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5. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L, Min, Josine L, Richmond, Rebecca C, Lu, Ake T, Sobczyk, Maria K, Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R, Mishra, Pashupati P, Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M, Ratliff, Scott M, Richardson, Tom G, Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D, Walker, Rosie M, Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R, Gieger, Christian, de Geus, Eco JC, Harris, Sarah E, Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon LR, Kresovich, Jacob K, Li, Shengxu, Lunetta, Kathryn L, Mangino, Massimo, Mason, Dan, McIntosh, Andrew M, Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M, Ollikainen, Miina, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Polidoro, Silvia, Porteous, David J, Raitakari, Olli, Rich, Stephen S, Sandler, Dale P, Sillanpää, Elina, Smith, Alicia K, Southey, Melissa C, Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G, Van Den Berg, David J, van Dongen, Jenny, Wilson, James G, Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T, Binder, Alexandra M, Boomsma, Dorret I, Chen, Wei, Christensen, Kaare, Conneely, Karen N, Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A, Lehtimäki, Terho, Lohoff, Falk W, Milani, Lili, Milne, Roger L, Probst-Hensch, Nicole, Reiner, Alex P, Ritz, Beate, and Rotter, Jerome I

Subjects
Prevention, Nutrition, Aging, Human Genome, Genetics, Generic health relevance, Inflammatory and immune system, Good Health and Well Being, Adiposity, Biomarkers, C-Reactive Protein, CpG Islands, DNA Methylation, Educational Status, Epigenesis, Genetic, Genetic Loci, Genetic Markers, Genome, Human, Genome-Wide Association Study, Granulocytes, Humans, Immunity, Innate, Lipid Metabolism, Multifactorial Inheritance, Plasminogen Activator Inhibitor 1, DNA methylation, GWAS, Epigenetic clock, Genetics of DNA Methylation Consortium, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundBiological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.ResultsLeveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.ConclusionThis study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Published
2021

6. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Aging, Parkinson's Disease, Genetics, 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

9. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO (Dementia Genetics Spanish Consortium), EADB, EADB, IFGC (International FTD-Genomics Consortium), IPDGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Alzheimer’s disease, Amyotrophic lateral sclerosis, Dementia with Lewy bodies, Frontotemporal dementia, Longevity, Multiple sclerosis, Neurodegenerative disease, PLCG2, Parkinson’s disease, Phospholipase C Gamma 2, Progressive supranuclear palsy, Alzheimer's disease, Parkinson's disease, Alzheimer's Disease, frontotemporal dementia, dementia with Lewy-bodies, progressive suprauclear palsy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, neurodegenerative disease, longevity, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

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

Author

Metspalu, Andres, Nelis, Mari, Mägi, Reedik, Esko, Tõnu, Trpchevska, Natalia, Freidin, Maxim B., Broer, Linda, Oosterloo, Berthe C., Yao, Shuyang, Zhou, Yitian, Vona, Barbara, Bishop, Charles, Bizaki-Vallaskangas, Argyro, Canlon, Barbara, Castellana, Fabio, Chasman, Daniel I., Cherny, Stacey, Christensen, Kaare, Concas, Maria Pina, Correa, Adolfo, Elkon, Ran, Mengel-From, Jonas, Gao, Yan, Giersch, Anne B.S., Girotto, Giorgia, Gudjonsson, Alexander, Gudnason, Vilmundur, Heard-Costa, Nancy L., Hertzano, Ronna, Hjelmborg, Jacob v.B., Hjerling-Leffler, Jens, Hoffman, Howard J., Kaprio, Jaakko, Kettunen, Johannes, Krebs, Kristi, Kähler, Anna K., Lallemend, Francois, Launer, Lenore J., Lee, I-Min, Leonard, Hampton, Li, Chuan-Ming, Lowenheim, Hubert, Magnusson, Patrik K.E., van Meurs, Joyce, Milani, Lili, Morton, Cynthia C., Mäkitie, Antti, Nalls, Mike A., Nardone, Giuseppe Giovanni, Nygaard, Marianne, Palviainen, Teemu, Pratt, Sheila, Quaranta, Nicola, Rämö, Joel, Saarentaus, Elmo, Sardone, Rodolfo, Satizabal, Claudia L., Schweinfurth, John M., Seshadri, Sudha, Shiroma, Eric, Shulman, Eldad, Simonsick, Eleanor, Spankovich, Christopher, Tropitzsch, Anke, Lauschke, Volker M., Sullivan, Patrick F., Goedegebure, Andre, Cederroth, Christopher R., Williams, Frances M.K., and Nagtegaal, Andries Paul

