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2. Prospective Effects of Self-Rated Health on Dementia Risk in Two Twin Studies of Aging

Author

Pilgrim, M. J. D., Beam, C. R., Nygaard, M., Finkel, Deborah, Pilgrim, M. J. D., Beam, C. R., Nygaard, M., and Finkel, Deborah

Abstract

Subjective health ratings are associated with dementia risk such that those who rate their health more poorly have increased risk for dementia. The genetic and environmental mechanisms underlying this association are unclear, as prior research cannot rule out whether the association is due to genetic confounds. The current study addresses this gap in two samples of twins, one from Sweden (N = 548) and one from Denmark (N = 4,373). Using genetically-informed, bivariate regression models, we assessed whether additive genetic effects explained the association between subjective health and dementia risk as indexed by a latent variable proxy measure. Age at intake, sex, education, depressive symptomatology, and follow-up time between subjective health and dementia risk assessments were included as covariates. Results indicate that genetic variance and other sources of confounding accounted for the majority of the effect of subjective health ratings on dementia risk. After adjusting for genetic confounding and other covariates, a small correlation was observed between subjective health and latent dementia risk in the Danish sample (rE = −.09, p <.05). The results provide further support for the genetic association between subjective health and dementia risk, and also suggest that subjective ratings of health measures may be useful for predicting dementia risk.

Published
2024
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3. Decoding the historical tale: COVID-19 impact on haematological malignancy patients—EPICOVIDEHA insights from 2020 to 2022

