjavík study. For the present work, we assembled a series of prospective multivariate regression models to interrogate whether NTRA parameters mediate the 5-year longitudinal relationship between physical activity and LEF in AGES-Reykjavík participants. Healthy elderly volunteers from the AGES-Reykjavík cohort underwent mid-thigh X-ray CT scans along with a four-part battery of LEF tasks: normal gait speed, fastest-comfortable gait speed, isometric leg strength, and timed up-and-go. These data were recorded at two study timepoints which were separated by approximately 5 years: AGES-I (n = 3157) and AGES-II (n = 3098). Participants in AGES-I were likewise administered a survey to approximate their weekly frequency of engaging in moderate-to-vigorous physical activity (PAAGES-I). Using a multivariate mediation analysis framework, linear regression models were assembled to test whether NTRA parameters mediated the longitudinal relationship between PAAGES-I and LEFAGES-II; all models were covariate-adjusted for age, sex, BMI, and baseline LEF, and results were corrected for multiple statistical comparisons. Our first series of models confirmed that all four LEF tasks were significantly related to PAAGES-I; next, modelling the relationship between PAAGES-I and NTRAAGES-II identified muscle amplitude (Nm) and location (μm) as potential mediators of LEF to test. Finally, adding these two parameters into our PAAGES-I → LEFAGES-II models attenuated the prior effect of PAAGES-I; bootstrapping confirmed Nm and μm as significant partial mediators of the PAAGES-I → LEFAGES-II relationship, with the strongest effect found in isometric leg strength. This work describes a novel approach toward clarifying the mechanisms that underly the relationship between physical activity and LEF in aging individuals. Identifying Nm and μm as significant partial mediators of this relationship provides strong evidence that physical activity protects aging mobility through the preservation of both lean tissue quantity and quality.
Published: 2021

5. Dementia risk in the general population: large-scale external validation of prediction models in the AGES-Reykjavik study

Author: Mirjam I. Geerlings, Vilmundur Gudnason, Lenore J. Launer, Jet M.J. Vonk, and Jacoba P. Greving
Subjects: Male, Aging, medicine.medical_specialty, Epidemiology, Calibration (statistics), Population, Neurodegenerative, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Predictive Value of Tests, Validation, Systematic risk, Acquired Cognitive Impairment, medicine, Humans, Dementia, 030212 general & internal medicine, education, Netherlands, education.field_of_study, business.industry, Prevention, Reproducibility of Results, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's disease, Neuro-Epidemiology, Prognosis, medicine.disease, Brain Disorders, Cognitive test, Clinical trial, Population Surveillance, Neurological, Public Health and Health Services, Female, business, Alzheimer’s disease, 030217 neurology & neurosurgery, Predictive modelling, Demography
Abstract: We aimed to evaluate the external performance of prediction models for all-cause dementia or AD in the general population, which can aid selection of high-risk individuals for clinical trials and prevention. We identified 17 out of 36 eligible published prognostic models for external validation in the population-based AGES-Reykjavik Study. Predictive performance was assessed with c statistics and calibration plots. All five models with a c statistic > .75 (.76–.81) contained cognitive testing as a predictor, while all models with lower c statistics (.67–.75) did not. Calibration ranged from good to poor across all models, including systematic risk overestimation or overestimation for particularly the highest risk group. Models that overestimate risk may be acceptable for exclusion purposes, but lack the ability to accurately identify individuals at higher dementia risk. Both updating existing models or developing new models aimed at identifying high-risk individuals, as well as more external validation studies of dementia prediction models are warranted.
Published: 2021

6. Sex-specific 25-hydroxyvitamin D threshold concentrations for functional outcomes in older adults: PRoject on Optimal VItamin D in Older adults (PROVIDO)

Author: Stephen B. Kritchevsky, Gregory E. Hicks, Tamara B. Harris, Anne R. Cappola, Peggy M. Cawthon, Vilmundur Gudnason, Luigi Ferrucci, Mary Frances Cotch, Gudny Eiriksdottir, Kristine E. Ensrud, Eleanor M. Simonsick, Michelle Shardell, Richard D. Semba, Eric S. Orwoll, Nancy Chiles Shaffer, and Jack M. Guralnik
Subjects: Male, medicine.medical_specialty, Population, Medicine (miscellaneous), 030204 cardiovascular system & hematology, Physical function, vitamin D deficiency, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Internal medicine, medicine, Vitamin D and neurology, Humans, 030212 general & internal medicine, Vitamin D, education, Aged, Aged, 80 and over, education.field_of_study, Nutrition and Dietetics, business.industry, Physical Functional Performance, Vitamin D Deficiency, medicine.disease, Sex specific, Gait, United States, Gait speed, Preferred walking speed, Original Research Communications, Italy, Body Composition, Female, Independent Living, business
Abstract: BACKGROUND: Threshold serum 25-hydroxyvitamin D [25(OH)D] concentrations for extraskeletal outcomes are uncertain and could differ from recommendations (20–30 ng/mL) for skeletal health. OBJECTIVES: We aimed to identify and validate sex-specific threshold 25(OH)D concentrations for older adults’ physical function. METHODS: Using 5 large prospective, population-based studies—Age, Gene/Environment Susceptibility-Reykjavik (n = 4858, Iceland); Health, Aging, and Body Composition (n = 2494, United States); Invecchiare in Chianti (n = 873, Italy); Osteoporotic Fractures in Men (n = 2301, United States); and Study of Osteoporotic Fractures (n = 5862, United States)—we assessed 16,388 community-dwelling adults (10,376 women, 6012 men) aged ≥65 y. We analyzed 25(OH)D concentrations with the primary outcome (incident slow gait: women
Published: 2021

7. [The relationship between lack of educational attainment, cardiovascular risk factors, atherosclerosis and coronary artery disease]

Author: Karl, Andersen, Thor, Aspelund, Elias Freyr, Gudmundsson, Gunnar, Sigurdsson, Sigurdur, Sigurdsson, Gudlaug, Björnsdottir, Bolli, Thorsson, Thordur, Hardarsson, and Vilmundur, Gudnason
Subjects: Male, Cardiovascular Diseases, Heart Disease Risk Factors, Risk Factors, Iceland, Educational Status, Humans, Pneumothorax, Female, General Medicine, Coronary Artery Disease, Atherosclerosis, Plaque, Atherosclerotic
Abstract: INTRODUCTION: Educational attainment is related to improved health and longevity. We investigated the relationship between educational attainment and cardiovascular risk factors, subclinical atherosclerosis, and incidence of coronary artery disease. MATERIAL AND METHODS: The Reykjavik REFINE study is a population-based study recruiting 6616 subjects, 25-69 years of age from the greater Reykjavik area in 2005-2011. Baseline measurements of cardiovascular risk factors were performed, and all participants had a carotid ultrasound examination to detect subclinical atherosclerotic lesions. Clinical follow-up of cardiovascular disease during a ten-year period was performed. Educational attainment was related to clinical outcome measures. RESULTS: The study population comprised of 3251 men and 3365 women. The proportion of the study population with primary school education only was 20.1%, 31.2% had vocational training, 12.3% had high school education and 36.4% were university graduates. Traditional cardiovascular risk factors were generally higher among subjects with primary school education only. Compared to subjects with university education, the odds ratio of having severe atherosclerotic plaque was 1.84 (95% CI 1.40-2.43) among those with primary school education only and 1.49 (95% CI 1.16-1.91) among subjects with vocational training. The subjects with high school or university education were less likely to develop significant cardiovascular disease during the 10-year follow-up period. CONCLUSION: Primary school and vocational training compared to university education are associated with risk factors of atherosclerotic disease, subclinical carotid plaque, and incidence of cardiovascular disease. The reason for this disparity remains to be clarified but socioeconomic inequality related to less educational attainment might be involved
Published: 2022

8. Diffuse idiopathic skeletal hyperostosis in elderly Icelanders and its association with the metabolic syndrome: the AGES-Reykjavik Study

Author: Halldór Jónsson, E Steingrímsson, Vilmundur Gudnason, Sigurdur Sigurdsson, Thor Aspelund, L. J. Launer, A B Auðunsson, and G.J. Eliasson
Subjects: Male, Pediatrics, medicine.medical_specialty, common, Immunology, Iceland, Large population, Comorbidity, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Prevalence, medicine, Icelanders, Humans, Immunology and Allergy, 030212 general & internal medicine, Aged, Diffuse Idiopathic Skeletal Hyperostosis, Aged, 80 and over, Metabolic Syndrome, 030203 arthritis & rheumatology, Hyperostosis, Diffuse Idiopathic Skeletal, business.industry, General Medicine, medicine.disease, humanities, common.group, Female, Metabolic syndrome, Tomography, X-Ray Computed, business
Abstract: OBJECTIVES: To describe the prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in a large population-based study of elderly Icelanders, with particular reference to weight related factors and the metabolic syndrome. METHODS: The study population comprised 5321 participants aged 68–96 (2276 males mean age 76(5) and 3045 females mean age 77(6)) from the AGES-Reykjavik Study. DISH diagnosis was based on CT scans, and interpreted strictly by the Resnick criteria and additional suggestions for CT interpretation by Oudkerk et al. Radiology readings were done by a radiology resident with sample readings by two experienced radiologists. RESULTS: A diagnosis of DISH was made in 13.7% of males and 2.8% of females. There was no association with age, but a strong association was seen with the metabolic syndrome (OR 2.12 (1.69–2.64), p=3,9×10(−11)). Among the components of the metabolic syndrome the association with DISH was significant for the insulin resistance criterion, (OR 1.66 (1.32–2.01), p
Published: 2021

9. Associations of ω-3 Fatty Acids With Interstitial Lung Disease and Lung Imaging Abnormalities Among Adults

Author: Gunnar Gudmundsson, Brian T. Steffen, Steven M. Kawut, Josée Dupuis, Elias F Gudmundsson, Michael Y. Tsai, Hanfei Xu, Eric A. Hoffman, Vilmundur Gudnason, Ganesh Raghu, John S. Kim, George T. O'Connor, David J. Lederer, Gary M. Hunninghake, Imre Noth, Erin D. Michos, Rachel A. Murphy, Gisli Thor Axelsson, R. Graham Barr, William S. Harris, Anna J. Podolanczuk, and Ramachandran S. Vasan
Subjects: Male, medicine.medical_specialty, Epidemiology, Population, Lower risk, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, Risk Factors, Internal medicine, Fatty Acids, Omega-3, medicine, Humans, 030212 general & internal medicine, education, Aged, Aged, 80 and over, chemistry.chemical_classification, education.field_of_study, business.industry, Hazard ratio, Interstitial lung disease, Original Contribution, Odds ratio, Middle Aged, medicine.disease, Hospitalization, Epidemiologic Studies, Cross-Sectional Studies, 030228 respiratory system, chemistry, Docosahexaenoic acid, Fatty Acids, Unsaturated, Female, Lung Diseases, Interstitial, Tomography, X-Ray Computed, business, Polyunsaturated fatty acid
Abstract: Docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, attenuates interstitial lung disease (ILD) in experimental models, but human studies are lacking. We examined associations of circulating levels of DHA and other polyunsaturated fatty acids with hospitalization and death due to ILD over 12 years in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6,573). We examined cross-sectional associations with CT lung abnormalities in MESA (2000–2012; n = 6,541), the Framingham Heart Study (2005–2011; n = 3,917), and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) (2002–2006; n = 1,106). Polyunsaturated fatty acid levels were determined from fasting blood samples and extracted from plasma phospholipids (MESA and AGES-Reykjavik) or red blood cell membranes (Framingham Heart Study). Higher DHA levels were associated with a lower risk of hospitalization due to ILD (per standard-deviation increment, adjusted rate ratio = 0.69, 95% confidence interval (CI): 0.48, 0.99) and a lower rate of death due to ILD (per standard-deviation increment, adjusted hazard ratio = 0.68, 95% CI: 0.47, 0.98). Higher DHA was associated with fewer interstitial lung abnormalities on computed tomography (per natural log increment, pooled adjusted odds ratio = 0.65, 95% CI: 0.46, 0.91). Higher DHA levels were associated with a lower risk of hospitalization and death due to ILD and fewer lung abnormalities on computed tomography in a meta-analysis of data from population-based cohort studies.
Published: 2020

10. Bone density and strength from thoracic and lumbar CT scans both predict incident vertebral fractures independently of fracture location

Author: Elizabeth J. Samelson, Dennis E. Anderson, Brett T. Allaire, David L. Kopperdahl, Mary L. Bouxsein, Douglas P. Kiel, Fjola Johannesdottir, Vilmundur Gudnason, Miriam A. Bredella, Tony M. Keaveny, and Sigurdur Sigurdsson
Subjects: musculoskeletal diseases, Male, 0301 basic medicine, Thorax, medicine.medical_specialty, Bone density, Endocrinology, Diabetes and Metabolism, Osteoporosis, Population, 030209 endocrinology & metabolism, Article, 03 medical and health sciences, 0302 clinical medicine, Lumbar, Bone Density, Humans, Medicine, education, Aged, Aged, 80 and over, Bone mineral, education.field_of_study, Lumbar Vertebrae, business.industry, medicine.disease, Case-Control Studies, Orthopedic surgery, Fracture (geology), Spinal Fractures, Female, 030101 anatomy & morphology, Tomography, X-Ray Computed, business, Nuclear medicine
Abstract: In a population-based study, we found that computed tomography (CT)-based bone density and strength measures from the thoracic spine predicted new vertebral fracture as well as measures from the lumbar spine, suggesting that CT scans at either the thorax or abdominal regions are useful to assess vertebral fracture risk. Prior studies have shown that computed tomography (CT)-based lumbar bone density and strength measurements predict incident vertebral fracture. This study investigated whether CT-based bone density and strength measurements from the thoracic spine predict incident vertebral fracture and compared the performance of thoracic and lumbar bone measurements to predict incident vertebral fracture. This case-control study of community-based men and women (age 74.6 ± 6.6) included 135 cases with incident vertebral fracture at any level and 266 age- and sex-matched controls. We used baseline CT scans to measure integral and trabecular volumetric bone mineral density (vBMD) and vertebral strength (via finite element analysis, FEA) at the T8 and L2 levels. Association between these measurements and vertebral fracture was determined by using conditional logistic regression. Sensitivity and specificity for predicting incident vertebral fracture were determined for lumbar spine and thoracic bone measurements. Bone measurements from T8 and L2 predicted incident vertebral fracture equally well, regardless of fracture location. Specifically, for predicting vertebral fracture at any level, the odds ratio (per 1-SD decrease) for the vBMD and strength measurements at L2 and T8 ranged from 2.0 to 2.7 (p
Published: 2020

11. Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes

Author: William S. Harris, Jason H Y Wu, Matti Uusitupa, Barbara McKnight, Tomi-Pekka Tuomainen, Amanda M. Fretts, Qi Sun, Julie K. Bassett, Allison M. Hodge, Fumiaki Imamura, Rozenn N. Lemaitre, David S. Siscovick, Hung-Ju Lin, Nona Sotoodehnia, Michael Y. Tsai, Lynne E. Wagenknecht, Kalina Rajaobelina, Kuo-Liong Chien, Sabita S. Soedamah-Muthu, Renata Micha, Liana C Del Gobbo, Rachel A. Murphy, Markku Laakso, Dariush Mozaffarian, Albert Koulman, Nita G. Forouhi, Ulf Risérus, Graham G. Giles, Janette de Goede, Andres V Ardisson Korat, Nathan L. Tintle, Nicholas J. Wareham, Waqas Qureshi, Johanna M. Geleijnse, Maria Lankinen, Mackenzie K Senn, Cécilia Samieri, Lars Lind, Wei-Sin Yang, Yun-yu Chen, Frank B. Hu, Matti Marklund, Jyrki K. Virtanen, Alexis C. Wood, Vilmundur Gudnason, Tzu-An Chen, Chaoyu Yu, Luc Djoussé, Jennifer G. Robinson, Catherine Helmer, Kerry L. M. Wong, Ingeborg A. Brouwer, Medical and Clinical Psychology, Imamura, Fumiaki [0000-0002-6841-8396], Marklund, Matti [0000-0002-3320-796X], Ardisson Korat, Andres V [0000-0003-4599-2245], Lankinen, Maria [0000-0002-9158-283X], Qureshi, Waqas [0000-0002-5189-4417], Wong, Kerry [0000-0002-4400-2257], Bassett, Julie K [0000-0003-0799-4821], Tintle, Nathan [0000-0003-1447-9107], Brouwer, Ingeborg A [0000-0002-8762-382X], Chien, Kuo-Liong [0000-0003-4979-8351], Chen, Yun-Yu [0000-0001-7009-7838], Wood, Alexis C [0000-0001-7616-2119], Geleijnse, Johanna M [0000-0001-7638-0589], Giles, Graham G [0000-0003-4946-9099], de Goede, Janette [0000-0002-6174-0681], Gudnason, Vilmundur [0000-0001-5696-0084], Harris, William S [0000-0003-3042-9353], Hodge, Allison [0000-0001-5464-2197], Koulman, Albert [0000-0001-9998-051X], McKnight, Barbara [0000-0002-3180-666X], Riserus, Ulf [0000-0002-8620-4586], Samieri, Cecilia [0000-0001-9809-7506], Senn, Mackenzie [0000-0002-0298-8142], Siscovick, David S [0000-0003-0461-175X], Soedamah-Muthu, Sabita S [0000-0002-8830-3502], Sun, Qi [0000-0002-8480-1563], Tuomainen, Tomi-Pekka [0000-0002-1949-3787], Wareham, Nick J [0000-0003-1422-2993], Wu, Jason HY [0000-0003-2073-3562], Micha, Renata [0000-0002-3983-1632], Mozaffarian, Dariush [0000-0001-7958-9492], Forouhi, Nita G [0000-0002-5041-248X], Apollo - University of Cambridge Repository, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Health Sciences, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Ardisson Korat, Andres V. [0000-0003-4599-2245], Bassett, Julie K. [0000-0003-0799-4821], Brouwer, Ingeborg A. [0000-0002-8762-382X], Chen, Yun-yu [0000-0001-7009-7838], Wood, Alexis C. [0000-0001-7616-2119], Geleijnse, Johanna M. [0000-0001-7638-0589], Giles, Graham G. [0000-0003-4946-9099], Harris, William S. [0000-0003-3042-9353], Siscovick, David S. [0000-0003-0461-175X], Soedamah-Muthu, Sabita S. [0000-0002-8830-3502], Wareham, Nick J. [0000-0003-1422-2993], Wu, Jason H. Y. [0000-0003-2073-3562], and Forouhi, Nita G. [0000-0002-5041-248X]
Subjects: Male, Nutrition and Disease, Physiology, Type 2 diabetes, 030204 cardiovascular system & hematology, Biochemistry, LEHA, Geographical locations, 0302 clinical medicine, Endocrinology, Mathematical and Statistical Techniques, Voeding en Ziekte, Medicine and Health Sciences, Macromolecular Structure Analysis, Medicine, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Human Nutrition & Health, 2. Zero hunger, chemistry.chemical_classification, RISK, Lipid Analysis, PLASMA, Incidence (epidemiology), Incidence, Fatty Acids, Statistics, Humane Voeding & Gezondheid, General Medicine, ASSOCIATION, Middle Aged, Metaanalysis, Lipids, CANCER, 3. Good health, Type 2 Diabetes, ADIPOSE-TISSUE, BETA-CELL TURNOVER, Lipogenesis, Physical Sciences, Endokrinologi och diabetes, COFFEE CONSUMPTION, Female, Metabolic Networks and Pathways, Research Article, Endocrine Disorders, BIOMARKERS, Endocrinology and Diabetes, Research and Analysis Methods, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, Diabetes Mellitus, Life Science, Humans, CORONARY-HEART-DISEASE, Statistical Methods, Molecular Biology, Aged, VLAG, business.industry, Fatty acid, Biology and Life Sciences, medicine.disease, United States, PHOSPHOLIPIDS, Human nutrition, Metabolism, chemistry, Diabetes Mellitus, Type 2, Metabolic Disorders, North America, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, People and places, business, Dyslipidemia, Mathematics
Abstract: Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D., Fumiaki Imamura and colleagues investigate the association between concentrations of fatty acid involved in de-novo lipogensis and incidence of Type 2 diabetes., Author summary Why was this study done? De novo lipogenesis (DNL) is a metabolic pathway involved in the endogenous synthesis of specific fatty acids, such as 16:0, 16:1n7, 18:0, and 18:1n9, and it is linked to the pathophysiology of cardiometabolic diseases, including type 2 diabetes (T2D). Circulating or tissue concentrations of these fatty acids have been investigated for the associations with T2D incidence in epidemiological research. However, published studies reported inconsistent associations inconsistently and were subject to publication bias. Summary evidence is not available to date for the associations between these fatty acids and T2D incidence. An integration of available cohort studies would increase statistical power and allow assessment of generalizability, standardization of analytical strategies, and evidence synthesis with the potential publication bias minimized. What did the researchers do and find? As a part of the Fatty Acids and Outcomes Research Consortium (FORCE), we conducted new individual-participant data analyses of 17 cohort studies of a total of 65,225 adults free of T2D at baseline, among whom 15,383 developed incident T2D over up to 20 years of follow-up. The cohort studies analyzed the associations between fatty acids (16:0, 16:1n7, 18:0, and 18:1n9) and the risk of developing T2D with standardized analytic strategy. In pooled analyses, each of the fatty acids was positively associated with a higher risk of developing T2D. The associations were independent of major risk factors for T2D, such as age, sex, race/ethnicity, socioeconomic characteristics, smoking status, physical activity, and obesity. What do these findings mean? The findings provide the first summary evidence to date for the positive relationships of concentrations of the DNL-related fatty acids with a risk of T2D, indicating the strong relevance of DNL and its determinants to the development of T2D. These fatty acids potentially reflect the status of DNL activity, which may be stimulated or suppressed by a combination of carbohydrate intake, alcohol intake, polyunsaturated fatty acid intake, and other lifestyle and clinical factors. Therefore, the current findings indicate the need for investigation into determinants and consequences of elevated concentrations of these fatty acids. Despite several advantages of our individual-level data analysis in this pooling project, the results cannot establish whether elevated concentrations of these fatty acids caused the development of T2D or whether underlying peripheral or hepatic insulin resistance, for example, may elevate both the fatty acid concentrations and the risk of T2D independently.
Published: 2020

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

Author: Valur Emilsson, Valborg Gudmundsdottir, Alexander Gudjonsson, Thorarinn Jonmundsson, Brynjolfur G. Jonsson, Mohd A. Karim, Marjan Ilkov, James R. Staley, Elias F. Gudmundsson, Lenore J. Launer, Jan H. Lindeman, Nicholas M. Morton, Thor Aspelund, John R. Lamb, Lori L. Jennings, Vilmundur Gudnason, Emilsson, Valur [0000-0001-9982-0524], Gudmundsdottir, Valborg [0000-0002-7459-1603], Jonmundsson, Thorarinn [0000-0001-9158-0087], Gudmundsson, Elias F [0000-0002-7661-4872], Launer, Lenore J [0000-0002-3238-7612], Morton, Nicholas M [0000-0001-8218-8462], Aspelund, Thor [0000-0002-7998-5433], Jennings, Lori L [0000-0001-5130-8417], Gudnason, Vilmundur [0000-0001-5696-0084], and Apollo - University of Cambridge Repository
Subjects: Proteomics, Male, Genotype, Proteome, Science, 631/208/205/2138, 45/43, Iceland, General Physics and Astronomy, 631/45/475, Genome-wide association studies, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 82/80, Prognostic markers, 692/53/2422, Humans, Disease, Exome, Genetic Predisposition to Disease, Aged, Multidisciplinary, article, General Chemistry, Blood Proteins, Female
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., Finding the genetic basis of protein expression can elucidate the genetic mechanisms of disease. Here, the authors link low-frequency and common DNA sequence variants to thousands of serum proteins, finding genetic overlap between circulating proteins and a wide range of common diseases.
Published: 2022

13. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Università degli Studi di Ferrara (UniFE), Boston University [Boston] (BU), VU University Medical Center [Amsterdam], University of Bristol [Bristol], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Imperial College London, Karolinska Institutet [Stockholm], Institute for Molecular Bioscience, University of Queensland [Brisbane], Statens Serum Institut [Copenhagen], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, National Institute on Aging [Baltimore, MD, USA] (NIH), University of Michigan [Ann Arbor], University of Michigan System, University of Maryland School of Medicine, University of Maryland System, The University of Western Australia (UWA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Wake Forest University, National Institute for Health and Welfare [Helsinki], The Wellcome Trust Sanger Institute [Cambridge], University of Iceland [Reykjavik], University of Washington [Seattle], University of Groningen [Groningen], University of Glasgow, William Harvey Research Institute, Barts and the London Medical School, Université de Lausanne (UNIL), deCODE genetics [Reykjavik], Northwestern University Feinberg School of Medicine, Uppsala Universitet [Uppsala], University of Edinburgh, Medical Faculty [Mannheim], University of Graz, Ludwig-Maximilians-Universität München (LMU), Johannes Gutenberg - Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Hannover Medical School [Hannover] (MHH), Universität zu Lübeck [Lübeck], University of Exeter, Regeneron Pharmaceuticals [Tarrytown], University of Adelaide, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard T.H. Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. [0000-0001-7824-2569], McLachlan, Stela [0000-0003-0480-6143], Egan, Josephine [0000-0002-8945-0053], Hicks, Andrew A. [0000-0001-6320-0411], Thorand, Barbara [0000-0002-8416-6440], Hingorani, Aroon [0000-0001-8365-0081], Kivimaki, Mika [0000-0002-4699-5627], Koistinen, Heikki A. [0000-0001-7870-070X], Bakker, Stephan J. L. [0000-0003-3356-6791], Palmer, Colin N. A. [0000-0002-6415-6560], Jukema, J. Wouter [0000-0002-3246-8359], Sattar, Naveed [0000-0002-1604-2593], Snieder, Harold [0000-0003-1949-2298], Magnusson, Patrik K. [0000-0002-7315-7899], Blüher, Matthias [0000-0003-0208-2065], Wolffenbuttel, Bruce H. R. [0000-0001-9262-6921], Abecasis, Goncalo R. [0000-0003-1509-1825], Meigs, James B. [0000-0002-2439-2657], Wilson, James F. [0000-0001-5751-9178], Schwarz, Peter E. H. [0000-0001-6317-7880], Boehm, Bernhard O. [0000-0002-2706-7710], Metspalu, Andres [0000-0002-3718-796X], Deloukas, Panos [0000-0001-9251-070X], Körner, Antje [0000-0001-6001-0356], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Männistö, Satu [0000-0002-8668-3046], Franks, Paul W. [0000-0002-0520-7604], Hayward, Caroline [0000-0002-9405-9550], Vitart, Veronique [0000-0002-4991-3797], Kaprio, Jaakko [0000-0002-3716-2455], Visvikis-Siest, Sophie [0000-0001-8104-8425], Altshuler, David [0000-0002-7250-4107], Rudan, Igor [0000-0001-6993-6884], van Duijn, Cornelia M. [0000-0002-2374-9204], Pramstaller, Peter P. [0000-0002-9831-8302], Boehnke, Michael [0000-0002-6442-7754], Frayling, Timothy M. [0000-0001-8362-2603], Peyser, Patricia A. [0000-0002-9717-8459], Harst, Pim van der [0000-0002-2713-686X], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G. [0000-0002-5041-248X], Loos, Ruth J. F. [0000-0002-8532-5087], Salomaa, Veikko [0000-0001-7563-5324], Soranzo, Nicole [0000-0003-1095-3852], Boomsma, Dorret I. [0000-0002-7099-7972], Groop, Leif [0000-0002-0187-3263], Tuomi, Tiinamaija [0000-0002-8306-6202], Munroe, Patricia B. [0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering
Subjects: Male, Anorexia Nervosa, medicine.medical_treatment, 45/43, Insulin Resistance/genetics, SUSCEPTIBILITY, Quantitative trait, Impaired glucose tolerance, 0302 clinical medicine, Architecture, LS2_1, IMPUTATION, Insulin, ComputingMilieux_MISCELLANEOUS, Fasting, Publisher Correction, 3. Good health, [SDV] Life Sciences [q-bio], Kruppel-Like Transcription Factors/blood, Endokrinologi och diabetes, Science & Technology - Other Topics, Adult, Blood Glucose, European Continental Ancestry Group, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Kruppel-Like Transcription Factors, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, Sex characteristics, medicine.medical_specialty, Science, 631/208/205/2138, Endocrinology and Diabetes, General Biochemistry, Genetics and Molecular Biology, White People, Gender-differences, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2421, GLYCEMIC TRAITS, GENOME-WIDE ASSOCIATION, Glycemic, GENDER-DIFFERENCES, Science & Technology, IDENTIFICATION, 692/699/2743/2815, Blood Glucose/metabolism, Diagnostic markers, medicine.disease, Anorexia Nervosa/blood, 030104 developmental biology, Endocrinology, Glucose, Insulin/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Fasting/blood, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Kruppel-Like Transcription Factors/genetics, 0301 basic medicine, Identification, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome-wide association studies, Waist–hip ratio, LS4_5, RISK, ARCHITECTURE, Multidisciplinary, article, Type 2 diabetes, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Pre-diabetes, Medical Genetics, Risk, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, 3121 Internal medicine, 692/163/2743/137/773, NO, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Mendelian randomization, 631/208/480, Medicinsk genetik, business.industry, General Chemistry, Impaired fasting glucose, business
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
Published: 2021

14. Serum 25-Hydroxy-Vitamin D Status and Incident Hip Fractures in Elderly Adults: Looking Beyond Bone Mineral Density

Author: Thorhallur I. Halldorsson, Lenore J. Launer, Vilmundur Gudnason, Kristin Siggeirsdottir, Alfons Ramel, Laufey Steingrimsdottir, Hrafnhildur Eymundsdottir, Sigrun Sunna Skuladottir, M. F. Cotch, Ingibjörg Hjaltadóttir, and Gunnar Sigurdsson
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Physical function, Gastroenterology, Bone Density, Internal medicine, medicine, Vitamin D and neurology, Humans, Orthopedics and Sports Medicine, Prospective Studies, Vitamin D, Prospective cohort study, Femoral neck, Aged, Bone mineral, business.industry, Femur Neck, Hip Fractures, Incidence (epidemiology), Hazard ratio, Vitamin D Deficiency, Confidence interval, medicine.anatomical_structure, Female, business
Abstract: Observational studies have consistently reported a higher risk of fractures among those with low levels of serum 25-hydroxyvitamin D (25(OH)D). Emerging evidence suggests that low serum 25(OH)D levels may increase the rate of falls through impaired physical function. Examine to what extent baseline measures of volumetric bone mineral density (vBMD), absolute bone mineral content (BMC), and markers of physical function may explain incident hip fractures in older adults with different serum levels of 25(OH)D. A prospective study of 4309 subjects (≥66 years) recruited between 2002 and 2006 into the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study. Hip fractures occurring until the end of 2012 were extracted from hospital records. Prevalence of serum 25(OH)D deficiency (
Published: 2021

15. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021

16. Contributions of cerebral blood flow to associations between blood pressure levels and cognition the age, gene/environment susceptibility-Reykjavik study

Author: Mark A. van Buchem, Osorio Meirelles, Behnam Sabayan, Lenore J. Launer, Justine E. Moonen, Vilmundur Gudnason, and Sigurdur Sigurdsson
Subjects: Male, medicine.medical_specialty, Iceland, Blood Pressure, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, Cognition, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Humans, Dementia, Genetic Predisposition to Disease, Aged, Aged, 80 and over, business.industry, Age Factors, Brain, aged blood pressure, medicine.disease, Magnetic Resonance Imaging, Blood pressure, Cerebral blood flow, Cerebrovascular Circulation, Cardiology, Female, Gene-Environment Interaction, business, cerebral blood flow cognition, 030217 neurology & neurosurgery, circulatory and respiratory physiology, dementia
Abstract: Cerebral hypoperfusion leads to adverse sequalae including dementia. Midlife higher blood pressure (BP) can lead to low cerebral blood flow (CBF), but older persons may need higher BP to maintain cerebral perfusion. We investigated the associations among late-life BP, CBF, and cognition. Data are from 2498 participants with a mean age of 79.8 (SD, 4.7) years of the second exam of the AGES (Age, Gene/Environment Susceptibility)–Reykjavik Study. BP was measured, and phase-contrast (PC) magnetic resonance imaging was acquired to estimate total brain CBF PC . Cognitive outcomes included verbal and working memory, processing speed, mild cognitive impairment, and all-cause dementia. Relationships among late-life BP, CBF PC , and cognition were assessed with regression models, controlling for socio-demographics, BP level at midlife (at a mean age of 49.6 [SD, 5.9] years), cardiovascular factors, and total brain volume. In fully adjusted models, each mm Hg increase in late-life diastolic BP was associated with a −0.082 mL/min per 100 mL (95% CI −0.123 to −0.041) lower CBF PC . In contrast, each mm Hg increase in late-life systolic BP or pulse pressure was associated with a 0.027 mL/min per 100 mL (95% CI, 0.0065–0.048) and 0.061 mL/min per 100 mL (95% CI, 0.038–0.084) higher late-life CBF PC , respectively. Higher CBF PC was significantly related to higher cognitive scores for psychomotor speed, verbal, and working memory and to a lower odd of mild cognitive impairment or dementia, irrespective of late-life BP level. Higher late-life diastolic BP and systolic BP were differentially associated with CBF PC . Our findings suggest CBF is an important correlate of late-life cognition, independent of BP level.
Published: 2021

17. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

Author: Sina A. Gharib, Kenneth Rice, Donna K. Arnett, Tõnu Esko, Annemarie I. Luik, Niki Dimou, Dabeeru C. Rao, Pamela J. Schreiner, Melissa A. Richard, Reedik Mägi, Nicholette D. Palmer, Stefan Weiss, Han Chen, Solomon K. Musani, W. James Gauderman, Christian Gieger, Kari E. North, Salman M. Tajuddin, Diana van Heemst, Rainer Rauramaa, Stephen B. Kritchevsky, Henry Völzke, Minjung Kho, Michele K. Evans, Ruth J. F. Loos, Correa Adolfo, Pedro Marques-Vidal, Diane M. Becker, Claude Bouchard, José Haba-Rubio, Georg Homuth, Kurt Lohman, Nora Franceschini, Caizheng Yu, Peter Vollenweider, Ervin F. Fox, Thomas Meitinger, Karen Schwander, Heming Wang, Morris A. Swertz, Aldi T. Kraja, José Eduardo Krieger, Xiuqing Guo, Tangchun Wu, Raymond Noordam, Yongmei Liu, Michael R. Brown, Patrick C.N. Rensen, Annette Peters, Jingmin Liu, Tuomo Rankinen, Robert B. Wallance, Timo A. Lakka, Stephen S. Rich, Yun Ju Sung, Meian He, Till Roenneberg, Wanqing Wen, Dennis O. Mook-Kanamori, M. A. Province, Evangelos Evangelou, L. Adrienne Cupples, Maxime M Bos, Paul S. de Vries, Hans J. Grabe, Lisa R. Yanek, Jiwon Lee, Mario Sims, Bruce M. Psaty, Treva Rice, Tanika N. Kelly, Brenda W.J.H. Penninx, Brigitte Kühnel, Maria E. Graff, Alexandre C. Pereira, Daniel J. Gottlieb, Charles N. Rotimi, Lynne E. Wagenknecht, Ashley van der Spek, Lisa W. Martin, Jeffrey R. O'Connell, Changwei Li, James E. Hixson, Chuan Gao, Alisa K. Manning, Sharon L.R. Kardia, Stella Aslibekyan, Andres Metspalu, Sami Heikkinen, Maris Alver, Xiao-Ou Shu, Amy R. Bentley, Susan Redline, Konstantin Strauch, Tamara B. Harris, Yuri Milaneschi, L.F. Bielak, Marjan Ilkov, Myriam Fornage, Ilja M. Nolte, André G. Uitterlinden, Dina Vojinovic, Hugues Aschard, Paul Elliott, Kent D. Taylor, Najaf Amin, James M. Shikany, Yong-Bing Xiang, Jerome I. Rotter, Vilmundur Gudnason, Cornelia M. van Duijn, Ko Willems van Dijk, Andrea R. V. R. Horimoto, Jonathan Marten, Olli T. Raitakari, Vincent Laville, Pirjo Komulainen, Zhe Wang, Traci M. Bartz, Mary F. Feitosa, Mike A. Nalls, Eric Boerwinkle, Alanna C. Morrison, Melanie Waldenberger, Alexander P. Reiner, Christie M. Ballantyne, Wei Zheng, Raphael Heinzer, M. Arfan Ikram, Colleen M. Sitlani, Lisa de las Fuentes, Patricia B. Munroe, Patricia A. Peyser, Brian E. Cade, Tamar Sofer, Xiaofeng Zhu, Nienke R. Biermasz, Harold Snieder, Elise Lim, Tuomas O. Kilpeläinen, Ching-Ti Liu, Terho Lehtimäki, Thomas W. Winkler, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Stephen Sidney, Alan B. Zonderman, Charles Kooperberg, Leiden University Medical Center (LUMC), Universiteit Leiden, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Universität Regensburg (UR), National Institutes of Health [Bethesda] (NIH), University of Copenhagen = Københavns Universitet (UCPH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), The University of Texas Health Science Center at Houston (UTHealth), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Massachusetts General Hospital [Boston], Harvard T.H. Chan School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University of Mississippi Medical Center (UMMC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Alabama at Birmingham [ Birmingham] (UAB), University of Washington [Seattle], Universidade de São Paulo Medical School (FMUSP), Icelandic Heart Association [Kopavogur, Iceland] (IHA), University of Michigan [Ann Arbor], University of Michigan System, University of Georgia [USA], School of Public Health [Boston], Boston University [Boston] (BU), Wake Forest University, Pennington Biomedical Research Center, Louisiana State University (LSU), University of Edinburgh, University of Tartu, Imperial College London, University of Ioannina, Huazhong University of Science and Technology [Wuhan] (HUST), Helmholtz Zentrum München = German Research Center for Environmental Health, Fimlab Laboratories [Tampere, Finland], University of Tampere [Finland], Lausanne University Hospital, University of Groningen [Groningen], This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338., European Project: 602757,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HUMAN(2013), Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, University of Copenhagen = Københavns Universitet (KU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), Van Duijn, CM, Wang, Heming [0000-0002-1486-7495], Bentley, Amy R [0000-0002-0827-9101], Schwander, Karen [0000-0002-0193-4134], Manning, Alisa [0000-0003-0247-902X], Aschard, Hugues [0000-0002-7554-6783], Richard, Melissa [0000-0003-0129-9860], de Las Fuentes, Lisa [0000-0002-4689-325X], Feitosa, Mary [0000-0002-0933-2410], van der Spek, Ashley [0000-0001-7136-0159], Wang, Zhe [0000-0002-8046-4969], Marten, Jonathan [0000-0001-6916-2014], Laville, Vincent [0000-0003-4946-698X], Evangelou, Evangelos [0000-0002-5488-2999], He, Meian [0000-0002-2096-921X], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Marques-Vidal, Pedro [0000-0002-4548-8500], Nolte, Ilja M [0000-0001-5047-4077], Palmer, Nicholette D [0000-0001-8883-2511], Snieder, Harold [0000-0003-1949-2298], Weiss, Stefan [0000-0002-3553-4315], Yanek, Lisa R [0000-0001-7117-1075], Adolfo, Correa [0000-0002-9501-600X], Dimou, Niki [0000-0003-1678-9328], Heikkinen, Sami [0000-0002-6083-2402], Ikram, M Arfan [0000-0003-0372-8585], Krieger, Jose E [0000-0001-5464-1792], Lee, Jiwon [0000-0002-4079-7494], Liu, Jingmin [0000-0003-0001-6013], Martin, Lisa W [0000-0003-4352-0914], Metspalu, Andres [0000-0002-3718-796X], Rensen, Patrick CN [0000-0002-8455-4988], Rich, Stephen S [0000-0003-3872-7793], Rotter, Jerome I [0000-0001-7191-1723], Sofer, Tamar [0000-0001-8520-8860], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, André G [0000-0002-7276-3387], van Dijk, Ko Willems [0000-0002-2172-7394], Elliott, Paul [0000-0002-7511-5684], Esko, Tõnu [0000-0003-1982-6569], Grabe, Hans J [0000-0003-3684-4208], Zheng, Wei [0000-0003-1226-070X], Bouchard, Claude [0000-0002-0048-491X], Gudnason, Vilmundur [0000-0001-5696-0084], Loos, Ruth JF [0000-0002-8532-5087], Cupples, L Adrienne [0000-0003-0273-7965], Munroe, Patricia B [0000-0002-4176-2947], Liu, Ching-Ti [0000-0002-0703-0742], Apollo - University of Cambridge Repository, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), and UK DRI Ltd
Subjects: Male, 0301 basic medicine, Epidemiology, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Svefnrannsóknir, 0302 clinical medicine, MESH: Aged, 80 and over, Polymorphism (computer science), lcsh:Science, MESH: Phylogeny, Phylogeny, Aged, 80 and over, Genetics, MESH: Aged, [STAT.AP]Statistics [stat]/Applications [stat.AP], Multidisciplinary, MESH: Middle Aged, medicine.diagnostic_test, MESH: Polymorphism, Single Nucleotide, Chromosome Mapping, Middle Aged, Explained variation, Lipids, Sleep in non-human animals, Blóðfita, ddc, 3. Good health, MESH: Young Adult, Female, lipids (amino acids, peptides, and proteins), Erfðarannsóknir, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Adolescent, MESH: Sleep, Science, Biology, Polymorphism, Single Nucleotide, MESH: Genetic Loci, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Phylogenetics, Svefn, medicine, Humans, SNP, Dyslipidaemias, Aged, MESH: Adolescent, MESH: Humans, Faraldsfræði, PCSK9, MESH: Adult, General Chemistry, MESH: Lipids, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Sleep, Lipid profile, MESH: Chromosome Mapping, MESH: Female, 030217 neurology & neurosurgery
Abstract: Publisher's version (útgefin grein)., Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles., This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338. Study-specific acknowledgements can be found in the Supplementary Notes 2 and 4. The data on coronary artery disease have been contributed by the Myocardial Infarction Genetics and CARDIoGRAM investigators, and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.
Published: 2019

18. Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Author: Adolfo Correa, Dragana Vuckovic, Chuang Ming Li, Sheila R. Pratt, Vilmundur Gudnason, Robert C. Kaplan, Massimiliano Cocca, Giorgia Girotto, Frances M K Williams, Nona Sotoodehnia, Christopher Spankovich, T. Ryan Price, Charles E. Bishop, Johanna Jakobsdottir, W. T. Longstreth, Howard J. Hoffman, Karen Valle, Mark W. Christiansen, Erik Fransen, Helena R R Wells, John M. Schweinfurth, André G. Uitterlinden, Mohammad Arfan Ikram, Guy Van Camp, Daniel S. Evans, Paolo Gasparini, Linda Broer, Gregory J. Tranah, Marco Brumat, Andries Paul Nagtegaal, Mike A. Nalls, Mary Rachel Stimson, Sudha Seshadri, Gudny Eiriksdottir, Karen J. Cruickshanks, Yan Gao, Nancy L. Heard-Costa, Nuno R. Zilhão, James G. Wilson, Nathan Pankratz, André Goedegebure, Claire J. Steves, Otorhinolaryngology and Head and Neck Surgery, Internal Medicine, Epidemiology, Nagtegaal, A. P., Broer, L., Zilhao, N. R., Jakobsdottir, J., Bishop, C. E., Brumat, M., Christiansen, M. W., Cocca, M., Gao, Y., Heard-Costa, N. L., Evans, D. S., Pankratz, N., Pratt, S. R., Price, T. R., Spankovich, C., Stimson, M. R., Valle, K., Vuckovic, D., Wells, H., Eiriksdottir, G., Fransen, E., Ikram, M. A., Li, C. -M., Longstreth, W. T., Steves, C., Van Camp, G., Correa, A., Cruickshanks, K. J., Gasparini, P., Girotto, G., Kaplan, R. C., Nalls, M., Schweinfurth, J. M., Seshadri, S., Sotoodehnia, N., Tranah, G. J., Uitterlinden, A. G., Wilson, J. G., Gudnason, V., Hoffman, H. J., Williams, F. M. K., and Goedegebure, A.
Subjects: 0301 basic medicine, Male, Aging, Auditory Pathways, Genome-wide association study, Audiology, Genome-wide association studies, Mice, 0302 clinical medicine, Genetics research, GWAS, age-related hearing lo, Multidisciplinary, Middle Aged, Phenotype, age-related hearing loss, Meta-analysis, Medicine, Female, medicine.symptom, medicine.medical_specialty, Hearing loss, Science, Single-nucleotide polymorphism, Biology, Article, ARHL, 03 medical and health sciences, medicine, otorhinolaryngologic diseases, SNP, Animals, Humans, Genetic Predisposition to Disease, Hearing Loss, Gene, Reproducibility of Results, Molecular Sequence Annotation, Genetic architecture, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Previous research has shown that genes play a substantial role in determining a person’s susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.
Published: 2019

19. Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group

Author: David J. Stott, Christopher J. O'Donnell, Nuno R. Zilhão, Eric A. Whitsel, Fangui Sun, Leslie A. Lange, Xiuqing Guo, Kerri L. Wiggins, Hanfei Xu, Aishwarya Sundaresan, Dennis O. Mook-Kanamori, Christy L. Avery, Albert V. Smith, Xiaohui Li, Til Stürmer, Ayush Giri, Raymond Noordam, Joshua C. Bis, Walter Palmas, Adolfo Correa, Laura M. Raffield, Peter Rossing, Rikki M. Tanner, Tarunveer S. Ahluwalia, James A. Stewart, Helen R. Warren, Jie Yao, Colleen M. Sitlani, Vilmundur Gudnason, Adrienne Cupples, James S. Floyd, Bruce M. Psaty, Jerome I. Rotter, Marguerite R. Irvin, Jacklyn N. Hellwege, Donna K. Arnett, Adriana M. Hung, Ching-Ti Liu, Nita A. Limdi, Stella Trompet, Todd L. Edwards, Lenore J. Launer, J. Wouter Jukema, and Ian Ford
Subjects: Male, Pharmacogenomic Variants, Drug Resistance, Blood Pressure, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Logistic regression, DNA Methyltransferase 3A, 0302 clinical medicine, Risk Factors, DNA (Cytosine-5-)-Methyltransferases, 0303 health sciences, blood pressure, Single Nucleotide, Middle Aged, severe hypertension, DNA-Binding Proteins, Europe, Female, medicine.medical_specialty, hypertension, Clinical Sciences, Myosin Type V, Locus (genetics), Single-nucleotide polymorphism, Brief Communication, Polymorphism, Single Nucleotide, Risk Assessment, White People, 03 medical and health sciences, Clinical Research, Internal medicine, Genetics, Internal Medicine, medicine, Humans, Polymorphism, Antihypertensive Agents, Aged, 030304 developmental biology, genome-wide association study, Myosin Heavy Chains, business.industry, Human Genome, Neuropeptides, Odds ratio, United States, Confidence interval, Black or African American, Blood pressure, Cardiovascular System & Hematology, Genetic Loci, Pharmacogenetics, Case-Control Studies, treatment-resistant hypertension, Dystrophin-Associated Proteins, business, Transcription Factors
Abstract: BACKGROUND Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS We conducted a case–control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal ( RESULTS The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10−8) and in the race-combined analysis (P = 1.5 × 10−9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6–0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
Published: 2019

20. Pre-diagnostic 25-hydroxyvitamin D levels and survival in cancer patients

Author: Tamara B. Harris, Johanna E. Torfadottir, Vilmundur Gudnason, Lorelei A. Mucci, Laufey Steingrimsdottir, Unnur Valdimarsdóttir, Meir J. Stampfer, Thor Aspelund, Laufey Tryggvadottir, Edward Giovannucci, Mary Frances Cotch, and Hans-Olov Adami
Subjects: Male, Risk, Cancer Research, medicine.medical_specialty, Survival, Lower risk, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Internal medicine, Epidemiology, Vitamin D and neurology, Humans, Medicine, 030212 general & internal medicine, Vitamin D, Aged, Aged, 80 and over, Hematology, business.industry, Incidence, Cancer, Vitamin D Deficiency, medicine.disease, Total mortality, Blood draw, Oncology, 030220 oncology & carcinogenesis, Female, business, Cancer risk, Follow-Up Studies
Abstract: PURPOSE: Our main aim was to explore whether pre-diagnostic circulating levels of 25-hydroxyvitamin D (25(OH)D) among older individuals with cancer were associated with overall and cancer-specific survival after diagnosis. DESIGN: We used data from the Reykjavik-AGES Study on participants (n = 4,619) without cancer at entry, when blood samples were taken for 25(OH)D standardized measurements. The association with cancer risk, all-cause- and cancer-specific mortality was assessed among those later diagnosed with cancer, comparing four 25(OH)D categories, using 50–69.9 nmol/L as the reference category. RESULTS: Cancer was diagnosed in 919 participants on average 8.3 years after blood draw. No association was observed between the reference group and other 25(OH)D groups and total cancer incidence. Mean age at diagnosis was 80.9 (± 5.7) years. Of those diagnosed, 552 died during follow-up, 67% from cancer. Low pre-diagnostic levels of 25(OH)D < 30 nmol/L were significantly associated with increased total mortality (HR: 1.39, 95% CI 1.03, 1.88) and non-significantly with cancer-specific mortality (HR: 1.33, 95% CI 0.93, 1.90). Among patients surviving more than 2 years after diagnosis, higher pre-diagnostic 25(OH)D levels (≥ 70 nmol/L) were associated with lower risk of overall (HR: 0.68, 95% CI 0.46, 0.99) and cancer-specific mortality (HR: 0.47, 95% CI 0.26, 0.99). CONCLUSIONS: Among elderly cancer patients, low pre-diagnostic serum 25(OH)D levels (< 30 nmol/L) were associated with increased overall mortality.
Published: 2019

21. Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection

Author: David Adlam, Timothy M. Olson, Nicolas Combaret, Jason C. Kovacic, Siiri E. Iismaa, Abtehale Al-Hussaini, Megan M. O'Byrne, Sara Bouajila, Adrien Georges, Ketan Mishra, Peter S. Braund, Valentina d’Escamard, Siying Huang, Marios Margaritis, Christopher P. Nelson, Mariza de Andrade, Daniella Kadian-Dodov, Catherine A. Welch, Stephani Mazurkiewicz, Xavier Jeunemaitre, Claire Mei Yi Wong, Eleni Giannoulatou, Michael Sweeting, David Muller, Alice Wood, Lucy McGrath-Cadell, Diane Fatkin, Sally L. Dunwoodie, Richard Harvey, Cameron Holloway, Jean-Philippe Empana, Xavier Jouven, Jeffrey W. Olin, Rajiv Gulati, Marysia S. Tweet, Sharonne N. Hayes, Nilesh J. Samani, Robert M. Graham, Pascal Motreff, Nabila Bouatia-Naji, Loïc Belle, Patrick Dupouy, Pierre Barnay, Nicolas Meneveau, Martine Gilard, Gilles Rioufol, Grégoire Range, Philippe Brunel, Nicolas Delarche, Emmanuelle Filippi, Louis Le Bivic, Brahim Harbaoui, Hakim Benamer, Guillaume Cayla, Olivier Varenne, Stephane Peggy Manzo-Silberman, Johanne Silvain, Christian Spaulding, Christophe Caussin, Edouard Gerbaud, Yann Valy, René Koning, Thibault Lhermusier, Stanislas Champin, Emmanuel Salengro, Arnaud Fluttaz, Amer Zabalawi, Yves Cottin, Emmanuel Teiger, Christophe Saint-Etienne, Grégory Ducrocq, Stéphanie Marliere, Emmanuel Boiffard, Pierre Aubry, Jean Louis Georges, Didier Bresson, Fabien De Poli, Gaëtan Karrillon, Vincent Roule, Laurent Bali, Mathieu Valla, Antoine Gerbay, David Houpe, Olivier Dubreuil, Arsène Monnier, Norbert Mayaud, Aurélie Manchuelle, Philippe Commeau, Marc Bedossa, Majid Nikpay, Anuj Goel, Hong-Hee Won, Leanne M. Hall, Christina Willenborg, Stavroula Kanoni, Danish Saleheen, Theodosios Kyriakou, Jemma C. Hopewell, Thomas R. Webb, Lingyao Zeng, Abbas Dehghan, Maris Alver, Sebastian M. Armasu, Kirsi Auro, Andrew Bjonnes, Daniel I. Chasman, Shufeng Chen, Ian Ford, Nora Franceschini, Christian Gieger, Christopher Grace, Stefan Gustafsson, Jie Huang, Shih-Jen Hwang, Yun Kyoung Kim, Marcus E. Kleber, King Wai Lau, Xiangfeng Lu, Yingchang Lu, Leo P. Lyytikäinen, Evelin Mihailov, Alanna Morrison, Natalia Pervjakova, Liming Qu, Lynda M. Rose, Elias Salfati, Richa Saxena, Markus Scholz, Albert V. Smith, Emmi Tikkanen, Andre Uitterlinden, Xueli Yang, Weihua Zhang, Wei Zhao, Paul S. de Vries, Natalie R. van Zuydam, Sonia S. Anand, Lars Bertram, Frank Beutner, George Dedoussis, Philippe Frossard, Dominique Gauguier, Alison H. Goodall, Omri Gottesman, Marc Haber, Bok-Ghee Han, Jianfeng Huang, Shapour Jalilzadeh, Thorsten Kessler, Inke R. König, Lars Lannfelt, Wolfgang Lieb, Lars Lind, Cecilia M. Lindgren, Maisa Lokki, Patrik K. Magnusson, Nadeem H. Mallick, Narinder Mehra, Thomas Meitinger, Fazal-ur-Rehman Memon, Andrew P. Morris, Markku S. Nieminen, Nancy L. Pedersen, Annette Peters, Loukianos S. Rallidis, Asif Rasheed, Maria Samuel, Svati H. Shah, Juha Sinisalo, Kathleen E. Stirrups, Stella Trompet, Laiyuan Wang, Khan S. Zaman, Diego Ardissino, Eric Boerwinkle, Ingrid B. Borecki, Erwin P. Bottinger, Julie E. Buring, John C. Chambers, Rory Collins, L Adrienne Cupples, John Danesh, Ilja Demuth, Roberto Elosua, Stephen E. Epstein, Tõnu Esko, Mary F. Feitosa, Oscar H. Franco, Maria Grazia Franzosi, Christopher B. Granger, Dongfeng Gu, Vilmundur Gudnason, Alistair S. Hall, Anders Hamsten, Tamara B. Harris, Stanley L. Hazen, Christian Hengstenberg, Albert Hofman, Erik Ingelsson, Carlos Iribarren, J Wouter Jukema, Pekka J. Karhunen, Bong-Jo Kim, Jaspal S. Kooner, Iftikhar J. Kullo, Terho Lehtimäki, Ruth J. Loos, Olle Melander, Andres Metspalu, Winfried März, Colin N. Palmer, Markus Perola, Thomas Quertermous, Daniel J. Rader, Paul M. Ridker, Samuli Ripatti, Robert Roberts, Veikko Salomaa, Dharambir K. Sanghera, Stephen M. Schwartz, Udo Seedorf, Alexandre F. Stewart, David J. Stott, Joachim Thiery, Pierre A. Zalloua, Christopher J. O'Donnell, Muredach P. Reilly, Themistocles L. Assimes, John R. Thompson, Jeanette Erdmann, Robert Clarke, Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Panos Deloukas, Heribert Schunkert, Martin Farrall, Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, Mayo Clinic [Rochester], Service de Cardiologie Maladies Vasculaires [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Victor Chang Cardiac Research Institute, University of New South Wales [Sydney] (UNSW), St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Department of Cardiovascular Medicine, Mayo Clinic, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), and Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)
Subjects: Adult, Male, medicine.medical_specialty, Myocardial infarction, Coronary Vessel Anomalies, Fibromuscular dysplasia, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Prevalence, Fibromuscular Dysplasia, Humans, 030212 general & internal medicine, Vascular Diseases, Artery dissection, MESH: Australia, United Kingdom, USA, Coronary Vessel Anomalies / epidemiology, Endothelin-1 / genetics, Microfilament proteins / genetics, Genetic association, Aged, Endothelin-1, business.industry, Microfilament Proteins, Australia, Cardiovascular disease in women, Middle Aged, medicine.disease, R1, United States, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Case-Control Studies, Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, France, Cardiology and Cardiovascular Medicine, Scad, business
Abstract: Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
Published: 2019

22. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author: Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center
Subjects: Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract: © The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant
Published: 2019

23. Disentangling the genetics of lean mass

Author: Tuomas O. Kilpeläinen, Jacqueline S. L. Kloth, Nam H. Cho, Peter Vollenweider, Georg Homuth, Unnur Thorsteinsdottir, Nicole C. Wright, Wen-Chi Chou, Yongmei Liu, Kari Stefansson, Kim M. Huffman, Ida Malkin, Andrew P. Morris, Robert Luben, Shad B. Smith, Lei Yu, Joel Eriksson, Aarno Palotie, Veikko Salomaa, Michael J. Econs, Liesbeth Vandenput, Elizabeth A. Streeten, Albert Hofman, Elisabeth Widen, Emmi Tikkanen, Braxton D. Mitchell, Natasja M. van Schoor, Caroline Hayward, Liisa Byberg, Joanne M. Jordan, Bruce M. Psaty, Elisabeth Steinhagen-Thiessen, Magnus Karlsson, Harry Campbell, John C. Chambers, Fernando Rivadeneira, Johan G. Eriksson, Jari Lahti, Reiner Biffar, James F. Wilson, Luda Diatchenko, Jerome I. Rotter, Eric S. Orwoll, Launer J. Lenore, Cornelia M. van Duijn, Frances M K Williams, Munro Peacock, David A. Bennett, Annette Peters, Ali A. Aghdassi, Gudny Eiriksdottir, Weihua Zhang, Östen Ljunggren, Daniel L. Koller, Nicole Soranzo, Patricia A. Thompson, Jane A. Cauley, John A Robbins, Mattias Lorentzon, Igor Rudan, Thomas Illig, Claes Ohlsson, Ilja Demuth, Zoltán Kutalik, Aron S. Buchman, Jian'an Luan, Erik Ingelsson, Natalia Campos-Obando, Karol Estrada, Chan Soo Shin, Lisette Stolk, Gudmar Thorleifsson, Douglas P. Kiel, Michael N. Weedon, Lars Bertram, Fiona E. McGuigan, Ben A. Oostra, Thomas Meitinger, Mary F. Feitosa, Christian Gieger, Jean Wactawski-Wende, Yanhua Zhou, Serkalem Demissie, Najaf Amin, Anke W. Enneman, Håkan Melhus, Stuart H. Ralston, Johanna Kuusisto, Markku Laakso, Mark Walker, Tim D. Spector, Karl Michaëlsson, John-Olov Jansson, Richard L. Prince, Leif Mosekilde, Sabine Schipf, Carolina Medina-Gomez, Antti Jula, Carrie M. Nielson, Bente L. Langdahl, André G. Uitterlinden, Kay-Tee Khaw, Ruth J. F. Loos, Kristina Åkesson, Albert V. Smith, Tamara B. Harris, Cynthia A. Thomson, Karin M. A. Swart, Unnur Styrkarsdottir, Yi-Hsiang Hsu, Anne B. Newman, Murielle Bochud, M. Carola Zillikens, Alena Stančáková, Markus M. Lerch, Maria Nethander, Gregory Livshits, Dawn Waterworth, Christina M. Lill, Henry Völzke, Steven R. Cummings, Lise B. Husted, Cecilia M. Lindgren, Jaspal S. Kooner, Joshua R. Lewis, Katri Räikkönen, Linda Broer, Inês Barroso, Teemu Kuulasmaa, Jeffery R. O'Connell, Harald Grallert, William E. Kraus, Nicholas J. Wareham, Lars Lind, David Karasik, H-Erich Wichmann, Gregory J. Tranah, Mao Fu, Toby Johnson, Samuli Ripatti, Dan Mellström, Suzanne Satterfield, Jing Hua Zhao, Hyung Jin Choi, Vilmundur Gudnason, Lisette C. P. G. M. de Groot, Stephen B. Kritchevsky, Zhao Chen, Norman Klopp, Till Ittermann, Daniel S. Evans, Phillip L. De Jager, Ingrid B. Borecki, Laura M. Yerges-Armstrong, Peggy M. Cawthon, Thomas Lang, Markus Perola, Internal Medicine, Epidemiology, Clinical Genetics, General practice, APH - Societal Participation & Health, APH - Aging & Later Life, Epidemiology and Data Science, and APH - Personalized Medicine
Subjects: Adipose Tissue/metabolism, Male, 0301 basic medicine, Medicine (miscellaneous), Body Fluid Compartments/metabolism, Genome-wide association study, FTO gene, ADAMTS Proteins, Absorptiometry, Photon, Versicans, 0302 clinical medicine, Electric Impedance, European Continental Ancestry Group/genetics, Aged, 80 and over, 2. Zero hunger, Genetics, Extracellular Matrix Proteins, Nutrition and Dietetics, ADAMTS Proteins/genetics, RNA-Binding Proteins, Body Fluid Compartments, Middle Aged, metabolic profile, Nutritional Biology, body fat, Original Research Communications, Phenotype, Adipose Tissue, Body Composition, Receptor, Melanocortin, Type 4, Female, Bioelectrical impedance analysis, Adult, meta-analysis of genome-wide association studies, Versicans/genetics, Adolescent, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Biology, Extracellular Matrix Proteins/genetics, meta-Analysis of genome-wide association studies, Polymorphism, Single Nucleotide, White People, Young Adult, 03 medical and health sciences, Humans, Receptor, Melanocortin, Type 4/genetics, skeletal muscle, Allele, Muscle, Skeletal, VLAG, Aged, Global Nutrition, Wereldvoeding, Body Composition/genetics, body composition, Muscle, Skeletal/metabolism, 030109 nutrition & dietetics, Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics, RNA-Binding Proteins/genetics, Genetic architecture, Lean body mass, Genome-Wide Association Study
Abstract: Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
Published: 2019

24. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort

Author: Elias Freyr Gudmundsson, Gudlaug Björnsdottir, Sigurdur Sigurdsson, Karl Andersen, Bolli Thorsson, Thor Aspelund, and Vilmundur Gudnason
Subjects: Male, Predictive Value of Tests, Risk Factors, Humans, Calcium, Female, Coronary Artery Disease, Prospective Studies, Cardiology and Cardiovascular Medicine, Tomography, X-Ray Computed, Risk Assessment, Plaque, Atherosclerotic
Abstract: Coronary artery calcium (CAC) and carotid plaque are markers of atherosclerosis and predict future coronary heart disease (CHD) events. The aim of this study was to investigate associations between CAC and carotid plaque in asymptomatic individuals, also in relation to predicted CHD-risk and incident events. A secondary aim was to compare predictive value between CAC, carotid plaque, and total carotid plaque area (TPA) as predictors for future CHD-events.The REFINE-Reykjavik study is prospective and population-based with CAC-scoring and carotid plaque ultrasound assessment, both presence and area. A total of 948 individuals without clinical CHD were included in the study. CAC scores were categorized into 0,1-100,101-300 and 300, and carotid plaque into none, minimal and significant. Three models were applied adjusted for age, sex, and each of the Framingham risk score (FRS), local CHD risk score and established CHD risk factors.Combined carotid plaque- and CAC-presence was highly prevalent, 69.5% for males and 41.7% for females (54.5% overall). TPA outperformed base models in CHD prediction, resulting in statistically significant area under the receiver operator characteristic curve (AUC) increase ranging from 0.02 to 0.05. Most CHD-events in females occurred in individuals classified as low-risk with respect to traditional risk factors but with a gradient in observed risk across carotid plaque categories.Carotid plaque was strongly associated with the presence and extent of CAC in asymptomatic individuals in a population-based cohort. Carotid plaque predicts incident CHD events over risk scores and may be useful for refined risk prediction in females.
Published: 2021

25. Growth Rate in Childhood and Adolescence and the Risk of Breast and Prostate Cancer: A Population-Based Study

Author: Inga Thorsdottir, Thorhallur I. Halldorsson, Unnur Valdimarsdóttir, Ingibjorg Gunnarsdottir, Johanna E. Torfadottir, Gertraud Maskarinec, Alfheidur Haraldsdottir, Laufey Tryggvadottir, Laufey Steingrimsdottir, Hans-Olov Adami, Vilmundur Gudnason, Thor Aspelund, Ragnar Bjarnason, and Bryndis Eva Birgisdottir
Subjects: Oncology, Male, medicine.medical_specialty, Adolescent, Epidemiology, Iceland, Breast Neoplasms, Growth, Prostate cancer, Breast cancer, Risk Factors, Internal medicine, medicine, Humans, Child, Aged, Proportional Hazards Models, business.industry, Proportional hazards model, Hazard ratio, Prostatic Neoplasms, Middle Aged, medicine.disease, Confidence interval, Body Height, Population based study, Increased risk, Female, business, Rate of growth, Follow-Up Studies
Abstract: Growth rate is regulated by hormonal pathways that might affect early cancer development. We explored the association between rate of growth in height from ages 8 to 13 years (childhood) and from age 13 to attainment of adult height (adolescence), as measured at study entry, and the risk of breast or prostate cancer. Participants were 2,037 Icelanders born during 1915–1935, who took part in the Reykjavik Study, established in 1967. Height measurements were obtained from school records and at study entry. We used multivariable Cox regression models to calculate hazard ratios with 95% confidence intervals of breast and prostate cancer by rates of growth in tertiles. During a mean follow-up of 66 years (women) and 64 years (men), 117 women were diagnosed with breast cancer and 118 men with prostate cancer (45 with advanced disease). Women in the highest growth-rate tertile in adolescence had a higher risk of breast cancer (hazard ratio = 2.4, 95% confidence interval: 1.3, 4.3) compared with women in the lowest tertile. A suggestive inverse association was observed for highest adolescent growth rate in men and advanced prostate cancer: hazard ratio = 0.4, 95% confidence interval: 0.2, 1.0. Rapid growth, particularly in adolescence may affect cancer risk later in life.
Published: 2021

26. Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies

Author: Luc Djoussé, Graham G. Giles, Maria Lankinen, Cécilia Samieri, Linda Snetselaar, Bruce M. Psaty, Toshiharu Ninomiya, Renata Micha, Yoichiro Hirakawa, Vilmundur Gudnason, Joan Lindsay, Allison M. Hodge, Lyn M. Steffen, Leanne K. Küpers, Jyrki K. Virtanen, Kay-Tee Khaw, Frank Qian, Mackenzie K Senn, Federica Laguzzi, Michael Y. Tsai, Qi Sun, Catherine Helmer, Ingeborg A. Brouwer, Yangbo Sun, Matti Marklund, Wendy Post, William S. Harris, Andres V. Ardisson Korat, Julie K. Bassett, Danielle Laurin, Pierre-Hugues Carmichael, David S. Siscovick, Jennifer G. Robinson, Yun-yu Chen, Johanna M. Geleijnse, Ulf Risérus, Alexis C. Wood, Rebecca D. Jackson, Nicholas J. Wareham, Aleix Sala-Vila, Jaako Mursu, Rachel A. Murphy, Markku Laakso, Jason H Y Wu, Dariush Mozaffarian, Rozenn N. Lemaitre, Nathan L. Tintle, Gudny Eiriksdottir, Fumiaki Imamura, Kuo-Liong Chien, Karin Leander, Nita G. Forouhi, Fatty Acids, Aladdin H. Shadyab, Frank B. Hu, Peilin Shi, Heidi Lai, Tintle, Nathan L [0000-0003-1447-9107], Imamura, Fumiaki [0000-0002-6841-8396], Virtanen, Jyrki K [0000-0002-0648-999X], Forouhi, Nita G [0000-0002-5041-248X], Geleijnse, Johanna M [0000-0001-7638-0589], Giles, Graham G [0000-0003-4946-9099], Gudnason, Vilmundur [0000-0001-5696-0084], Hodge, Allison [0000-0001-5464-2197], Laakso, Markku [0000-0002-3394-7749], Wareham, Nicholas J [0000-0003-1422-2993], Sun, Qi [0000-0002-8480-1563], Lemaitre, Rozenn N [0000-0002-7038-1844], Mozaffarian, Dariush [0000-0001-7958-9492], Apollo - University of Cambridge Repository, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tintle, Nathan L. [0000-0003-1447-9107], Virtanen, Jyrki K. [0000-0002-0648-999X], Forouhi, Nita G. [0000-0002-5041-248X], Geleijnse, Johanna M. [0000-0001-7638-0589], Giles, Graham G. [0000-0003-4946-9099], Wareham, Nicholas J. [0000-0003-1422-2993], Lemaitre, Rozenn N. [0000-0002-7038-1844], Health Sciences, APH - Health Behaviors & Chronic Diseases, and APH - Mental Health
Subjects: Male, Nutrition and Disease, 49/47, General Physics and Astronomy, Physiology, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, Risk Factors, Cause of Death, Voeding en Ziekte, Medicine, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, ALL-CAUSE MORTALITY, Cause of death, RISK, chemistry.chemical_classification, Aged, 80 and over, Multidisciplinary, Public Health, Global Health, Social Medicine and Epidemiology, ASSOCIATION, Middle Aged, LONG-CHAIN OMEGA-3-FATTY-ACIDS, 3. Good health, Multidisciplinary Sciences, ADIPOSE-TISSUE, CARDIOVASCULAR-DISEASE, Docosahexaenoic acid, Meta-analysis, Science & Technology - Other Topics, Female, 692/499, Polyunsaturated fatty acid, Science, BIOMARKERS, Predictive markers, Lower risk, Fatty Acids and Outcomes Research Consortium (FORCE), Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2423, Fatty Acids, Omega-3, Life Science, Humans, CORONARY-HEART-DISEASE, SDG 14 - Life Below Water, Aged, VLAG, Science & Technology, business.industry, Mortality, Premature, Fatty acid, General Chemistry, DOCOSAHEXAENOIC ACID, Protective Factors, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, chemistry, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, FISH CONSUMPTION, business, Follow-Up Studies
Abstract: The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15–18%, at least p, Associations between of omega-3 fatty acids and mortality are not clear. Here the authors report that, based on a pooled analysis of 17 prospective cohort studies, higher blood omega-3 fatty acid levels correlate with lower risk of all-cause mortality.
Published: 2021

27. Serum FSH Is Associated With BMD, Bone Marrow Adiposity, and Body Composition in the AGES-Reykjavik Study of Older Adults

Author: Susan K. Ewing, Trisha F. Hue, Kaipin Xu, Clifford J. Rosen, Mone Zaidi, Xiaojuan Li, Sigurdur Sigurdsson, Ann V. Schwartz, Vilmundur Gudnason, Tamara B. Harris, Gina N Woods, Annegreet G Veldhuis-Vlug, Anne L. Schafer, Eric Vittinghoff, Deborah M. Kado, Gudny Eiriksdottir, Phuong T. Le, and Gunnar Sigurdsson
Subjects: Male, medicine.medical_specialty, Aging, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Iceland, Context (language use), Biochemistry, Cohort Studies, Endocrinology, Bone Density, Bone Marrow, Internal medicine, Medicine, Humans, Longitudinal Studies, Quantitative computed tomography, Testosterone, Clinical Research Articles, Adiposity, Aged, Bone mineral, Aged, 80 and over, medicine.diagnostic_test, business.industry, Biochemistry (medical), medicine.disease, Lipid Metabolism, Menopause, Cross-Sectional Studies, Quartile, Lean body mass, Body Composition, Female, Follicle Stimulating Hormone, business, Cohort study
Abstract: Context Follicle-stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high after menopause. Loss of bone mineral density (BMD) and gain of bone marrow adiposity (BMA) and body fat mass also occur during this time. In mice, blocking the action of FSH increases bone mass and decreases fat mass. Objective To investigate the associations between endogenous FSH levels and BMD, BMA, and body composition in older adults, independent of estradiol and testosterone levels. Design, Setting, and Participants Older adults from the AGES-Reykjavik Study, an observational cohort study. Main Outcome Measures Areal BMD, total body fat, and lean mass were measured with dual-energy x-ray absorptiometry. Lumbar vertebral BMA was measured by 1H-magnetic resonance spectroscopy. Volumetric BMD and visceral and subcutaneous adipose tissue (VAT, SAT) areas were measured with quantitative computed tomography. The least squares means procedure was used to determine sex hormone–adjusted associations between quartiles of serum FSH and BMD, BMA, and body composition. Results In women (N = 238, mean age 81 years), those in the highest FSH quartile, compared with the lowest quartile, had lower adjusted mean spine integral BMD (−8.6%), lower spine compressive strength index (−34.8%), higher BMA (+8.4%), lower weight (−8.4%), lower VAT (−17.6%), lower lean mass (−6.1%), and lower fat mass (−11.9%) (all P < 0.05). In men, FSH level was not associated with any outcome. Conclusions Older postmenopausal women with higher FSH levels have higher BMA, but lower BMD and lower fat and lean mass, independent of estradiol and testosterone levels. Longitudinal studies are needed to better understand the underlying mechanisms.
Published: 2020