Published
2022
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11. Tattoo ink exposure is associated with lymphoma and skin cancers – a Danish study of twins.

Author

Clemmensen, Signe Bedsted, Mengel-From, Jonas, Kaprio, Jaakko, Frederiksen, Henrik, and von Bornemann Hjelmborg, Jacob

Subjects
*BASAL cell carcinoma, *SKIN cancer, *MEDICAL sciences, *TWIN studies, *PUBLIC health
Abstract

Background: We aim to study the potential association between tattoo ink exposure and development of certain types of cancers in the recently established Danish Twin Tattoo Cohort. Tattoo ink is known to transfer from skin to blood and accumulate in regional lymph nodes. We are concerned that tattoo ink induces inflammation at the deposit site, leading to chronic inflammation and increasing risk of abnormal cell proliferation, especially skin cancer and lymphoma. Methods: We conducted two designs of twin studies to improve confounder control: A cohort study of 2,367 randomly selected twins and a case-control study of 316 twins born in the period 1960–1996. Cancer diagnoses (ICD-10) were retrieved from the Danish Cancer Registry and tattoo ink exposure from the Danish Twin Tattoo survey from 2021. The analysis addressed effects of time-varying exposure. Results: In the case-control study, individual-level analysis resulted in a hazard of skin cancer (of any type except basal cell carcinoma) that was 1.62 times higher among tattooed individuals (95% CI: 1.08–2.41). Twin-matched analysis of 14 twin pairs discordant for tattoo ink exposure and skin cancer showed HR = 1.33 (95% CI: 0.46–3.84). For skin cancer and lymphoma, increased hazards were found for tattoos larger than the palm of a hand: HR = 2.37 (95% CI: 1.11–5.06) and HR = 2.73 (95% CI: 1.33–5.60), respectively. In the cohort study design, individual-level analysis resulted in a hazard ratio of 3.91 (95% CI: 1.42–10.8) for skin cancer and 2.83 (95% CI: 1.30–6.16) for basal cell carcinoma. Conclusion: In conclusion, our study suggests an increased hazard of lymphoma and skin cancers among tattooed individuals, demonstrated through two designs: a twin cohort and a case-cotwin study. We are concerned that tattoo ink interacting with surrounding cells may have severe consequences. Studies that pinpoint the etiological pathway of tattoo ink induced carcinogenesis are recommended to benefit public health. [ABSTRACT FROM AUTHOR]

Published
2025
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12. Age-Dependent DNA Methylation Variability on the X-Chromosome in Male and Female Twins.

Author

Tan, Qihua, Alo, Hikmat, Nygaard, Marianne, Sørensen, Mette, Saleh, Alisa, Mengel-From, Jonas, and Christensen, Kaare

Subjects
MONOZYGOTIC twins, DNA methylation, DNA analysis, REGRESSION analysis, AGING
Abstract