Author

Salmanton-Garcia, J., Marchesi, F., Farina, F., Weinbergerova, B., Itri, F., Davila-Valls, J., Martin-Perez, S., Glenthoj, A., Hersby, D. S., Gomes da Silva, M., Nunes Rodrigues, R., Lopez-Garcia, A., Cordoba, R., Bilgin, Y. M., Falces-Romero, I., El-Ashwah, S., Emarah, Z., Besson, C., Kohn, M., Van Doesum, J., Ammatuna, E., Marchetti, M., Labrador, J., Zambrotta, G. P. M., Verga, L., Jaksic, O., Nucci, M., Piukovics, K., Cabirta-Touzon, A., Jimenez, M., Arellano, E., Espigado, I., Blennow, O., Nordlander, A., Meers, S., van Praet, J., Aiello, T. F., Garcia-Vidal, C., Fracchiolla, N., Sciume, M., Seval, G. C., Zak, P., Buquicchio, C., Tascini, C., Grafe, S. K., Schonlein, M., Adzic-Vukicevic, T., Bonuomo, V., Cattaneo, C., Nizamuddin, S., Cernan, M., Plantefeve, G., Prin, R., Szotkovski, T., Collins, G. P., Dargenio, M., Petzer, V., Wolf, D., Colovic, N., Prezioso, L., Valkovic, T., Passamonti, F., Mendez, G. -A., Sili, U., Vena, A., Bavastro, M., Limongelli, A., Duarte, R. F., Ledoux, M. -P., Cvetanoski, M., Stojanoski, Z., Machado, M., Batinic, J., Magliano, G., Biernat, M. M., Pantic, N., Poulsen, C. B., Cuccaro, A., Del Principe, M. I., Kulasekararaj, A., Ormazabal-Velez, I., Busca, A., Demirkan, F., Ijaz, M., Klimko, N., Stoma, I., Khostelidi, S., Fernandez, N., Omrani, A. S., Bergantim, R., De Jonge, N., Fouquet, G., Navratil, M., Abu-Zeinah, G., Samarkos, M., Maertens, J., De Ramon, C., Guidetti, A., Magyari, F., Gonzalez-Lopez, T. J., Lahmer, T., Finizio, O., Ali, N., Pinczes, L. I., Lavilla-Rubira, E., Romano, A., Merelli, M., Delia, M., Calbacho, M., Meletiadis, J., Antic, D., Hernandez-Rivas, J. -A., Marques de Almeida, J., Al-Khabori, M., Hoenigl, M., Tisi, M. C., Khanna, N., Barac, A., Eisa, N., Di Blasi, R., Lievin, R., Miranda-Castillo, C., Bahr, N. C., Lamure, S., Papa, M. V., Yahya, A., Aujayeb, A., Novak, J., Erben, N., Fernandez-Galan, M., Ribera-Santa Susana, J. -M., Rinaldi, I., Fazzi, R., Piedimonte, M., Dulery, R., Gonzaga, Y., Soto-Silva, A., Sapienza, G., Serris, A., Drgona, Groh, A., Serrano, L., Gavriilaki, E., Tragiannidis, A., Prattes, J., Coppola, N., Otasevic, V., Mladenovic, M., Mitrovic, M., Miskovic, B., Jindra, P., Zompi, S., Sacchi, M. V., Krekeler, C., Infante, M. S., Garcia-Bordallo, D., Colak, G. M., Mayer, J., Nygaard, M., Hanakova, M., Racil, Z., Bonanni, Matteo, Koehler, P., Rahimli, L., Cornely, O. A., Pagano, Livio, Martin-Vallejo, F. J., Zdziarski, P., Zarrinfer, H., Wittig, J., Win, S., Wai-Man, V., Visek, B., Vinh, D. C., Vehreschild, M., Varricchio, G., Tsirigotis, P., Torres-Tienza, A., Tanase, A. D., Tafuri, A., Stamouli, M., Sramek, J., Soussain, C., Shirinova, A., Schubert, J., Schalk, E., Salehi, M. R., Saleh, M., Rosati, G., Roldan, E., Reizine, F., Rego, M., Regalado-Artamendi, I., Popova, M., Pinto, F., Philippe, L., Orth, H. M., Ommen, H. -B., Obr, A., Nunez-Martin-Buitrago, L., Noel, N., Neuhann, J., Nadali, G., Nacov, J. A., Munhoz Alburquerque, A. M., Mitra, M. E., Mikulska, M., Mellinghoff, S., Mechtel, B., Martin-Gonzalez, J. -A., Malak, S., Loureiro-Amigo, J., Lorenzo De La Pena, L., Liberti, G., Landau, M., Lacej, I., Kolditz, M., Kho, C. S., Khedr, R. A., Karthaus, M., Karlsson, L. K., Jimenez-Lorenzo, M. -J., Izuzquiza, M., Hoell-Neugebauer, B., Herbrecht, R., Heath, C. H., Guolo, F., Grothe, J., Giordano, A., Gerasymchuk, S., Garcia-Sanz, R., Garcia-Pouton, N., Funke, V. A. M., Fung, M., Flasshove, C., Fianchi, Luana, Essame, J., Egger, M., Drenou, B., Dragonetti, G., Desole, M., Della Pepa, R., Deau Fischer, B., De Kort, E., De Cabo, E., Danion, F., Daguindau, E., Cushion, T., Cremer, L., Criscuolo, Marianna, Cordini, G., Cingolani, Antonella, Ciceri, F., Chowdhury, F. R., Chelysheva, E., Chauchet, A., Chai, L. Y. A., Ceesay, M. M., Busch, E., Brehon, M., Borducchi, D. M. M., Booth, S., Bologna, S., Berg Venemyr, C., Bailen-Almorox, R., Antoniadou, A., Anastasopoulou, A. N., Altuntas, F., Bonanni M., Pagano L. (ORCID:0000-0001-8287-928X), Fianchi L., Criscuolo M., Cingolani