28. Circulating serum microRNAs including senescent miR-31-5p are associated with incident fragility fractures in older postmenopausal women with type 2 diabetes mellitus

Author: Ursula Heilmeier, Matthias Hackl, Fabian Schroeder, Soheyla Torabi, Puneet Kapoor, Klemens Vierlinger, Gudny Eiriksdottir, Elias Freyr Gudmundsson, Tamara B. Harris, Vilmundur Gudnason, Thomas M. Link, Johannes Grillari, and Ann V. Schwartz
Subjects: Aged, 80 and over, Histology, Physiology, Endocrinology, Diabetes and Metabolism, Postmenopause, MicroRNAs, Absorptiometry, Photon, Diabetes Mellitus, Type 2, Bone Density, Humans, Female, Circulating MicroRNA, Osteoporotic Fractures, Aged
Abstract: Fragility fractures are an important hallmark of aging and an increasingly recognized complication of Type 2 diabetes (T2D). T2D individuals have been found to exhibit an increased fracture risk despite elevated bone mineral density (BMD) by dual x-ray absorptiometry (DXA). However, BMD and FRAX-scores tend to underestimate fracture risk in T2D. New, reliable biomarkers are therefore needed. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity. Serum miRNA-classifiers were recently found to discriminate T2D women with and without prevalent fragility fractures with high specificity and sensitivity (AUC 0.90). However, the association of circulating miRNAs with incident fractures in T2D has not been examined yet. In 168 T2D postmenopausal women in the AGES-Reykjavik cohort, miRNAs were extracted from baseline serum and a panel of 10 circulating miRNAs known to be involved in diabetic bone disease and aging was quantified by qPCR and Ct-values extracted. Unadjusted and adjusted Cox proportional hazard models assessed the associations between serum miRNAs and incident fragility fracture. Additionally, Receiver operating curve (ROC) analyses were performed. Of the included 168 T2D postmenopausal women who were on average 77.2 ± 5.6 years old, 70 experienced at least one incident fragility fracture during the mean follow-up of 5.8 ± 2.7 years. We found that 3 serum miRNAs were significantly associated with incident diabetic fragility fracture: while low expression of miR-19b-1-5p was associated with significantly lower risk of incident fragility fracture (HR 0.84 (95% CI: 0.71-0.99, p = 0.0323)), low expression of miR-203a and miR-31-5p was each significantly associated with a higher risk of incident fragility fracture per unit increase in Ct-value (miR-203a: HR 1.29 (95% CI: 1.12-1.49), p = 0.0004, miR-31-5p HR 1.27 (95% CI: 1.06-1.52), p = 0.009). Hazard ratios of the latter two miRNAs remained significant after adjustments for age, body mass index (BMI), areal bone mineral density (aBMD), clinical FRAX or FRAXaBMD. Women with miR-203a and miR-31-5p serum levels in the lowest expression quartiles exhibited a 2.4-3.4-fold larger fracture risk than women with miR-31-5p and miR-203a serum expressions in the highest expression quartile (0.002 ≤ p ≤ 0.039). Women with both miR-203a and miR-31-5p serum levels below the median had a significantly increased fracture risk (Unadjusted HR 3.26 (95% CI: 1.57-6.78, p = 0.001) compared to those with both expression levels above the median, stable to adjustments. We next built a diabetic fragility signature consisting of the 3 miRNAs that showed the largest associations with incident fracture (miR-203a, miR-31-5p, miR-19b-1-5p). This 3-miRNA signature showed with an AUC of 0.722 comparable diagnostic accuracy in identifying incident fractures to any of the clinical parameters such as aBMD, Clinical FRAX or FRAXaBMD alone. When the 3 miRNAs were combined with aBMD, this combined 4-feature signature performed with an AUC of 0.756 (95% CI: 0.680, 0.823) significantly better than aBMD alone (AUC 0.666, 95% CI: 0.585, 0.741) (p = 0.009). Our data indicate that specific serum microRNAs including senescent miR-31-5p are associated with incident fragility fracture in older diabetic women and can significantly improve fracture risk prediction in diabetics when combined with aBMD measurements of the femoral neck.
Published: 2022

29. A New Panel-Estimated GFR, Including β

Author: Lesley A, Inker, Sara J, Couture, Hocine, Tighiouart, Alison G, Abraham, Gerald J, Beck, Harold I, Feldman, Tom, Greene, Vilmundur, Gudnason, Amy B, Karger, John H, Eckfeldt, Bertram L, Kasiske, Michael, Mauer, Gerjan, Navis, Emilio D, Poggio, Peter, Rossing, Michael G, Shlipak, Andrew S, Levey, and Hans-Henrik, Parving
Subjects: Adult, Male, Adolescent, Iohexol, Black People, Severity of Illness Index, White People, Young Adult, Humans, Cystatin C, Renal Insufficiency, Chronic, Edetic Acid, Aged, Aged, 80 and over, Reproducibility of Results, Middle Aged, Chromium Radioisotopes, Iothalamic Acid, Lipocalins, Black or African American, Intramolecular Oxidoreductases, Case-Control Studies, Creatinine, Female, beta 2-Microglobulin, Glomerular Filtration Rate
Abstract: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRStudy of diagnostic test accuracy.Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants.Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race.GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 mNo representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.The 4-marker panel eGFR is as accurate as eGFR
Published: 2020

30. Stroke

Author: Paul M. Thompson, Joshua C. Bis, Julian N. Trollor, Siggi Siggurdsson, Leonie Lampe, Piyush Gampawar, Myriam Fornage, Neda Jahanshad, Dina Vojinovic, Jiyang Jiang, Christophe Tzourio, Helena Schmidt, Shuo Li, Ian J. Deary, Lewis C. Becker, Karen A. Mather, Najaf Amin, Rui Xia, Bernard Mazoyer, Arno Villringer, Albert V. Smith, Henry Brodaty, Jeroen van der Grond, Vilmundur Gudnason, Rainer Malik, Christine Fennema-Notestine, Brian G. Kral, Asta Håberg, Clinton B. Wright, David C. Liewald, Sudha Seshadri, Claudia L. Satizabal, Bruce M. Psaty, Ralph L. Sacco, Reinhold Schmidt, Lisa R. Yanek, Mark Jenkinson, Qiong Yang, Jose R. Romero, Fidel Alfaro-Almagro, Philippe Amouyel, Margaret J. Wright, William T. Longstreth, Muralidharan Sargurupremraj, Mark E. Bastin, John B.J. Kwok, M. Arfan Ikram, David J. Stott, Nicole Dueker, Lukas Pirpamer, Perminder S. Sachdev, Stéphanie Debette, Edith Hofer, Ludovica Griffanti, Alexa S. Beiser, Nicola J. Armstrong, Stephen M. Smith, Lloyd T. Elliott, Wei Wen, J. Wouter Jukema, William S. Kremen, Markus Scholz, Anbupalam Thalamuthu, Peter R. Schofield, Clifford R. Jack, Stella Trompet, Gennady V. Roshchupkin, Matthias L. Schroeter, Joanna M. Wardlaw, Thomas H. Mosley, Michelle Luciano, Lenore J. Launer, Meike W. Vernooij, Maria J. Knol, Pauline Maillard, Charles DeCarli, Jonathan Marchini, Rebecca F. Gottesman, Paul A. Nyquist, Martin Dichgans, Zoe Morris, Cornelia M. van Duijn, David Ames, Veronica A. Witte, Hieab H.H. Adams, Mark A. Logue, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidemiology, and Clinical Genetics
Subjects: Male, Aging, Cardiorespiratory Medicine and Haematology, 0302 clinical medicine, pathology [Brain], pathology [White Matter], 2.1 Biological and endogenous factors, risk factors, Aetiology, genetics [Genetic Predisposition to Disease], 0303 health sciences, neuroimaging, Middle Aged, White Matter, Cerebral Small Vessel Diseases, Stroke, medicine.anatomical_structure, VINTAGE, Neurological, Deep white matter hyperintensities, Female, diagnostic imaging [Cerebral Small Vessel Diseases], Cardiology and Cardiovascular Medicine, Cartography, white matter, Biotechnology, brain, Clinical Sciences, Article, diagnostic imaging [White Matter], White matter, 03 medical and health sciences, Clinical Research, Genetic variation, Genetics, Acquired Cognitive Impairment, medicine, Humans, Genetic Predisposition to Disease, ddc:610, HEALTHY, diagnostic imaging [Brain], 030304 developmental biology, Aged, Advanced and Specialized Nursing, Neurology & Neurosurgery, genome-wide association study, business.industry, Prevention, Human Genome, Neurosciences, Brain Disorders, Clinical neurology, Periventricular white matter hyperintensities, genetics [Cerebral Small Vessel Diseases], pathology [Cerebral Small Vessel Diseases], Dementia, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
Published: 2020

31. Dietary patterns in adolescence and risk of colorectal cancer: a population-based study

Author: Guðny Sjofn, Thordardottir, Kristjana, Einarsdottir, Marianna, Thordardottir, Laufey, Tryggvadottir, Unnur A, Valdimarsdottir, Vilmundur, Gudnason, Laufey, Steingrimsdottir, Thor, Aspelund, Bryndis Eva, Birgisdottir, and Johanna E, Torfadottir
Subjects: Male, Meat, Adolescent, Research, Animals, Humans, Female, Colorectal Neoplasms, Aged, Diet, Proportional Hazards Models
Abstract: To study whether dietary patterns in adolescence are associated with risk of colorectal cancer (CRC).Food frequency data were obtained from the AGES-Reykjavik study, conducted between 2002 and 2006, which included 5,078 (58% women) participants with mean age of 77 (± 5.8) years. Principal component analysis was used to identify dietary patterns. Participants were followed through linkage to the Icelandic Cancer Registry. Multivariable Cox models were used to calculate hazard ratios (HR) of CRC and 95% confidence interval (CI) by dietary patterns.During the follow-up period (mean 8.2 years), 136 participants (75 women and 61 men) were diagnosed with CRC. The main dietary pattern in adolescence was characterized by high intake of traditional food items consumed in the earlier half of the twentieth century, namely, salted or smoked meat and fish, milk, offal, rye bread, and oatmeal. Compared to the lowest tertile, the middle tertile of this pattern was associated with increased risk of CRC (HR 1.63, 95% CI 1.04-2.57), while the highest tertile was not statistically associated with CRC (HR 1.48, 95% CI 0.93-2.37), except among women (HR 2.06, 95% CI 1.11-3.84).These data suggest that strong adherence to a traditional Icelandic diet in adolescence might increase the risk of CRC, particularly among women. More research is need on the association between food items and dietary patterns of relevance to CRC at different points in the life cycle.
Published: 2020

32. Type 2 diabetes, change in depressive symptoms over time, and cerebral small vessel disease – Longitudinal data of the AGES-Reykjavik Study

Author: Lenore J. Launer, Thomas T. van Sloten, Jennifer Ding, Sigurdur Sigurdsson, Vilmundur Gudnason, Coen D.A. Stehouwer, Sytze P. Rensma, Interne Geneeskunde, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), MUMC+: Centrum voor Chronische Zieken (3), MUMC+: HVC Pieken Maastricht Studie (9), and MUMC+: MA Interne Geneeskunde (3)
Subjects: Male, Research design, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Iceland, 030209 endocrinology & metabolism, Disease, Type 2 diabetes, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Dementia, Longitudinal Studies, 030212 general & internal medicine, Epidemiology/Health Services Research, education, POPULATION, SCALE, Depression (differential diagnoses), Aged, Aged, 80 and over, RISK, Advanced and Specialized Nursing, education.field_of_study, HYPERTENSION, Depression, business.industry, DEMENTIA, Brain, Organ Size, ASSOCIATION, medicine.disease, Magnetic Resonance Imaging, Diabetes Mellitus, Type 2, Cerebral Small Vessel Diseases, Cardiology, Female, Geriatric Depression Scale, business, STANDARDS
Abstract: OBJECTIVE Type 2 diabetes has been associated with depression. However, the underlying pathophysiological mechanisms remain unknown. Cerebral small vessel disease, a consequence of diabetes, may lead to depression. Therefore, we evaluated whether cerebral small vessel disease mediates the association between type 2 diabetes and higher depressive symptoms. RESEARCH DESIGN AND METHODS We used longitudinal data from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, with examinations from 2002 to 2006 and 5 years later. Type 2 diabetes was defined as self-reported history of type 2 diabetes, use of blood glucose–lowering drugs, or fasting blood glucose level ≥7.0 mmol/L. Cerebral small vessel disease load was quantified in a composite score based on MRI-defined presence of high white matter hyperintensity volume, low total brain parenchyma volume, and subcortical infarcts, cerebral microbleeds, and large perivascular spaces. The 5-year change in the 15-item Geriatric Depression Scale score (GDS-15) was measured between baseline and follow-up. RESULTS Included were 2,135 individuals without dementia and baseline depression (baseline age 74.5 [SD 4.6] years, 1,245 women [58.3%], and 197 [9.2%] with diabetes). The GDS-15 score increased 0.4 (SD 1.6) points over time. Baseline diabetes was associated with a greater increase in the GDS-15 score (β = 0.337; 95% CI 0.094; 0.579), adjusted for age, sex, education, and cardiovascular risk factors. Baseline cerebral small vessel disease and change of cerebral small vessel disease statistically significantly mediated a part of this association. CONCLUSIONS Type 2 diabetes is associated with a greater increase in depressive symptoms score over 5 years, and cerebral small vessel disease partly explains this association.
Published: 2020

33. Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose

Author: Yingchang Lu, Denis Rybin, Paul M. Ridker, Tamara B. Harris, Ruth J. F. Loos, Tuomo Rankinen, Patricia A. Peyser, Nora Franceschini, Adolfo Correa, Caroline Hayward, Jerome I. Rotter, Ayse Demirkan, Mohsen Ghanbari, Alison D. Murray, Jonathan Marten, Peitao Wu, Mike A. Nalls, Lawrence F. Bielak, Cornelia M. van Duijn, Salman M. Tajuddin, Yize Li, Michael M. Province, Jingmin Liu, Lynda M. Rose, André G. Uitterlinden, D. C. Rao, Solomon K. Musani, Vilmundur Gudnason, Albert V. Smith, Sharon L.R. Kardia, Raymond Noordam, Susan Redline, Erwin P. Bottinger, Daniel I. Chasman, Lenore J. Launer, Alan B. Zonderman, Renée de Mutsert, Mary F. Feitosa, Ching-Ti Liu, James G. Wilson, Dina Vojinovic, Charles Kooperberg, Josée Dupuis, Najaf Amin, Claude Bouchard, Jose C. Florez, Linda Kao, Dennis O. Mook-Kanamori, Karen Schwander, Blair H. Smith, Michele K. Evans, David S. Siscovick, Jason L. Vassy, James B. Meigs, Sridharan Raghavan, Donna K. Arnett, Trudy Voortman, Jun Liu, Epidemiology, Internal Medicine, Li, Yize [0000-0003-1074-281X], Marten, Jonathan [0000-0001-6916-2014], Raghavan, Sridharan [0000-0003-0643-4873], Ghanbari, Mohsen [0000-0002-9476-7143], Liu, Jun [0000-0001-5288-3042], Voortman, Trudy [0000-0003-2830-6813], Bouchard, Claude [0000-0002-0048-491X], Dupuis, Josée [0000-0003-2871-3603], Vassy, Jason L [0000-0001-6113-5564], Apollo - University of Cambridge Repository, Meyre, David, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: Male, Oncology, Aging, Epidemiology, Social Sciences, Genome-wide association study, Endocrinology, 0302 clinical medicine, Sociology, Smoking Habits, Psychology, Aetiology, Incidence, Statistics, Genomics, Fasting, Type 2 Diabetes, 3. Good health, Physical Sciences, Medicine, Type 2, medicine.medical_specialty, Genotype, Endocrine Disorders, Science, Single-nucleotide polymorphism, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Clinical Research, Diabetes Mellitus, Genetics, Genome-Wide Association Studies, Humans, SNP, Smoking habits, Polymorphism, Statistical Methods, Trait Locus Analysis, Aged, Behavior, Tobacco Smoke and Health, Prevention, Biology and Life Sciences, Computational Biology, medicine.disease, Glucose, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, Feasibility Studies, TCF7L2, Mathematics, Blood Glucose, 0301 basic medicine, Candidate gene, Type 2 diabetes, Cohort Studies, Habits, Mathematical and Statistical Techniques, Consortia, Polymorphism (computer science), Medicine and Health Sciences, 2.1 Biological and endogenous factors, Multidisciplinary, Diabetes, Epidemiology of Aging, Single Nucleotide, Metaanalysis, Middle Aged, Female, Reykingar, Research Article, Adult, Risk, General Science & Technology, Black People, 030209 endocrinology & metabolism, Research and Analysis Methods, Polymorphism, Single Nucleotide, Cigarette Smoking, Sykursýki, Internal medicine, Tobacco, medicine, Erfðafræði, Nutrition, business.industry, Human Genome, Human Genetics, Genome Analysis, Good Health and Well Being, Metabolic Disorders, business, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p, WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The grant funding of WHI are R21 HL123677, R56 DK104806 and R01 MD012765 to NF. The FamHS was funded by R01HL118305 and R01HL117078 NHLBI grants, and 5R01DK07568102 and 5R01DK089256 NIDDK grant." and "The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (project # Z01-AG000513 and human subjects protocol number 09-AGN248). Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL119443, HL087660, HL054464, HL054457, and HL054481) of the National Institutes of Health. Ruth loos is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). The Rotterdam Study GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006- 01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002- 01254). The ERF study was further supported by ENGAGE consortium and CMSB. Highthroughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWORFBR 047.017.043).ERF was further supported by the ZonMw grant (project 91111025), and this work was partially supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6- 4278). This study is also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to Drs. Meigs, Dupuis and Florez, NIDDK K24 DK080140 to Dr. Meigs, and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr. Florez. The HERITAGE Family Study was supported by National Heart, Lung, and Blood Institute grant HL-45670. The Women's Genome Health Study is supported by the National Heart, Lung, and Blood Instutute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913). Additional support for endpoint collection was provided by the National Heart, Lung, and Blood Institute under ARRA funding (HL099355). HyperGEN (Hypertension Genetic Epidemiology Network): The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673- 12. The AGES study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease)”and “Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6, the Scottish Funding Council HR03006 and the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z) for Stratifying Resilience and Depression Longitudinally (STRADL). Genotyping was funded by the UK's Medical Research Council. Jose C. Florez, NIDDK K24 DK110550 The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Additionally, one or more authors are affiliated with the following commercial entities: Interleukin Genetics, GlaxoSmithKline, Daiichi-Sankyo, AstraZeneca, Data Tecnica International LLC, Illumina Inc., University of California Healthcare, Janssen Pharmaceuticals, Goldfinch Bio, and Novo Nordisk. Please see the Competing Interests Statement for additional details. The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
Published: 2020