We aimed to explore the age-dependent epigenetic variability on the X-chromosome with consideration of X-chromosome inactivation by applying a sex-stratified regression analysis to DNA methylation array data on X-linked CpGs in aging identical twins. We found 13 X-linked CpGs showing age-related significant increase in variability in males (FDR < 0.05) but none in females. In females, we found a significantly higher proportion of CpGs showing increased variability with age among nominally significant (p < 0.05) CpGs under inactivation, but not among CpGs escaping inactivation. Survival analysis showed a slight trend of correlation by directional change in the variable CpGs with mortality in males. Compared with females, the male X-chromosome can be more vulnerable to epigenetic instability during aging. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Genome-Wide Epistatic Network Analyses of Semantic Fluency in Older Adults

Author

Tan, Qihua, primary, Li, Weilong, additional, Nygaard, Marianne, additional, An, Ping, additional, Feitosa, Mary, additional, Wojczynski, Mary K., additional, Zmuda, Joseph, additional, Arbeev, Konstantin, additional, Ukraintseva, Svetlana, additional, Yashin, Anatoliy, additional, Christensen, Kaare, additional, and Mengel-From, Jonas, additional

Published
2024
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20. Markers of Mitochondrial Function and DNA Repair Associated with Physical Function in Centenarians

Author

Sanchez-Roman, Ines, Ferrando, Beatriz, Myrup Holst, Camilla, Mengel-From, Jonas, Hoei Rasmussen, Signe, Thinggaard, Mikael, Bohr, Vilhelm A., Christensen, Kaare, Stevnsner, Tinna, Sanchez-Roman, Ines, Ferrando, Beatriz, Myrup Holst, Camilla, Mengel-From, Jonas, Hoei Rasmussen, Signe, Thinggaard, Mikael, Bohr, Vilhelm A., Christensen, Kaare, and Stevnsner, Tinna

Abstract

Mitochondrial dysfunction and genomic instability are key hallmarks of aging. The aim of this study was to evaluate whether maintenance of physical capacities at very old age is associated with key hallmarks of aging. To investigate this, we measured mitochondrial bioenergetics, mitochondrial DNA (mtDNA) copy number and DNA repair capacity in peripheral blood mononuclear cells from centenarians. In addition, circulating levels of NAD+/NADH, brain-derived neurotrophic factor (BDNF) and carbonylated proteins were measured in plasma and these parameters were correlated to physical capacities. Centenarians without physical disabilities had lower mitochondrial respiration values including ATP production, reserve capacity, maximal respiration and non-mitochondrial oxygen-consumption rate and had higher mtDNA copy number than centenarians with moderate and severe disabilities (p < 0.05). In centenarian females, grip strength had a positive association with mtDNA copy number (p < 0.05), and a borderline positive trend for activity of the central DNA repair enzyme, APE 1 (p = 0.075), while a negative trend was found with circulating protein carbonylation (p = 0.07) in the entire cohort. Lastly, a trend was observed for a negative association between BDNF and activity of daily living disability score (p = 0.06). Our results suggest that mechanisms involved in maintaining mitochondrial function and genomic stability may be associated with maintenance of physical function in centenarians., Mitochondrial dysfunction and genomic instability are key hallmarks of aging. The aim of this study was to evaluate whether maintenance of physical capacities at very old age is associated with key hallmarks of aging. To investigate this, we measured mitochondrial bioenergetics, mitochondrial DNA (mtDNA) copy number and DNA repair capacity in peripheral blood mononuclear cells from centenarians. In addition, circulating levels of NAD+/NADH, brain-derived neurotrophic factor (BDNF) and carbonylated proteins were measured in plasma and these parameters were correlated to physical capacities. Centenarians without physical disabilities had lower mitochondrial respiration values including ATP production, reserve capacity, maximal respiration and non-mitochondrial oxygen-consumption rate and had higher mtDNA copy number than centenarians with moderate and severe disabilities (p < 0.05). In centenarian females, grip strength had a positive association with mtDNA copy number (p < 0.05), and a borderline positive trend for activity of the central DNA repair enzyme, APE 1 (p = 0.075), while a negative trend was found with circulating protein carbonylation (p = 0.07) in the entire cohort. Lastly, a trend was observed for a negative association between BDNF and activity of daily living disability score (p = 0.06). Our results suggest that mechanisms involved in maintaining mitochondrial function and genomic stability may be associated with maintenance of physical function in centenarians.