A. (ORCID:0000-0002-3793-2755), Salmanton-Garcia, J., Marchesi, F., Farina, F., Weinbergerova, B., Itri, F., Davila-Valls, J., Martin-Perez, S., Glenthoj, A., Hersby, D. S., Gomes da Silva, M., Nunes Rodrigues, R., Lopez-Garcia, A., Cordoba, R., Bilgin, Y. M., Falces-Romero, I., El-Ashwah, S., Emarah, Z., Besson, C., Kohn, M., Van Doesum, J., Ammatuna, E., Marchetti, M., Labrador, J., Zambrotta, G. P. M., Verga, L., Jaksic, O., Nucci, M., Piukovics, K., Cabirta-Touzon, A., Jimenez, M., Arellano, E., Espigado, I., Blennow, O., Nordlander, A., Meers, S., van Praet, J., Aiello, T. F., Garcia-Vidal, C., Fracchiolla, N., Sciume, M., Seval, G. C., Zak, P., Buquicchio, C., Tascini, C., Grafe, S. K., Schonlein, M., Adzic-Vukicevic, T., Bonuomo, V., Cattaneo, C., Nizamuddin, S., Cernan, M., Plantefeve, G., Prin, R., Szotkovski, T., Collins, G. P., Dargenio, M., Petzer, V., Wolf, D., Colovic, N., Prezioso, L., Valkovic, T., Passamonti, F., Mendez, G. -A., Sili, U., Vena, A., Bavastro, M., Limongelli, A., Duarte, R. F., Ledoux, M. -P., Cvetanoski, M., Stojanoski, Z., Machado, M., Batinic, J., Magliano, G., Biernat, M. M., Pantic, N., Poulsen, C. B., Cuccaro, A., Del Principe, M. I., Kulasekararaj, A., Ormazabal-Velez, I., Busca, A., Demirkan, F., Ijaz, M., Klimko, N., Stoma, I., Khostelidi, S., Fernandez, N., Omrani, A. S., Bergantim, R., De Jonge, N., Fouquet, G., Navratil, M., Abu-Zeinah, G., Samarkos, M., Maertens, J., De Ramon, C., Guidetti, A., Magyari, F., Gonzalez-Lopez, T. J., Lahmer, T., Finizio, O., Ali, N., Pinczes, L. I., Lavilla-Rubira, E., Romano, A., Merelli, M., Delia, M., Calbacho, M., Meletiadis, J., Antic, D., Hernandez-Rivas, J. -A., Marques de Almeida, J., Al-Khabori, M., Hoenigl, M., Tisi, M. C., Khanna, N., Barac, A., Eisa, N., Di Blasi, R., Lievin, R., Miranda-Castillo, C., Bahr, N. C., Lamure, S., Papa, M. V., Yahya, A., Aujayeb, A., Novak, J., Erben, N., Fernandez-Galan, M., Ribera-Santa Susana, J. -M., Rinaldi, I., Fazzi, R., Piedimonte, M., Dulery, R., Gonzaga, Y., Soto-Silva, A., Sapienza, G., Serris, A., Drgona, Groh, A., Serrano, L., Gavriilaki, E., Tragiannidis, A., Prattes, J., Coppola, N., Otasevic, V., Mladenovic, M., Mitrovic, M., Miskovic, B., Jindra, P., Zompi, S., Sacchi, M. V., Krekeler, C., Infante, M. S., Garcia-Bordallo, D., Colak, G. M., Mayer, J., Nygaard, M., Hanakova, M., Racil, Z., Bonanni, Matteo, Koehler, P., Rahimli, L., Cornely, O. A., Pagano, Livio, Martin-Vallejo, F. J., Zdziarski, P., Zarrinfer, H., Wittig, J., Win, S., Wai-Man, V., Visek, B., Vinh, D. C., Vehreschild, M., Varricchio, G., Tsirigotis, P., Torres-Tienza, A., Tanase, A. D., Tafuri, A., Stamouli, M., Sramek, J., Soussain, C., Shirinova, A., Schubert, J., Schalk, E., Salehi, M. R., Saleh, M., Rosati, G., Roldan, E., Reizine, F., Rego, M., Regalado-Artamendi, I., Popova, M., Pinto, F., Philippe, L., Orth, H. M., Ommen, H. -B., Obr, A., Nunez-Martin-Buitrago, L., Noel, N., Neuhann, J., Nadali, G., Nacov, J. A., Munhoz Alburquerque, A. M., Mitra, M. E., Mikulska, M., Mellinghoff, S., Mechtel, B., Martin-Gonzalez, J. -A., Malak, S., Loureiro-Amigo, J., Lorenzo De La Pena, L., Liberti, G., Landau, M., Lacej, I., Kolditz, M., Kho, C. S., Khedr, R. A., Karthaus, M., Karlsson, L. K., Jimenez-Lorenzo, M. -J., Izuzquiza, M., Hoell-Neugebauer, B., Herbrecht, R., Heath, C. H., Guolo, F., Grothe, J., Giordano, A., Gerasymchuk, S., Garcia-Sanz, R., Garcia-Pouton, N., Funke, V. A. M., Fung, M., Flasshove, C., Fianchi, Luana, Essame, J., Egger, M., Drenou, B., Dragonetti, G., Desole, M., Della Pepa, R., Deau Fischer, B., De Kort, E., De Cabo, E., Danion, F., Daguindau, E., Cushion, T., Cremer, L., Criscuolo, Marianna, Cordini, G., Cingolani, Antonella, Ciceri, F., Chowdhury, F. R., Chelysheva, E., Chauchet, A., Chai, L. Y. A., Ceesay, M. M., Busch, E., Brehon, M., Borducchi, D. M. M., Booth, S., Bologna, S., Berg Venemyr, C., Bailen-Almorox, R., Antoniadou, A., Anastasopoulou, A. N., Altuntas, F., Bonanni M., Pagano L. (ORCID:0000-0001-8287-928X), Fianchi L., Criscuolo M., and Cingolani A. (ORCID:0000-0002-3793-2755)