34. Quantitative 3D imaging parameters improve prediction of hip osteoarthritis outcome

Author: T Turmezei, H. Jonsson, Thor Aspelund, Kenneth E. S. Poole, Andrew H. Gee, Graham M. Treece, Vilmundur Gudnason, Sigurdur Sigurdsson, Turmezei, T D [0000-0003-0365-8054], Treece, G M [0000-0003-0047-6845], Aspelund, T [0000-0002-7998-5433], Apollo - University of Cambridge Repository, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Turmezei, T. D. [0000-0003-0365-8054], Treece, G. M. [0000-0003-0047-6845], Aspelund, T. [0000-0002-7998-5433], Turmezei, TD [0000-0003-0365-8054], and Treece, GM [0000-0003-0047-6845]
Subjects: Male, Computer science, 123, medicine.medical_treatment, Radiography, lcsh:Medicine, Osteoarthritis, Osteoarthritis, Hip, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Odds Ratio, 692/4023/1670/407, lcsh:Science, Multidisciplinary, Statistics, article, Middle Aged, Liðamót, Outcome (probability), 3. Good health, Slitgigt, 639/166/985, Female, Hip Joint, 139, Biomedical engineering, 3D, Adult, 141, musculoskeletal diseases, medicine.medical_specialty, Joint replacement, 639/705/531, Statistical parametric mapping, Predictive markers, 03 medical and health sciences, Physical medicine and rehabilitation, Imaging, Three-Dimensional, 692/53/2423, Therapy development, medicine, Hip osteoarthritis, Humans, Joint (geology), Aged, 030203 arthritis & rheumatology, Þrívídd, business.industry, lcsh:R, Gold standard (test), medicine.disease, Case-Control Studies, lcsh:Q, business
Abstract: Publisher's version (útgefin grein), Osteoarthritis is an increasingly important health problem for which the main treatment remains joint replacement. Therapy developments have been hampered by a lack of biomarkers that can reliably predict disease, while 2D radiographs interpreted by human observers are still the gold standard for clinical trial imaging assessment. We propose a 3D approach using computed tomography—a fast, readily available clinical technique—that can be applied in the assessment of osteoarthritis using a new quantitative 3D analysis technique called joint space mapping (JSM). We demonstrate the application of JSM at the hip in 263 healthy older adults from the AGES-Reykjavík cohort, examining relationships between 3D joint space width, 3D joint shape, and future joint replacement. Using JSM, statistical shape modelling, and statistical parametric mapping, we show an 18% improvement in prediction of joint replacement using 3D metrics combined with radiographic Kellgren & Lawrence grade (AUC 0.86) over the existing 2D FDA-approved gold standard of minimum 2D joint space width (AUC 0.73). We also show that assessment of joint asymmetry can reveal significant differences between individuals destined for joint replacement versus controls at regions of the joint that are not captured by radiographs. This technique is immediately implementable with standard imaging technologies., K.P. acknowledges the support of Cambridge NIHR Biomedical Research Centre. T.T. thanks the Wellcome Trust for funding support (100676/Z/12/Z) for part of this work. All authors acknowledge funding support grants from the National Institute on Aging (NO1-AG-1-2100), Bethesda, USA, and the Icelandic Government. All authors thank Dr Ilya Burkov, formerly PhD student at the University of Cambridge, for his work on segmentation of the proximal femur from CT data, Professor Lee Shepstone, University of East Anglia, for guidance with generalised estimating equation analysis, and Professor Karl Friston, University College London, for guidance with statistical parametric mapping analysis.
Published: 2020

35. Assessing cardiovascular risks from a mid-thigh CT image: A tree-based machine learning approach using radiodensitometric distributions

Author: Kyle J. Edmunds, Paolo Gargiulo, Vilmundur Gudnason, Ugo Carraro, Marco Recenti, Carlo Ricciardi, Sigurdur Sigurdsson, Verkfræðideild (HR), Department of Engineering (RU), Læknadeild (HÍ), Institute of Biomedical and Neural Engineering (IBNE) (RU), Tæknisvið (HR), School of Technology (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskólinn í Reykjavík, Reykjavik University, Háskóli Íslands, University of Iceland, Ricciardi, C., Edmunds, K. J., Recenti, M., Sigurdsson, S., Gudnason, V., Carraro, U., Gargiulo, P., and Faculty of Medicine (UI)
Subjects: Male, Sarcopenia, lcsh:Medicine, 030204 cardiovascular system & hematology, computer.software_genre, Logistic regression, Cardiovascular System, Cardiovascular risks, Machine Learning, Tissue changes, Sneiðmyndatökur, 0302 clinical medicine, Risk Factors, Cardiovascular Disease, Vefjabreytingar, Feature (machine learning), Skeletal muscle strength, Medicine, Cross-sectional area, Tree based, lcsh:Science, Computed tomography, Aged, 80 and over, Multidisciplinary, Aldraðir, Kransæðasjúkdómar, Regression analysis, Heart, Middle Aged, Random forest, Algorithm, Cardiovascular Diseases, Tissue type, Female, Biomedical engineering, Algorithms, CT, Human, Beinin, Logistic Model, Cardiovascular health, Cardiology, NTRA, Heart failure, Machine learning, Article, 03 medical and health sciences, Age, Humans, Raförvun, Aged, Heart Failure, Hjartabilun, business.industry, Risk Factor, lcsh:R, Mass, Coronary heart disease, Vöðvar, Logistic Models, Electrical stimulation, lcsh:Q, Artificial intelligence, business, Tomography, X-Ray Computed, computer, 030217 neurology & neurosurgery
Abstract: Publisher's version (útgefin grein), The nonlinear trimodal regression analysis (NTRA) method based on radiodensitometric CT distributions was recently developed and assessed for the quantification of lower extremity function and nutritional parameters in aging subjects. However, the use of the NTRA method for building predictive models of cardiovascular health was not explored; in this regard, the present study reports the use of NTRA parameters for classifying elderly subjects with coronary heart disease (CHD), cardiovascular disease (CVD), and chronic heart failure (CHF) using multivariate logistic regression and three tree-based machine learning (ML) algorithms. Results from each model were assembled as a typology of four classification metrics: total classification score, classification by tissue type, tissue-based feature importance, and classification by age. The predictive utility of this method was modelled using CHF incidence data. ML models employing the random forests algorithm yielded the highest classification performance for all analyses, and overall classification scores for all three conditions were excellent: CHD (AUCROC: 0.936); CVD (AUCROC: 0.914); CHF (AUCROC: 0.994). Longitudinal assessment for modelling the prediction of CHF incidence was likewise robust (AUCROC: 0.993). The present work introduces a substantial step forward in the construction of non-invasive, standardizable tools for associating adipose, loose connective, and lean tissue changes with cardiovascular health outcomes in elderly individuals., The authors wish to thank the University Hospital Landspitali in Reykjavik for the infrastructural support.
Published: 2020

36. Characteristics of incidence hip fracture cases in older adults participating in the longitudinal AGES-Reykjavik study

Author: M. F. Cotch, Laufey Steingrimsdottir, L. J. Launer, Kristin Siggeirsdottir, Thorhallur I. Halldorsson, Gunnar Sigurdsson, Vilmundur Gudnason, Sigrun Sunna Skuladottir, Ingibjörg Hjaltadóttir, and Alfons Ramel
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Iceland, Poison control, 030209 endocrinology & metabolism, Timed Up and Go test, 03 medical and health sciences, 0302 clinical medicine, Bone Density, Risk Factors, Internal medicine, medicine, Humans, Mass index, Prospective Studies, Prospective cohort study, Postural Balance, Aged, Bone mineral, Hip fracture, business.industry, Hip Fractures, Incidence, medicine.disease, Confidence interval, Time and Motion Studies, Lean body mass, Female, 030101 anatomy & morphology, business
Abstract: Poor physical function and body composition my partly predict the risk of falls leading to fracture regardless of bone mineral density. To examine the relationship between body composition, physical function, and other markers of health with hip fractures in older community-dwelling Icelandic adults. A prospective cohort of 4782 older adults from the AGES-Reykjavik study. Baseline recruitment took place between 2002 and 2006, and information on hip fractures occurring through 2012 was extracted from clinical records. Using multivariate regression analyses, baseline measures of bone health, physical function, and body composition were compared between those who later experienced hip fractures and to those who did not. Associations with the risk of fractures were quantified using Cox regression. Mean age was 76.3 years at baseline. After adjustment for age, regression showed that male hip fracture cases compared with non-cases had (mean (95% confidence interval)) significantly lower thigh muscle cross-sectional area − 5.6 cm2 (− 10.2, − 1.1), poorer leg strength – 28 N (− 49, − 7), and decreased physical function as measured by longer timed up and go test 1.1 s (0.5, 1.7). After adjustment for age, female cases had, compared with non-cases, lower body mass index − 1.5 kg/m2 (− 2.1, − 0.9), less lean mass − 1.6 kg (− 2.5, − 0.8), thigh muscle cross-sectional area − 4.4 cm2 (− 6.5, − 2.3), and worse leg strength − 16 N (− 25, − 6). These differences largely persisted after further adjustment for bone mineral density (BMD), suggesting that body composition may contribute to the risk of fracture independent of bone health. When examining the association between these same factors and hip fractures using Cox regression, the same conclusions were reached. After accounting for age and BMD, older adults who later experienced a hip fracture had poorer baseline measures of physical function and/or body composition, which may at least partly contribute to the risk of falls leading to fracture.
Published: 2020

37. A pooled-analysis of age and sex based coronary artery calcium scores percentiles

Author: Vilmundur Gudnason, Aeilko H. Zwinderman, Paulo A. Lotufo, Elias F. Gudmundsson, Maurice W J de Ronde, Paolo Raggi, Bruce Cooil, Isabela M. Benseñor, Sara-Joan Pinto-Sietsma, Thor Aspelund, Matthew J. Budoff, S. Matthijs Boekholdt, Yuki Ohmoto-Sekine, Mariette Biemond, R. Nils Planken, Amir M. Khoshiwal, Gastroenterology and Hepatology, Graduate School, Radiology and Nuclear Medicine, ACS - Pulmonary hypertension & thrombosis, Cardiology, ACS - Atherosclerosis & ischemic syndromes, Epidemiology and Data Science, APH - Methodology, and ACS - Heart failure & arrhythmias
Subjects: Adult, Male, Percentile, Computed Tomography Angiography, Population, MEDLINE, Coronary Artery Disease, 030204 cardiovascular system & hematology, Percentile nomogram, Coronary Angiography, Asymptomatic, 030218 nuclear medicine & medical imaging, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Age Distribution, Sex Factors, Predictive Value of Tests, Risk Factors, Multidetector Computed Tomography, medicine, Humans, Radiology, Nuclear Medicine and imaging, cardiovascular diseases, Sex Distribution, education, Vascular Calcification, Computed tomography, Aged, Aged, 80 and over, education.field_of_study, business.industry, Age Factors, nutritional and metabolic diseases, Nomogram, Middle Aged, medicine.disease, Calcium score, Race Factors, Nomograms, Sample size determination, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Risk assessment, Demography
Abstract: Background Age and sex based coronary artery calcium score (CAC) percentiles have been used to improve coronary artery disease (CAD) risk prediction. However, the main limitation of the CACs percentiles currently in use is that they are often based on single studies. We performed a pooled analysis of all available studies that reported on CAC percentiles, in order to develop more generalizable age and sex nomograms. Methods PubMed/Medline and Embase were searched for studies that reported nomograms of age and sex-based CACs percentiles. Studies were included if they reported data collected among asymptomatic individuals without a history of cardiovascular disease. Absolute CACs for each specific percentile stratum were pooled and new percentiles were generated taking into account the sample size of the study. Results We found 831 studies, of which 12 met the inclusion criteria. Data on CACs percentiles of 134,336 Western and 33,488 Asians were pooled separately, rendering a weighted CACs percentile nomogram available at https://www.calciumscorecalculator.com . Our weighted percentiles differed by up to 24% from the nomograms in use today. Conclusions Our pooled age and sex based CACs percentiles based on over 155,000 individuals should provide a measure of risk that is more applicable to a wider population than the ones currently in use and hopefully will lead to better risk assessment and treatment decisions.
Published: 2020

38. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author: Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. Barnes, Medical Informatics, Epidemiology, Internal Medicine, Weng, Lu-Chen [0000-0003-1475-4930], Hall, Amelia Weber [0000-0002-7915-0313], Tucker, Nathan R [0000-0002-5071-4218], Chaffin, Mark D [0000-0002-1234-5562], Roselli, Carolina [0000-0001-5267-6756], Barnes, Michael R [0000-0001-9097-7381], Mifsud, Borbala [0000-0003-3429-3094], Hayward, Caroline [0000-0002-9405-9550], Concas, Maria Pina [0000-0003-3598-2537], Boutin, Thibaud [0000-0003-4754-1675], Kolcic, Ivana [0000-0001-7918-6052], Rudan, Igor [0000-0001-6993-6884], Souza, Renan P [0000-0002-9479-4432], Giedraitis, Vilmantas [0000-0003-3423-2021], Ingelsson, Erik [0000-0003-2256-6972], Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Hicks, Andrew A [0000-0001-6320-0411], Sundström, Johan [0000-0003-2247-8454], Nelson, Christopher P [0000-0001-8025-2897], Riaz, Muhammad B [0000-0002-5512-1745], Sinagra, Gianfranco [0000-0003-2700-8478], Mishra, Pashupati P [0000-0001-5177-3431], Caulfield, Mark J [0000-0001-9295-3594], Dominiczak, Anna [0000-0003-4913-3608], Risch, Lorenz [0000-0003-2692-6699], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Isaacs, Aaron [0000-0001-5037-4834], van Duijn, Cornelia M [0000-0002-2374-9204], Gudnason, Vilmundur [0000-0001-5696-0084], Smith, Albert V [0000-0003-1942-5845], Loos, Ruth JF [0000-0002-8532-5087], Preuss, Michael H [0000-0001-5266-8465], Correa, Adolfo [0000-0002-9501-600X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Waldenberger, Melanie [0000-0003-0583-5093], Mangino, Massimo [0000-0002-2167-7470], Rienstra, Michiel [0000-0002-2581-070X], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Fatkin, Diane [0000-0002-9010-9856], Brody, Jennifer A [0000-0001-8509-148X], Rice, Kenneth [0000-0002-3071-7278], Pattaro, Cristian [0000-0002-4119-0109], Wouter Jukema, J [0000-0002-3246-8359], Weiss, Stefan [0000-0002-3553-4315], Havulinna, Aki S [0000-0002-4787-8959], Sääksjärvi, Katri [0000-0002-5061-4911], Salomaa, Veikko [0000-0001-7563-5324], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Lakatta, Edward G [0000-0002-4772-0035], Lin, Honghuang [0000-0003-3043-3942], Lunetta, Kathryn L [0000-0002-9268-810X], Murray, Alison D [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Uitterlinden, André [0000-0002-7276-3387], Peters, Ulrike [0000-0001-5666-9318], Alonso, Alvaro [0000-0002-2225-8323], Ehret, Georg B [0000-0002-5730-0675], Soliman, Elsayed Z [0000-0001-5632-8150], Gogarten, Stephanie M [0000-0002-7231-9745], Kerr, Kathleen F [0000-0002-6438-9583], Abdullah Said, M [0000-0003-2920-7745], Orini, Michele [0000-0001-5773-0344], Ramirez, Julia [0000-0003-4130-5866], Van Duijvenboden, Stefan [0000-0001-8897-558X], Gudbjartsson, Daniel F [0000-0002-5222-9857], Sulem, Patrick [0000-0001-7123-6123], Thorolfsdottir, Rosa B [0000-0001-7475-0398], Benjamin, Emelia J [0000-0003-4076-2336], Stefansson, Kari [0000-0003-1676-864X], Ellinor, Patrick T [0000-0002-2067-0533], Jamshidi, Yalda [0000-0003-0151-6482], Lubitz, Steven A [0000-0002-9599-4866], Munroe, Patricia B [0000-0002-4176-2947], Apollo - University of Cambridge Repository, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Cardiovascular Centre (CVC), Ntalla, I., Weng, L. -C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract: Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.
Published: 2020

39. Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis

Author: Simon P. Hart, Vilmundur Gudnason, Yingze Zhang, Hiroto Hatabu, Rebecca Braybrooke, R. Gisli Jenkins, Shwu-Fan Ma, Michael Ng, Carlos Flores, George T. O'Connor, Ma'en Obeidat, Nik Hirani, Brian D. Hobbs, Megan L. Paynton, Amy Dressen, Ayodeji Adegunsoye, Helen Booth, Dominic Furniss, Philippe Joubert, Eunice Oballa, Ian Sayers, Martin D. Tobin, Krina T. Zondervan, Richard Hubbard, Xuan Li, Yohan Bossé, John D. Newell, Beatriz Guillen-Guio, Ann B. Millar, Wim Timens, Mary E. Strek, Gunnar Gudmundsson, Philip L. Molyneaux, Gary M. Hunninghake, Ani Manichaikul, Tasha E. Fingerlin, Rachel K. Putman, Richard J. Allen, Vidyia Navaratnam, Maria Molina-Molina, Don D. Sin, Helen Parfrey, Luke M. Kraven, Moira K. B. Whyte, Xuting R. Sheng, Phuwanat Sakornsakolpat, David J. Lederer, David C. Nickle, Ian P. Hall, Brian L. Yaspan, Louise V. Wain, Toby M. Maher, Gauri Saini, Ke Hao, Michael Hill, Naftali Kaminski, Andrew P. Morris, Hanfei Xu, Justin M. Oldham, David A. Schwartz, Robin J. McAnulty, Michael H. Cho, Victor E. Ortega, Margaret Neighbors, Imre Noth, William A. Fahy, Action for Pulmonary Fibrosis, National Institute for Health Research, British Lung Foundation, Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: Male, Pathology, Epidemiology, Respiratory System, Kinesins, Gene Expression, Genome-wide association study, Cell Cycle Proteins, TOR Serine-Threonine Kinases/metabolism, VARIANTS, Critical Care and Intensive Care Medicine, Idiopathic pulmonary fibrosis, 0302 clinical medicine, KIF15, TELOMERES, genetics, 030212 general & internal medicine, Respiratory system, 11 Medical and Health Sciences, RISK, TOR Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, respiratory system, Middle Aged, MAD1L1, 3. Good health, medicine.anatomical_structure, SURVIVAL, epidemiology, Female, Life Sciences & Biomedicine, Kinesin/genetics, Signal Transduction, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Spindle Apparatus, DIAGNOSIS, Risk Assessment, REGION, 03 medical and health sciences, Critical Care Medicine, General & Internal Medicine, medicine, Genetics, Erfðafræði, Humans, Genetic Predisposition to Disease, Aged, Cell Cycle Proteins/genetics, Lungnasjúkdómar, Lung, Science & Technology, DEPTOR, business.industry, MUTATIONS, Case-control study, Editorials, RTEL1, medicine.disease, Epithelium, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Genarannsóknir, 030228 respiratory system, EVENT, Case-Control Studies, GAIN, business, Intracellular Signaling Peptides and Proteins/genetics, Idiopathic Pulmonary Fibrosis/genetics, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Measurements and Main Results: We identified and replicated threenewgenome-wide significant (P, R.J.A. is an Action for Pulmonary Fibrosis Research Fellow. L.V.W. holds a GSK/British Lung Foundation Chair in Respiratory Research. R.G.J. is supported by a National Institute for Health Research (NIHR) Research Professorship (NIHR reference RP-2017-08-ST2-014). I.N. is supported by the NHLBI (R01HL130796). B.G.-G. is funded by Agencia Canaria de Investigación, Innovación y Sociedad de la Información (TESIS2015010057) cofunded by European Social Fund. J.M.O. is supported by the NHLBI (K23HL138190). C.F. is supported by the Spanish Ministry of Science, Innovation and Universities (grant RTC-2017-6471-1; Ministerio de Ciencia e Innovacion/Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea) cofinanced by the European Regional Development Funds “A way of making Europe” from the European Union and by agreement OA17/008 with Instituto Tecnológico y de Energías Renovables to strengthen scientific and technological education, training, research, development and innovation in Genomics, Personalized Medicine and Biotechnology. The Spain Biobank array genotyping service was performed at CEGEN-PRB3-ISCIII, which is supported by PT17/0019, of the PE I+D+i 2013–2016, funded by Instituto de Salud Carlos III, and cofinanced by the European Regional Development Funds. P.L.M. is an Action for Pulmonary Fibrosis Research Fellow. M.O. is a fellow of the Parker B. Francis Foundation and a Scholar of the Michael Smith Foundation for Health Research. B.D.H. is supported by NIH K08 HL136928, Parker B. Francis Research Opportunity Award. M.H.C. and G.M.H. are supported by NHLBI grants R01HL113264 (M.H.C.), R01HL137927 (M.H.C.), R01HL135142 (M.H.C. and G.M.H.), R01111024 (G.M.H.), and R01130974 (G.M.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. T.M.M. is supported by an NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017) and a British Lung Foundation Chair in Respiratory Research (C17-3). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health. I.P.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. I.S. is supported by Medical Research Council (G1000861) and Asthma UK (AUK-PG-2013-188). D.F. was supported by an Intermediate Fellowship from the Wellcome Trust (097152/Z/11/Z). This work was partially supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. V.N. is funded by an NIHR Clinical Lectureship. G.G. is supported by project grant 141513-051 from the Icelandic Research Fund and Landspitali Scientific Fund A-2016-023, A-2017-029, and A-2018-025. D.J.L. and A.M. are supported by Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SNP Health Association Resource (SHARe) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California) and the Broad Institute of Harvard and Massachusetts Institute of Technology (Boston, Massachusetts) using the Affymetrix Genome-Wide Human SNP Array 6.0. This work was supported by NIH grants R01 HL131565 (A.M.), R01 HL103676 (D.J.L.), and R01 HL137234 (D.J.L.).
Published: 2020

40. Genetic overlap between vascular pathologies and Alzheimer's dementia and potential causal mechanisms

Author: Yen Feng Lin, Albert V. Smith, Rebecca A. Betensky, Deborah Blacker, Thor Aspelund, Lenore J. Launer, Vilmundur Gudnason, and Jordan W. Smoller
Subjects: Male, 0301 basic medicine, Apolipoprotein E, Mediation (statistics), Epidemiology, Single-nucleotide polymorphism, Disease, Neuropsychological Tests, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Apolipoproteins E, 0302 clinical medicine, Developmental Neuroscience, Alzheimer Disease, Risk Factors, medicine, Humans, Dementia, Cognitive Dysfunction, Alzheimer s dementia, Aged, business.industry, Health Policy, Brain, Cognition, medicine.disease, White Matter, Peptide Fragments, Hyperintensity, Psychiatry and Mental health, 030104 developmental biology, Microvessels, Female, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract: Introduction We sought to examine the genetic overlap between vascular pathologies and Alzheimer's disease (AD) dementia, and the potential mediating role of vascular pathologies between AD-related genetic variants and late-life cognition. Methods For 2907 stroke-free older individuals, we examined the association of polygenic risk scores for AD dementia (ADPRSs) with vascular pathologies and with cognition. Mediation analyses addressed whether association between ADPRSs and cognition was mediated by a vascular pathology. Results ADPRSs were associated with lobar cerebral microbleeds, white matter lesion load, and coronary artery calcification, mostly explained by single nucleotide polymorphisms in the 19q13 region. The effect of ADPRSs on cognition was partially but significantly mediated by cerebral microbleeds, white matter lesions, and coronary artery calcification. Discussion Our findings provide evidence for genetic overlap, mostly due to apolipoprotein E ( APOE ) gene, between vascular pathologies and AD dementia. The association between AD polygenic risk and late-life cognition is mediated in part via effects on vascular pathologies.
Published: 2018

41. The AGES-Reykjavik Study suggests that change in kidney measures is associated with subclinical brain pathology in older community-dwelling persons

Author: M. Arfan Ikram, Jie Ding, Vilmundur Gudnason, Sanaz Sedaghat, Andrew S. Levey, Osorio Meirelles, Lenore J. Launer, Sigurdur Sigurdsson, Mark A. van Buchem, Gudny Eiriksdottir, and Epidemiology
Subjects: Male, Pathology, medicine.medical_specialty, Urinary system, Population, Renal function, Kidney, Article, albuminuria, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, subcortical infarcts, Humans, Medicine, Prospective Studies, 030212 general & internal medicine, Renal Insufficiency, Chronic, education, Serum Albumin, Aged, Subclinical infection, glomerular filtration rate, Creatinine, education.field_of_study, business.industry, Incidence, white matter hyperintensity, Odds ratio, Magnetic Resonance Imaging, White Matter, cortical infarcts, Confidence interval, chemistry, Nephrology, Cerebral Small Vessel Diseases, microbleeds, Disease Progression, Albuminuria, Female, Independent Living, medicine.symptom, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Decreased glomerular filtration rate (GFR) and albuminuria may be accompanied by brain pathology. Here we investigated whether changes in these kidney measures are linked to development of new MRI-detected infarcts and microbleeds, and progression of white matter hyperintensity volume. The study included 2671 participants from the population-based AGES-Reykjavik Study (mean age 75, 58.7% women). GFR was estimated from serum creatinine, and albuminuria was assessed by urinary albumin-to-creatinine ratio. Brain MRI was acquired at baseline (2002-2006) and 5 years later (2007-2011). New MRI-detected infarcts and microbleeds were counted on the follow-up scans. White matter hyperintensity progression was estimated as percent change in white matter hyperintensity volumes between the two exams. Participants with a large eGFR decline (over 3 ml/min/1.73m2 per year) had more incident subcortical infarcts (odds ratio 1.53; 95% confidence interval 1.05, 2.22), and more marked progression of white matter hyperintensity volume (difference: 8%; 95% confidence interval: 4%, 12%), compared to participants without a large decline. Participants with incident albuminuria (over 30 mg/g) had 21% more white matter hyperintensity volume progression (95% confidence interval: 14%, 29%) and 1.86 higher odds of developing new deep microbleeds (95% confidence interval 1.16, 2.98), compared to participants without incident albuminuria. The findings were independent of cardiovascular risk factors. Changes in kidney measures were not associated with occurrence of cortical infarcts. Thus, larger changes in eGFR and albuminuria are associated with increased risk for developing manifestations of cerebral small vessel disease. Individuals with larger changes in these kidney measures should be considered as a high risk population for accelerated brain pathology.
Published: 2018

42. The risk of developing a mismatch repair deficient colorectal cancer after undergoing cholecystectomy

Author: Thor Aspelund, Jon G. Jonasson, Matthías Halldórsson, Michael Hauptmann, Sigurdis Haraldsdottir, Kristín Huld Haraldsdóttir, Vilmundur Gudnason, Petur Snaebjornsson, and Elias F. Gudmundsson
Subjects: Male, congenital, hereditary, and neonatal diseases and abnormalities, Colorectal cancer, DNA repair, medicine.medical_treatment, Iceland, MLH1, DNA Mismatch Repair, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Cholecystectomy, Epigenetics, neoplasms, Gene, Aged, Aged, 80 and over, business.industry, Gastroenterology, Microsatellite instability, Middle Aged, medicine.disease, Immunohistochemistry, digestive system diseases, Logistic Models, Case-Control Studies, 030220 oncology & carcinogenesis, Cancer research, Female, Microsatellite Instability, 030211 gastroenterology & hepatology, DNA mismatch repair, Colorectal Neoplasms, business
Abstract: Mismatch repair deficient (dMMR) colorectal cancer (CRC) is caused by inactivation of the MMR DNA repair system, most commonly via epigenetic inactivation of the MLH1 gene, and these tumors occur most frequently in the right colon. The objective was to determine whether cholecystectomy (CCY) increases the risk of a dMMR CRC by comparing CCY incidence in patients with dMMR CRC and proficient MMR (pMMR) CRC to unaffected controls.All patients diagnosed with CRC in Iceland from 2000 to 2009 (n = 1171) were included. They had previously been screened for dMMR by immunohistochemistry (n = 129 were dMMR). Unaffected age- and sex-matched controls (n = 17,460) were obtained from large Icelandic cohort studies. Subjects were cross-referenced with all pathology databases in Iceland to establish who had undergone CCY. Odds ratios were calculated using unconditional logistic regression.Eighteen (13.7%) dMMR CRC cases and 90 (8.7%) pMMR CRC cases had undergone CCY compared to 1532 (8.8%) controls. CCY-related odds ratios (OR) were 1.06 (95% CI 0.90-1.26, p = .577) for all CRC, 1.16 (95% CI 0.66-2.05 p = .602) for dMMR CRCand 1.04 (95% CI 0.83-1.29, p = .744) for pMMR CRC. Furthermore, OR for dMMR CRC was 0.51 (95% CI 0.16-1.67, p = .266), 2.04 (95% CI 0.92-4.50, p = .080) and 1.08 (95% CI 0.40-2.89, p = .875) 10 years, 10-20 years and 20 years after a CCY, respectively.There was no evidence of increased risk of developing dMMR CRC after CCY although a borderline significantly increased 2-fold risk was observed 10-20 years after CCY. Larger studies are warranted to examine this further.
Published: 2018

43. Predictors of carotid plaque progression over a 4-year follow-up in the Reykjavik REFINE-study

Author: Bolli Thorsson, Sigurdur Sigurdsson, Gudlaug Bjornsdottir, Ran Sturlaugsdottir, Vilmundur Gudnason, Thor Aspelund, and Gudny Eiriksdottir
Subjects: Carotid Artery Diseases, Male, medicine.medical_specialty, Time Factors, Waist, Carotid Artery, Common, Plaque progression, Population, Iceland, Disease, 030204 cardiovascular system & hematology, Carotid Intima-Media Thickness, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, medicine, Humans, Longitudinal Studies, Prospective Studies, 030212 general & internal medicine, education, Aged, education.field_of_study, Framingham Risk Score, Surrogate endpoint, business.industry, Middle Aged, Plaque, Atherosclerotic, chemistry, Low-density lipoprotein, Plaque area, Disease Progression, Cardiology, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business
Abstract: Carotid plaque is an arterial marker suggested as a surrogate end point for cardiovascular disease. The aim of this study was to examine the association of risk factors at visit 1 with plaque formation and progression of total plaque area (TPA) during follow-up.We examined 1894 participants (50-69 years of age) in the population-based REFINE (Risk Evaluation For INfarct Estimates)-Reykjavik study.Among those with no plaque at baseline, plaque formation was associated with low density lipoprotein, sex, waist, former smoker and physical activity. Furthermore, both the Icelandic Heart Association (IHA) coronary heart disease (CHD) risk score and the atherosclerotic cardiovascular disease (ASCVD) risk score were highly associated with plaque formation in these individuals (p 0.001) and a better cardiovascular health score was protective. In those with plaque present at baseline, metabolic syndrome was associated with increased risk, while older age and statin use were associated with reduced risk of new plaque formation. Statin use was the only factor associated with the relative TPA progression, where participants not on treatment had 5.7% (p=0.029) greater rate of progression compared with statin users.A number of conventional risk factors at visit 1 were individually associated with plaque formation, also when combined into CHD and ASCVD risk scores, but not with the relative progression in TPA. Medical intervention with statins can reduce the relative progression rate of TPA in the general population with low grade of atherosclerosis, supporting statin use to slow progression of atherosclerosis.
Published: 2018

44. Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

Author: C M van Duijn, James S. Floyd, Maarit A. Laaksonen, André G. Uitterlinden, Colleen M. Sitlani, Y-Di Chen, H J Lin, Christopher Newton-Cheh, Kent D. Taylor, Albert V. Smith, Til Stürmer, Kari E. North, Peter W. Macfarlane, Dennis O. Mook-Kanamori, Raymond Noordam, Yun Li, Jun Li, Tamar Sofer, Raul Mendez-Giraldez, Adrienne M. Stilp, Cathy C. Laurie, Ian Ford, Christy L. Avery, Stella Trompet, Nona Sotoodehnia, Jeffrey Roach, T.B. Harris, Jennifer A. Brody, Susan R. Heckbert, L. A. Cupples, J. C. Bis, Ruifang Li-Gao, Christopher J. O'Donnell, Vilmundur Gudnason, Robert C. Kaplan, Brendan M. Buckley, R. de Mutsert, Jan A. Kors, Steve Cummings, Elsayed Z. Soliman, Xiaohui Li, Kati Kristiansson, Linda Broer, Alexander P. Reiner, Joop Jukema, Aaron Isaacs, Evan L. Busch, Craig R. Lee, Amanda A. Seyerle, Heather M. Highland, Kathleen F. Kerr, Bruce M. Psaty, Leslie A. Lange, Qing Duan, Veikko Salomaa, Kenneth Rice, James D. Stewart, Stephanie M. Gogarten, E. A. Whitsel, Kirk C. Wilhelmsen, Daniel S. Evans, Yongmei Liu, Bruno H. Stricker, Fangui Sun, Kimmo Porthan, A. Hofman, Gina M. Peloso, L. J. Launer, Kerri L. Wiggins, Melanie D. Napier, Jerome I. Rotter, Frits R. Rosendaal, James G. Wilson, Ramachandran S. Vasan, Kardiologian yksikkö, Department of Medicine, Clinicum, Genetica & Celbiologie, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, Epidemiology, Internal Medicine, Medical Informatics, and Erasmus MC other
Subjects: Male, 0301 basic medicine, Influencing antihypertensive response, Aging, Sodium Chloride Symporter Inhibitors, Blood-pressure response, Gene-environment interactions, Ethnic populations, VARIANTS, Cardiovascular, Bioinformatics, Cohort Studies, Electrocardiography, Cardiovascular drugs, Heart Rate, Polymorphism (computer science), HYPERTENSIVE PATIENTS, Epidemiology, 80 and over, Ethnicity, WIDE ASSOCIATION, Pharmacology & Pharmacy, Longitudinal Studies, Aged, 80 and over, Wide association, Genomewide association, Variants, Single Nucleotide, Pharmacology and Pharmaceutical Sciences, Genomics, Middle Aged, CARDIOVASCULAR DRUGS, 3. Good health, 317 Pharmacy, Molecular Medicine, Female, Cohort study, medicine.drug, Adult, medicine.medical_specialty, INFLUENCING ANTIHYPERTENSIVE RESPONSE, MEDLINE, UNITED-STATES, Polymorphism, Single Nucleotide, QT interval, Article, 03 medical and health sciences, BLOOD-PRESSURE RESPONSE, Genetics, medicine, Humans, Polymorphism, Thiazide, Hypertensive patients, Aged, Pharmacology, Selection bias, SELECTION BIAS, business.industry, Human Genome, R1, GENE-ENVIRONMENT INTERACTIONS, United States, 030104 developmental biology, Pharmacogenetics, Pharmacogenomics, GENOMEWIDE ASSOCIATION, business
Abstract: Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P
Published: 2018