Published
2024

26. Contributors

Author

Adams, Michelle M., primary, Albinet, Cédric, additional, Alicioglu, Banu, additional, Amami, Paolo, additional, André, Nathalie, additional, Ardic-Avci, Narin Ilgim, additional, Arslanoglou, Elizabeth, additional, Artioli, Guilherme Giannini, additional, Audiffren, Michel, additional, Aydogan, Hande Ozge, additional, Belchí, Francisco Javier, additional, Berman, Marvin H., additional, Bezdicek, Ondrej, additional, Bianco, Cynthia, additional, Boban, Jasmina, additional, Bueno Júnior, Carlos Roberto, additional, Butler, Blake E., additional, Cartelli, Daniele, additional, Casani, Augusto Pietro, additional, Celebi-Birand, Dilan, additional, Chen, Zikuan, additional, Chen, Zeyuan, additional, Chen, Bihong T., additional, Cherry, Katie E., additional, Chicherio, Christian, additional, Chio, Jeshya A., additional, Clavé, Pere, additional, Cogger, Victoria C., additional, Cominetti, Márcia Regina, additional, de Guzman, Ma Fe P., additional, del Moral, Maria Clarissa O., additional, Dolan, Eimear, additional, Dominguez, Jacqueline C., additional, Dommaraju, Premchand, additional, Ebo, Theresa, additional, Edler, Melissa K., additional, Erbaba, Begun, additional, Eskandari-Sedighi, Ghazaleh, additional, Fagot, Delphine, additional, Farajdokht, Fereshteh, additional, Fariñas, Isabel, additional, Felício, Laís Francielle Francisca, additional, Figueiredo, Luiz Felipe da Silva, additional, Fortuna, Karen L., additional, Galindo, Máximo Ibo, additional, Georgousopoulou, Ekavi N., additional, Gokarn, Rahul, additional, Gold, Gabriel, additional, Groetz, Hayley, additional, Gualano, Bruno, additional, Halliday, G.M., additional, Harrington, Erin E., additional, Heidenreich, Claudia, additional, Henčić, Boris, additional, Hernández, Rafael, additional, Herrmann, Björn, additional, Jančić, Jasna, additional, Jeżewski, R.C., additional, Kafaligonul, Hulusi, additional, Karakas, Hakki Muammer, additional, Karoglu-Eravsar, Elif Tugce, additional, Kiosses, Dimitris, additional, Kozic, Dusko, additional, Kövari, Enikö, additional, Kuller, Lewis H., additional, LaRocca, Thomas J., additional, Le Couteur, David G., additional, Lee, Gary Jek Chong, additional, Lertxundi, Unax, additional, López del Amo, Víctor, additional, Luciano de Almeida, Mariana, additional, Mahmoudi, Javad, additional, Malva, João O., additional, Manzine, Patricia Regina, additional, Martins, Beatriz, additional, Matthews, Douglas B., additional, McCormack, Derval, additional, Medrano, Juan, additional, Mellor, Duane D., additional, Meléndez, Juan C., additional, Mengel-From, Jonas, additional, Milić, Jelena, additional, Monkovic, Jody, additional, Monteiro-Junior, Renato Sobral, additional, Moreira, Ricardo, additional, Munger, Emily L., additional, Navari, Elena, additional, Newland, M. Christopher, additional, Novo, João, additional, Oriá, Reinaldo B., additional, O’Keeffe, Fiadhnait, additional, Panagiotakos, Demosthenes B., additional, Pereira, Frederico C., additional, Perez-Villalba, Ana, additional, Peron, Rafaela, additional, Preedy, Victor R., additional, Raghanti, Mary Ann, additional, Raimo, Simona, additional, Rajendram, Rajkumar, additional, Ramírez, Ana López, additional, Raposo, Ramon, additional, Raubenheimer, David, additional, Rawal, Punam, additional, Reese-Melancon, Celinda, additional, Reich, Hannah, additional, Requena, Carmen, additional, Ribeiro, Carlos Fontes, additional, Rodrigues, Ana Carolina de Mello Alves, additional, Rondón García, Luis Miguel, additional, Ruiz Trascastro, Rosa Raquel, additional, Sadigh-Eteghad, Saeed, additional, Salehpour, Farzad, additional, Samardžić, Janko, additional, Santangelo, Gabriella, additional, Satorres, Encarnación, additional, Shen, Andrew N., additional, Shepherd, C.E., additional, Simpson, Stephen J., additional, Solis, Marina Yazigi, additional, Solon-Biet, Samantha M., additional, Stankić, Dunja, additional, Strandberg, Timo E., additional, Suchy-Dicey, Astrid M., additional, Tapia, Andrea, additional, Thurnher, Majda M., additional, Álvarez-Merino, Paula, additional, Tomsen, Noemí, additional, Trojano, Luigi, additional, Tuz-Sasik, Melek Umay, additional, Urbanski, Henryk F., additional, Ureshino, Rodrigo Portes, additional, van Beeck, Ed, additional, Van Skike, Candice E., additional, Vatanabe, Izabela Pereira, additional, Wahl, Devin, additional, Westaway, David, additional, Wong, Shawn, additional, Wu, Long, additional, Xavier-Rocha, Túlio Brandão, additional, Zeković, Janko, additional, Zhang, Xin, additional, and Zhao, Liqin, additional