Abstract

Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe

Published
2024

4. Remember this : Age moderation of genetic and environmental contributions to verbal episodic memory from midlife through late adulthood

Author

Luczak, S. E., Beam, C. R., Pahlen, S., Lynch, M., Pilgrim, M., Reynolds, C. A., Panizzon, M. S., Catts, V. S., Christensen, K., Finkel, Deborah, Franz, C. E., Kremen, W. S., Lee, T., McGue, M., Nygaard, M., Plassman, B. L., Whitfield, K. E., Pedersen, N. L., Gatz, M., Luczak, S. E., Beam, C. R., Pahlen, S., Lynch, M., Pilgrim, M., Reynolds, C. A., Panizzon, M. S., Catts, V. S., Christensen, K., Finkel, Deborah, Franz, C. E., Kremen, W. S., Lee, T., McGue, M., Nygaard, M., Plassman, B. L., Whitfield, K. E., Pedersen, N. L., and Gatz, M.

Abstract

It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium constituted the analytic sample. Verbal episodic memory was assessed with immediate word list recall (N = 35,204 individuals; 21,792 twin pairs) and prose recall (N = 3805 individuals; 2028 twin pairs), with scores harmonized across studies. Average test performance was lower in successively older age groups for both measures. Twin models found significant age moderation for both measures, with total inter-individual variance increasing significantly with age, although it was not possible definitively to attribute the increase specifically to either genetic or environmental sources. Pooled results across all 12 studies were compared to results where we successively dropped each study (leave-one-out) to assure results were not due to an outlier. We conclude the models indicated an overall increase in variance for verbal episodic memory that was driven by a combination of increases in the genetic and nonshared environmental parameters that were not independently statistically significant. In contrast to reported results for other cognitive domains, differences in environmental exposures are comparatively important for verbal episodic memory, especially word list learning.

Published
2023
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5. Validation of the type 1 diabetes distress scale (T1-DDS) in a large Danish cohort:Content validation and psychometric properties

Author

Joensen, L. E., Lindgreen, P., Olesen, K., Nygaard, M., Hessler, D., Andersen, H. U., Christensen, J. O., Kielgast, U. L., Nørgaard, K., Pedersen-Bjergaard, U., Willaing, I., Joensen, L. E., Lindgreen, P., Olesen, K., Nygaard, M., Hessler, D., Andersen, H. U., Christensen, J. O., Kielgast, U. L., Nørgaard, K., Pedersen-Bjergaard, U., and Willaing, I.