45. Heritability and genome-wide associations studies of cerebral blood flow in the general population

Author: Oscar H. Franco, Gennady V. Roshchupkin, Albert V. Smith, Hieab H.H. Adams, Vilmundur Gudnason, Lenore J. Launer, Hazel I. Zonneveld, Meike W. Vernooij, André G. Uitterlinden, Cornelia M. van Duijn, Sigurdur Sigurdsson, M. Arfan Ikram, Epidemiology, Neurology, Radiology & Nuclear Medicine, and Internal Medicine
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Pathology, Population, Genome-wide association study, Biology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine.artery, medicine, Basilar artery, Humans, education, Genetic association, Aged, Aged, 80 and over, education.field_of_study, medicine.diagnostic_test, Brain, Magnetic resonance imaging, Heritability, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 030104 developmental biology, Cross-Sectional Studies, Neurology, Migraine, Cerebral blood flow, Cerebrovascular Circulation, Cardiology, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Cerebral blood flow is an important process for brain functioning and its dysregulation is implicated in multiple neurological disorders. While environmental risk factors have been identified, it remains unclear to what extent the flow is regulated by genetics. Here we performed heritability and genome-wide association analyses of cerebral blood flow in a population-based cohort study. We included 4472 persons free of cortical infarcts who underwent genotyping and phase-contrast magnetic resonance flow imaging (mean age 64.8 ± 10.8 years). The flow rate, cross-sectional area of the vessel, and flow velocity through the vessel were measured in the basilar artery and bilateral carotids. We found that the flow rate of the basilar artery is most heritable (h2 (SE) = 24.1 (9.8), p-value = 0.0056), and this increased over age. The association studies revealed two significant loci for the right carotid artery area (rs12546630, p-value = 2.0 × 10−8) and velocity (rs2971609, p-value = 1.4 × 10−8), with the latter showing a concordant effect in an independent sample (N = 1350, p-value = 0.057, meta-analyzed p-value = 2.5 × 10−9). These loci were also associated with other cerebral blood flow parameters below genome-wide significance, and rs2971609 lies in a known migraine locus. These findings establish that cerebral blood flow is under genetic control with potential relevance for neurological diseases.
Published: 2018

46. Computed tomography-based skeletal muscle and adipose tissue attenuation: Variations by age, sex, and muscle

Author: Elisa A. Marques, Vilmundur Gudnason, Palmi V. Jonsson, Pedro Figueiredo, Lenore J. Launer, Thor Aspelund, Tamara B. Harris, Thomas Lang, Sigurdur Sigurdsson, Kristin Siggeirsdottir, and Gudny Eiriksdottir
Subjects: Male, 0301 basic medicine, Aging, Adipose tissue, Computed tomography, Thigh, Medical and Health Sciences, Biochemistry, Muscle attenuation, 0302 clinical medicine, Endocrinology, Medicine, Tomography, education.field_of_study, medicine.diagnostic_test, Skeletal, Thigh muscles, Anatomy, X-Ray Computed, medicine.anatomical_structure, Trunk muscles, Adipose Tissue, Tissue density, Muscle, Biomedical Imaging, Female, Analysis of variance, Population, Article, 03 medical and health sciences, Genetics, Humans, Muscle, Skeletal, education, Molecular Biology, Aged, business.industry, Attenuation, Skeletal muscle, Cell Biology, Cross-Sectional Studies, 030104 developmental biology, Fat, Musculoskeletal, Tomography, X-Ray Computed, business, Gerontology, 030217 neurology & neurosurgery
Abstract: Objective This study aimed to investigate how skeletal muscle attenuation and adipose tissue (AT) attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle vary according to the targeted muscles, sex, and age. Design Population-based cross-sectional study. Setting Community-dwelling old population in Reykjavik, Iceland. Subjects A total of 5331 older adults (42.8% women), aged 66–96 years from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study, who participated in the baseline visit (between 2002 and 2006) and had valid thigh and abdominal computed tomography (CT) scans were studied. Methods Muscle attenuation and AT attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle were determined using CT. Linear mixed model analysis of variance was performed for each sex, with skeletal muscle or AT attenuation as the dependent variable. Results Muscle attenuation decreased, and AT attenuation increased with age in both sexes, and these differences were specific for each muscle, although not in all age groups. Age-related differences in muscle and AT attenuation varied with specific muscle. In general, for both sexes, skeletal muscle attenuation of the hamstrings declined more than average with age. Men and women displayed a different pattern in the age differences in AT attenuation for each muscle. Conclusions Our data support the hypotheses that skeletal muscle attenuation decreases, and AT attenuation increases with aging. In addition, our data add new evidence, supporting that age-related differences in skeletal muscle and AT attenuation vary between muscles.
Published: 2021

47. Comparison of glomerular filtration rate estimating equations derived from creatinine and cystatin C: validation in the Age, Gene/Environment Susceptibility-Reykjavik elderly cohort

Author: Olafur S. Indridason, Vilmundur Gudnason, Runolfur Palsson, Andrew S. Levey, Jonas Björk, Anders Grubb, and Ulf Nyman
Subjects: Adult, Male, medicine.medical_specialty, Iceland, 030232 urology & nephrology, Urology, Renal function, Estimating equations, 030204 cardiovascular system & hematology, Kidney Function Tests, urologic and male genital diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Cystatin C, Renal Insufficiency, Chronic, Prospective cohort study, Aged, Aged, 80 and over, Transplantation, Creatinine, biology, Receiver operating characteristic, business.industry, Middle Aged, female genital diseases and pregnancy complications, ROC Curve, chemistry, Nephrology, Cohort, biology.protein, Female, ORIGINAL ARTICLES, Iohexol, business, Glomerular Filtration Rate, medicine.drug
Abstract: BACKGROUND: Validation studies comparing glomerular filtration rate (GFR) equations based on standardized creatinine and cystatin C assays in the elderly are needed. The Icelandic Age, Gene/Environment Susceptibility-Kidney cohort was used to compare two pairs of recently developed GFR equations, the revised Lund–Malmö creatinine equation (LMR(Cr)) and the arithmetic mean of the LMR(Cr) and Caucasian, Asian, Paediatric and Adult cystatin C equations (MEAN(LMR+CAPA)), as well as the Full Age Spectrum creatinine equation (FAS(Cr)) and its combination with cystatin C (FAS(Cr+Cys)), with the corresponding pair of Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPI(Cr) and CKD-EPI(Cr+Cys)). METHODS: A total of 805 individuals, 74–93 years of age, underwent measurement of GFR (mGFR) using plasma clearance of iohexol. Four metrics were used to compare the performance of the GFR equations: bias, precision, accuracy [including the percentage of participants with estimated GFR (eGFR) within 30% of mGFR (P(30))] and the ability to detect mGFR 90%. LMR(Cr) and FAS(Cr) yielded significantly higher precision and P(30) than CKD-EPI(Cr), while bias was significantly worse. LMR(Cr), FAS(Cr) and CKD-EPI(Cr) showed similar ability to detect mGFR
Published: 2017

48. Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium

Author: Lori B. Chibnik, Osorio Meirelles, Joshua C. Bis, Christophe Tzourio, Bruce M. Psaty, Vilmundur Gudnason, Albert Hofman, Reem Waziry, Claudine Berr, Eric Boerwinkle, Catherine Helmer, Blossom C. M. Stephan, Carol Brayne, Frank J. Wolters, Alison Ower, Silke Kern, Lewis H. Kuller, Jean-François Dartigues, Ingmar Skoog, Mei Mei Wong, Leslie Grasset, M. Arfan Ikram, Anna Zettergren, M. Kamran Ikram, Fiona E. Matthews, Daniel Bos, Kristoffer Bäckman, Oscar L. Lopez, Thomas H. Mosley, Kendra Davis-Plourde, Lenore J. Launer, Stéphanie Debette, Sirwan K.L. Darweesh, Claudia L. Satizabal, Christoforos Hadjichrysanthou, Carole Dufouil, Myriam Fornage, Alexa S. Beiser, Sudha Seshadri, Epidemiology, Neurology, Radiology & Nuclear Medicine, Department of Epidemiology [Boston, MA, USA], Harvard School of Public Health, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Gothenburg (GU), School of Public Health [Boston], Boston University [Boston] (BU), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Medicine, University of Washington [Seattle], The University of Texas School of Public Health [Houston, TX, USA], The University of Texas Health Science Center at Houston (UTHealth), Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Imperial College London, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Nextel S.A. [Bilbao], University of Mississippi Medical Center (UMMC), Boston University School of Medicine (BUSM), Institute of Neuroscience and Physiology [Göteborg], Newcastle University [Newcastle], Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Alzheimer Cohorts Consortium is supported by an unrestricted grant from the Janssen Prevention Center to the Harvard T.H. Chan School of Public Health. Age, Gene/Environment Susceptibility (AGES) This study is supported by National Institute of Aging contracts (N01-AG-12100 and HHSN271201200022C) with contributions from the National Eye Institute, National Institute on Deafness and Other Communication Disorders, and the National Heart, Lung and Blood Institute, the National Institute of Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), Atherosclerosis Risk in Communities (ARIC) This study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data is collected by (U01 HL096812, HL096814, HL096899, HL096902, HL096917) with funding also provided by the National Institute of Neurologic Disorders and Stroke, Cardiovascular Health Study (CHS) This research was supported by contracts (HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086), and grants U01HL080295, U01HL130114 and HL105756 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by the National Institute on Aging (R01AG023629) and, in part, by grants (AG20098, AG15928, and AG05133). The funding sources did not have any role in the study design, collection, analysis, or interpretation of data, preparation of the manuscript, or decision to submit it for publication, Cognitive Function and Ageing Studies (CFAS) Medical Research Council (MRC) CFAS I was funded by the MRC (Research Grant: G9901400) and the National Health Service (NHS). CFAS II has been supported by the UK Medical Research Council (Research Grant:G06010220) and received additional support from the National Institute for Health Research (NIHR), comprehensive clinical research networks in West Anglia, Nottingham City and Nottinghamshire County NHS Primary Care trusts and the dementias and neurodegenerative disease research Network (DeNDRoN) in Newcastle, Framingham Heart Study (FHS) This work was supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (contracts N01-HC-25195 and HHSN268201500001I). This study was also supported by grants from the National Institute on Aging: (AG054076, U01-AG049505, and AG008122 (S. Seshadri)). S. Seshadri and A. Beiser were also supported by additional grants from the National Institute on Aging (R01AG049607, AG033193, AG033040) and the National Institute of Neurological Disorders and Stroke (R01-NS017950), The Gothenburg study This study was supported by grants from The Swedish Research Council 2012-5041, 2015-02830, 2013-8717, Swedish Research Council for Health, Working Life and Wellfare (no 2001-2646, 2003-0234, 2004-0150, 2006-0020, 2008-1229, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2001-2849, 2005-0762,2008-1210, 2013-2300, 013-2496, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Hja¨rnfonden, Sahlgrenska University Hospital (ALF), The Alzheimer’s Association Zenith Award (ZEN-01-3151), The Alzheimer’s Association Stephanie B. Overstreet Scholars (IIRG-00-2159), Alzheimer’s Association (IIRG-03-6168), The Alzheimer’s Association (IIRG-09-131338), Eivind och ElsaK:son Sylvans stiftelse, Stiftelsen So¨derstro¨m-Ko¨nigska Sjukhemmet, Stiftelsen fo¨ r Gamla Tja¨narinnor, Handlanden Hjalmar Svenssons Forskningsfond, Stiftelsen Professor Bror Gadelius’ Minnesfond, Swedish Alzheimer foundation, PAQUID The PAQUID cohort was supported by IPSEN France, NOVARTIS Pharma France, and the CNSA (Caisse Nationale de Solidarité et d’Autonomie). This study is supported by the Erasmus Medical Centre and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Further support was obtained from the Netherlands Consortium for Healthy Ageing and the Dutch Heart Foundation (2012T008). This research was further supported by funding from the European Union Seventh Framework Program (FP7/2007e2013) under grant agreement no. 601055, VPHDare@ IT (FP7-ICT-2011-9e601055), and funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 667375 (Co-STREAM) and under grant agreement no. 678543 (European Research Council (ERC) funded project: ORACLE). None of the funding organizations or sponsors were involved in study design, in collection, analysis, and interpretation of data, in writing of the report, or in the decision to submit the article for publication, The 3-Cites Study This study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor Segalen–Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme ‘‘Cohortes et collections de donne´es biologiques’’, Infrastructure for the CHARGE Consortium is supported in part by National Heart, Lung and Blood Institute (HL105756) and for the neurology working group by National Institutes of Aging (AG033193 and AG049505)., Berr, Claudine, Brayne, Carol [0000-0001-5307-663X], Matthews, Fiona [0000-0002-1728-2388], and Apollo - University of Cambridge Repository
Subjects: Male, Gerontology, medicine.medical_specialty, Epidemiology, [SDV]Life Sciences [q-bio], Population, Cohort Studies, New Consortium, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, medicine, Humans, Dementia, Prospective Studies, 030212 general & internal medicine, Poisson regression, education, Aged, Proportional Hazards Models, Aged, 80 and over, education.field_of_study, Proportional hazards model, business.industry, Incidence, Incidence (epidemiology), medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 1117 Public Health And Health Services, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Population Surveillance, Cohort, symbols, Female, Gene-Environment Interaction, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Alzheimer disease, Cohort analysis, business, Consortium, 030217 neurology & neurosurgery, Cohort study
Abstract: International audience; Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
Published: 2017

49. Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study

Author: Paul Mitchell, Alan D. Penman, Vilmundur Gudnason, Xiuqing Guo, Mark W. Christiansen, Yii-Der Ida Chen, Yang Hai, Alfred Tau Liang Gan, Yi-Jen Hung, Barbara E.K. Klein, Wen-Ling Liao, Richard A. Jensen, Wen-Jane Lee, Bruce M. Psaty, Kathryn P. Burdon, Ching J. Chen, Albert V. Smith, Lynn K. Stanwyck, Yong He Chong, Jie Jin Wang, Qiao Fan, Yucheng Jia, Georgia Kaidonis, Craig L. Hanis, Ronald Klein, Gavin Tan, Jihye Kim, Jane Kuo, Eli Ipp, Ching-Yu Cheng, Samuela Pollack, Fuu Jen Tsai, Tien Yin Wong, Gerald Liew, Mary Frances Cotch, Alkes L. Price, Jerome I. Rotter, Xiaohui Li, Kevin Sandow, Yu-Chuen Huang, Lucia Sobrin, Jamie E Craig, and Heather Hancock
Subjects: Male, Risk, Endocrinology, Diabetes and Metabolism, Physiology, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Risk factor, Aged, Genetic association, Genetics, Diabetic Retinopathy, business.industry, Genetics/Genomes/Proteomics/Metabolomics, Mendelian Randomization Analysis, Odds ratio, Middle Aged, medicine.disease, Lipids, 3. Good health, 030221 ophthalmology & optometry, Female, business, Dyslipidemia, Genome-Wide Association Study
Abstract: Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
Published: 2017

50. Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in the Elderly: AGES-Kidney and MESA-Kidney

Author: Andrew S. Levey, Li Fan, Vilmundur Gudnason, Tariq Shafi, Aghogho Okparavero, Ronit Katz, Gary F. Mitchell, Wendy S. Post, Meredith C. Foster, Michael G. Shlipak, Runolfur Palsson, and Lesley A. Inker
Subjects: Male, Aging, Kidney Disease, beta-trace protein, 030232 urology & nephrology, Serum protein, 030204 cardiovascular system & hematology, Cardiovascular, chemistry.chemical_compound, 0302 clinical medicine, cystatin C, 80 and over, Renal Insufficiency, Chronic, kidney function, GFR estimation, Aged, 80 and over, glomerular filtration rate, Kidney, education.field_of_study, biology, creatinine, Age Factors, Urology & Nephrology, Blood proteins, Lipocalins, Intramolecular Oxidoreductases, Filtration markers, medicine.anatomical_structure, Nephrology, Creatinine, Public Health and Health Services, biomarker, Female, Glomerular Filtration Rate, medicine.medical_specialty, Clinical Sciences, Population, Renal and urogenital, elderly, Article, β(2)-microglobulin, 03 medical and health sciences, Sex Factors, Clinical Research, Predictive Value of Tests, Internal medicine, medicine, Humans, beta(2)-microglobulin, Cystatin C, Renal Insufficiency, Chronic, education, Nutrition, Aged, business.industry, Beta-2 microglobulin, Prevention, Atherosclerosis, medicine.disease, United States, Cross-Sectional Studies, Endocrinology, chemistry, biology.protein, beta 2-Microglobulin, business, Biomarkers, Kidney disease
Abstract: Background Studies in chronic kidney disease populations suggest that the non–glomerular filtration rate (GFR) determinants of serum levels of the low-molecular-weight protein filtration markers cystatin C, β 2 -microglobulin (B2M), and beta-trace protein (BTP) are less affected by age, sex, and ethnicity than those of creatinine. Study Design Cross-sectional study. Setting & Participants Predominantly elderly participants selected from the Age, Gene/Environment Susceptibility Kidney Study (AGES-Kidney; N=683; mean [SD] age, 79 [4] years; GFR, 62 [17]mL/min/1.73 m 2 ) and from the Multi-Ethnic Study of Atherosclerosis Kidney Study (MESA-Kidney; N=273; mean [SD] age, 70.5 [9] years; GFR, 73 [19]mL/min/1.73 m 2 ). Predictors Demographic and clinical factors hypothesized to be associated with conditions affecting non-GFR determinants of the filtration markers. Outcomes Measured GFRs and estimated GFRs (eGFRs) based on creatinine, cystatin C, B2M, and BTP levels (eGFR cr, eGFR cys , eGFR B2M , and eGFR BTP , respectively). Residual associations of factors with eGFR after accounting for measured GFR as the parameter of interest. Results eGFR cys , eGFR B2M , and eGFR BTP had significantly less strong residual associations with age and sex than eGFR cr in both AGES-Kidney and MESA-Kidney and were not associated with ethnicity (black vs white) in MESA-Kidney. After adjusting for age, sex, and ethnicity, residual associations with most clinical factors were smaller than observed with age and sex. eGFR cys and eGFR B2M , but not eGFR BTP , had significant residual associations with C-reactive protein levels in both studies. Limitations Small sample size may limit power to detect associations. Participants may be healthier than the general population. Conclusions Similar to previous studies in chronic kidney disease, in community-dwelling elders, cystatin C, B2M, and BTP levels are less affected than creatinine level by age and sex and are not affected by ethnicity. Both cystatin C and B2M levels may be affected by inflammation. These findings are important for the development and use of GFR estimating equations based on low-molecular-weight serum proteins throughout the range in GFRs.
Published: 2017

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