Published
2021
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32. A Mass Spectrometry-Based Proteome Study of Twin Pairs Discordant for Incident Acute Myocardial Infarction within Three Years after Blood Sampling Suggests Novel Biomarkers.

Author

Beck, Hans Christian, Skovgaard, Asmus Cosmos, Mohammadnejad, Afsaneh, Palstrøm, Nicolai Bjødstrup, Nielsen, Palle Fruekilde, Mengel-From, Jonas, Hjelmborg, Jacob, Rasmussen, Lars Melholt, and Soerensen, Mette

Subjects
MYOCARDIAL infarction, TWIN studies, BLOOD sampling, INDUCTIVELY coupled plasma mass spectrometry, BIOMARKERS
Abstract

Acute myocardial infarction (AMI) is a major cause of mortality and morbidity worldwide, yet biomarkers for AMI in the short- or medium-term are lacking. We apply the discordant twin pair design, reducing genetic and environmental confounding, by linking nationwide registry data on AMI diagnoses to a survey of 12,349 twins, thereby identifying 39 twin pairs (48–79 years) discordant for their first-ever AMI within three years after blood sampling. Mass spectrometry of blood plasma identified 715 proteins. Among 363 proteins with a call rate > 50%, imputation and stratified Cox regression analysis revealed seven significant proteins (FDR < 0.05): FGD6, MCAM, and PIK3CB reflected an increased level in AMI twins relative to their non-AMI co-twins (HR > 1), while LBP, IGHV3-15, C1RL, and APOC4 reflected a decreased level in AMI twins relative to their non-AMI co-twins (HR < 1). Additional 50 proteins were nominally significant (p < 0.05), and bioinformatics analyses of all 57 proteins revealed biology within hemostasis, coagulation cascades, the immune system, and the extracellular matrix. A protein–protein-interaction network revealed Fibronectin 1 as a central hub. Finally, technical validation confirmed MCAM, LBP, C1RL, and APOC3. We put forward novel biomarkers for incident AMI, a part of the proteome field where markers are surprisingly rare and where additional studies are highly needed. [ABSTRACT FROM AUTHOR]

Published
2024
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37. A Review of Major Danish Biobanks:Advantages and Possibilities of Health Research in Denmark

Author

Laugesen, Kristina, Mengel-From, Jonas, Christensen, Kaare, Olsen, Jørn, Hougaard, David M., Boding, Lasse, Olsen, Anja, Erikstrup, Christian, Hetland, Merete Lund, Høgdall, Estrid, Kjaergaard, Alisa D., Sørensen, Erik, Brügmann, Anja, Petersen, Eva Rabing Brix, Brandslund, Ivan, Nordestgaard, Børge G., Jensen, Gorm B., Skajaa, Nils, Troelsen, Frederikke Schønfeldt, Fuglsang, Cecilia Hvitfeldt, Svingel, Lise Skovgaard, Sørensen, Henrik T., Laugesen, Kristina, Mengel-From, Jonas, Christensen, Kaare, Olsen, Jørn, Hougaard, David M., Boding, Lasse, Olsen, Anja, Erikstrup, Christian, Hetland, Merete Lund, Høgdall, Estrid, Kjaergaard, Alisa D., Sørensen, Erik, Brügmann, Anja, Petersen, Eva Rabing Brix, Brandslund, Ivan, Nordestgaard, Børge G., Jensen, Gorm B., Skajaa, Nils, Troelsen, Frederikke Schønfeldt, Fuglsang, Cecilia Hvitfeldt, Svingel, Lise Skovgaard, and Sørensen, Henrik T.

Abstract

Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health – Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications., Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio-and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health – Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.

Published
2023

38. Novel epigenetic biomarkers for hematopoietic cancer found in twins.

Author

Clemmensen, Signe B., Frederiksen, Henrik, Mengel-From, Jonas, Heikkinen, Aino, Kaprio, Jaakko, and Hjelmborg, Jacob vB.

Subjects
RISK assessment, PREDICTIVE tests, HEMATOLOGIC malignancies, GENOME-wide association studies, BLOOD testing, TWINS, EPIGENOMICS, EARLY detection of cancer, TUMOR markers, CANCER patients, DNA methylation, ONCOGENES, DISEASE risk factors
Abstract

Background and purpose: This article aims to identify epigenetic markers and detect early development of hematopoietic malignancies through an epigenome wide association study of DNA methylation data. Materials and methods: This register-based study includes 1,085 Danish twins with 31 hematopoietic malignancies and methylation levels from 450,154 5'-C-phospate-G-3' (CpG) sites. Associations between methylation levels and incidence of hematopoietic malignancy is studied through time-to-event regression. The matched case-cotwin design, where one twin has a malignancy and the cotwin does not, is applied to enhance control for unmeasured shared confounding and false discoveries. Predictive performance is validated in the independent Older Finnish Twin Cohort. Results and Interpretation: We identified 67 epigenetic markers for hematopoietic malignancies of which 12 are linked to genes associated with hematologic malignancies. For some markers, we discovered a 2-3-fold relative risk difference for high versus low methylation. The identification of these 67 sites enabled the formation of a predictor demonstrating a cross-validated time-varying area under the curve (AUC) of 92% 3 years after individual blood sampling and persistent performance above 70% up to 6 years after blood sampling. This predictive performance was to a large extent recovered in the validation sample showing an overall Harrell's C of 73%. In conclusion, from a large population representative twin study on hematopoietic cancers, novel epigenetic markers were identified that may prove useful for early diagnosis. [ABSTRACT FROM AUTHOR]

Published
2024
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39. Integrative analysis of clinical and epigenetic biomarkers of mortality

Author

Huan, Tianxiao, Nguyen, Steve, Colicino, Elena, Ochoa-Rosales, Carolina, Hill, W David, Brody, Jennifer A, Soerensen, Mette, Zhang, Yan, Baldassari, Antoine, Elhadad, Mohamed Ahmed, Toshiko, Tanaka, Zheng, Yinan, Domingo-Relloso, Arce, Lee, Dong Heon, Ma, Jiantao, Yao, Chen, Liu, Chunyu, Hwang, Shih-Jen, Joehanes, Roby, Fornage, Myriam, Bressler, Jan, van Meurs, Joyce B J, Debrabant, Birgit, Mengel-From, Jonas, Hjelmborg, Jacob, Christensen, Kaare, Vokonas, Pantel, Schwartz, Joel, Gahrib, Sina A, Sotoodehnia, Nona, Sitlani, Colleen M, Kunze, Sonja, Gieger, Christian, Peters, Annette, Waldenberger, Melanie, Deary, Ian J, Ferrucci, Luigi, Qu, Yishu, Greenland, Philip, Lloyd-Jones, Donald M, Hou, Lifang, Bandinelli, Stefania, Voortman, Trudy, Hermann, Brenner, Baccarelli, Andrea, Whitsel, Eric, Pankow, James S, Levy, Daniel, Ochoa‐Rosales, Carolina, Hill, W. David, Brody, Jennifer A., Domingo‐Relloso, Arce, Hwang, Shih‐Jen, van Meurs, Joyce B.J., Mengel‐From, Jonas, Gahrib, Sina A., Sitlani, Colleen M., Deary, Ian J., Lloyd‐Jones, Donald M., Pankow, James S., Meurs, Joyce B.J., National Institutes of Health (Estados Unidos), NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), NIH - Center for Information Technology (Estados Unidos), NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos), NIH - National Institute on Aging (NIA) (Estados Unidos), Fundación Merck Salud, Laughlin Family, Alpha Phi Foundation, Locke Charitable Foundation, National Center for Advancing Translational Sciences (Estados Unidos), NIH - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Estados Unidos), Danish Council for Independent Research, Unión Europea. Comisión Europea. 7 Programa Marco, United States of Department of Health & Human Services, NIH - National Institute of Environmental Health Sciences (NIEHS) (Estados Unidos), Biotechnology and Biological Sciences Research Council (Reino Unido), Royal Society (Reino Unido), Scottish Government, Age UK (Reino Unido), Centre for Cognitive Ageing and Cognitive Epidemiology (Reino Unido), Wellcome Trust, University of Edinburgh (Reino Unido), University of Queensland (Australia), Medical Research Council (Reino Unido), United States Department of Veterans Affairs, Massachusetts Veterans Education Research and Information Center (MAVERIC), Epidemiology, and Internal Medicine

Subjects
Epigenomics, Male, Aging, DNA methylation, Cell Biology, DNA Methylation, Cardiovascular disease, Epigenesis, Genetic, SDG 3 - Good Health and Well-being, Cardiovascular Diseases, Neoplasms, Machine learning, Humans, Mortality, Dna Methylation, Cancer, Cardiovascular Disease, Machine Learning, Biomarkers
Abstract

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p

Published
2022
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40. A Review of Major Danish Biobanks: Advantages and Possibilities of Health Research in Denmark

Author

Laugesen, Kristina, primary, Mengel-From, Jonas, additional, Christensen, Kaare, additional, Olsen, Jørn, additional, Hougaard, David M, additional, Boding, Lasse, additional, Olsen, Anja, additional, Erikstrup, Christian, additional, Hetland, Merete Lund, additional, Høgdall, Estrid, additional, Kjaergaard, Alisa D, additional, Sørensen, Erik, additional, Brügmann, Anja, additional, Petersen, Eva Rabing Brix, additional, Brandslund, Ivan, additional, Nordestgaard, Børge G, additional, Jensen, Gorm B, additional, Skajaa, Nils, additional, Troelsen, Frederikke Schønfeldt, additional, Fuglsang, Cecilia Hvitfeldt, additional, Svingel, Lise Skovgaard, additional, and Sørensen, Henrik T, additional

Published
2023
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42. A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants

Author

Bae, Harold, primary, Gurinovich, Anastasia, additional, Karagiannis, Tanya T., additional, Song, Zeyuan, additional, Leshchyk, Anastasia, additional, Li, Mengze, additional, Andersen, Stacy L., additional, Arbeev, Konstantin, additional, Yashin, Anatoliy, additional, Zmuda, Joseph, additional, An, Ping, additional, Feitosa, Mary, additional, Giuliani, Cristina, additional, Franceschi, Claudio, additional, Garagnani, Paolo, additional, Mengel-From, Jonas, additional, Atzmon, Gil, additional, Barzilai, Nir, additional, Puca, Annibale, additional, Schork, Nicholas J., additional, Perls, Thomas T., additional, and Sebastiani, Paola, additional

Published
2022
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46. Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score

Author

Torres, Guillermo G., primary, Dose, Janina, additional, Hasenbein, Tim P., additional, Nygaard, Marianne, additional, Krause-Kyora, Ben, additional, Mengel-From, Jonas, additional, Christensen, Kaare, additional, Andersen-Ranberg, Karen, additional, Kolbe, Daniel, additional, Lieb, Wolfgang, additional, Laudes, Matthias, additional, Görg, Siegfried, additional, Schreiber, Stefan, additional, Franke, Andre, additional, Caliebe, Amke, additional, Kuhlenbäumer, Gregor, additional, and Nebel, Almut, additional

Published
2022
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50. Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Author

Trpchevska, Natalia, primary, Freidin, Maxim B., additional, Broer, Linda, additional, Oosterloo, Berthe C., additional, Yao, Shuyang, additional, Zhou, Yitian, additional, Vona, Barbara, additional, Bishop, Charles, additional, Bizaki-Vallaskangas, Argyro, additional, Canlon, Barbara, additional, Castellana, Fabio, additional, Chasman, Daniel I., additional, Cherny, Stacey, additional, Christensen, Kaare, additional, Concas, Maria Pina, additional, Correa, Adolfo, additional, Elkon, Ran, additional, Mengel-From, Jonas, additional, Gao, Yan, additional, Giersch, Anne B.S., additional, Girotto, Giorgia, additional, Gudjonsson, Alexander, additional, Gudnason, Vilmundur, additional, Heard-Costa, Nancy L., additional, Hertzano, Ronna, additional, Hjelmborg, Jacob v.B., additional, Hjerling-Leffler, Jens, additional, Hoffman, Howard J., additional, Kaprio, Jaakko, additional, Kettunen, Johannes, additional, Krebs, Kristi, additional, Kähler, Anna K., additional, Lallemend, Francois, additional, Launer, Lenore J., additional, Lee, I-Min, additional, Leonard, Hampton, additional, Li, Chuan-Ming, additional, Lowenheim, Hubert, additional, Magnusson, Patrik K.E., additional, van Meurs, Joyce, additional, Milani, Lili, additional, Morton, Cynthia C., additional, Mäkitie, Antti, additional, Nalls, Mike A., additional, Nardone, Giuseppe Giovanni, additional, Nygaard, Marianne, additional, Palviainen, Teemu, additional, Pratt, Sheila, additional, Quaranta, Nicola, additional, Rämö, Joel, additional, Saarentaus, Elmo, additional, Sardone, Rodolfo, additional, Satizabal, Claudia L., additional, Schweinfurth, John M., additional, Seshadri, Sudha, additional, Shiroma, Eric, additional, Shulman, Eldad, additional, Simonsick, Eleanor, additional, Spankovich, Christopher, additional, Tropitzsch, Anke, additional, Lauschke, Volker M., additional, Sullivan, Patrick F., additional, Goedegebure, Andre, additional, Cederroth, Christopher R., additional, Williams, Frances M.K., additional, Nagtegaal, Andries Paul, additional, Metspalu, Andres, additional, Nelis, Mari, additional, Mägi, Reedik, additional, and Esko, Tõnu, additional

Published
2022
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