Abstract

Aim To validate the Type 1 Diabetes Distress Scale (T1-DDS) in a large sample of adults with Type 1 diabetes (T1D) from diabetes clinics in Denmark. Methods Altogether 40 adults with T1D were interviewed to explore the content of T1-DDS in a Danish setting and to validate the translation of the T1-DDS into Danish. Subsequently, a survey including T1-DDS, the Problem Areas In Diabetes scale (PAID-20), fear of hypoglycemia, social support, and diabetes duration was answered by 2201 people with T1D. Other person characteristics were collected from the National Patient Register. HbA1c was obtained from the Clinical Laboratory Information System. Data distribution, internal consistency, convergent and construct validity, factor structure, three weeks retest, and cut-points were explored. Results Interview data supported the relevance of all T1-DDS items for the assessment of diabetes distress among adults with T1D. The T1-DDS showed good content and acceptable construct validity, and the ability to detect high diabetes distress levels. A high correlation between T1-DDS and PAID-20 (rho = 0.91) was found. The retest scores showed a good reliability (all rho ≥0.68) with the highest variability in the Friends/Family Distress and Physician Distress subscales and the lowest variability in the Powerlessness and Eating Distress subscales of the T1-DDS. Qualitative findings pointed out relevant concerns of people with T1D, which were not included in the T1-DDS. Conclusion The study supports the use of the Danish T1-DDS, but also highlights that existing diabetes distress questionnaires including T1-DDS do not cover all potential diabetes stressors and worries., AIM: To validate the Type 1 Diabetes Distress Scale (T1-DDS) in a large sample of adults with Type 1 diabetes (T1D) from diabetes clinics in Denmark.METHODS: Altogether 40 adults with T1D were interviewed to explore the content of T1-DDS in a Danish setting and to validate the translation of the T1-DDS into Danish. Subsequently, a survey including T1-DDS, the Problem Areas In Diabetes scale (PAID-20), fear of hypoglycemia, social support, and diabetes duration was answered by 2201 people with T1D. Other person characteristics were collected from the National Patient Register. HbA1c was obtained from the Clinical Laboratory Information System. Data distribution, internal consistency, convergent and construct validity, factor structure, three weeks retest, and cut-points were explored.RESULTS: Interview data supported the relevance of all T1-DDS items for the assessment of diabetes distress among adults with T1D. The T1-DDS showed good content and acceptable construct validity, and the ability to detect high diabetes distress levels. A high correlation between T1-DDS and PAID-20 (rho = 0.91) was found. The retest scores showed a good reliability (all rho ≥0.68) with the highest variability in the Friends/Family Distress and Physician Distress subscales and the lowest variability in the Powerlessness and Eating Distress subscales of the T1-DDS. Qualitative findings pointed out relevant concerns of people with T1D, which were not included in the T1-DDS.CONCLUSION: The study supports the use of the Danish T1-DDS, but also highlights that existing diabetes distress questionnaires including T1-DDS do not cover all potential diabetes stressors and worries.

Published
2023

11. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author

Howe, LJ, Nivard, MG, Morris, TT, Hansen, AF, Rasheed, H, Cho, Y, Chittoor, G, Ahlskog, R, Lind, PA, Palviainen, T, van der Zee, MD, Cheesman, R, Mangino, M, Wang, Y, Li, S, Klaric, L, Ratliff, SM, Bielak, LF, Nygaard, M, Giannelis, A, Willoughby, EA, Reynolds, CA, Balbona, JV, Andreassen, OA, Ask, H, Baras, A, Bauer, CR, Boomsma, DI, Campbell, A, Campbell, H, Chen, Z, Christofidou, P, Corfield, E, Dahm, CC, Dokuru, DR, Evans, LM, de Geus, EJC, Giddaluru, S, Gordon, SD, Harden, KP, Hill, WD, Hughes, A, Kerr, SM, Kim, Y, Kweon, H, Latvala, A, Lawlor, DA, Li, L, Lin, K, Magnus, P, Magnusson, PKE, Mallard, TT, Martikainen, P, Mills, MC, Njolstad, PR, Overton, JD, Pedersen, NL, Porteous, DJ, Reid, J, Silventoinen, K, Southey, MC, Stoltenberg, C, Tucker-Drob, EM, Wright, MJ, Hewitt, JK, Keller, MC, Stallings, MC, Lee, JJ, Christensen, K, Kardia, SLR, Peyser, PA, Smith, JA, Wilson, JF, Hopper, JL, Hagg, S, Spector, TD, Pingault, J-B, Plomin, R, Havdahl, A, Bartels, M, Martin, NG, Oskarsson, S, Justice, AE, Millwood, IY, Hveem, K, Naess, O, Willer, CJ, Asvold, BO, Koellinger, PD, Kaprio, J, Medland, SE, Walters, RG, Benjamin, DJ, Turley, P, Evans, DM, Smith, GD, Hayward, C, Brumpton, B, Hemani, G, Davies, NM, Howe, LJ, Nivard, MG, Morris, TT, Hansen, AF, Rasheed, H, Cho, Y, Chittoor, G, Ahlskog, R, Lind, PA, Palviainen, T, van der Zee, MD, Cheesman, R, Mangino, M, Wang, Y, Li, S, Klaric, L, Ratliff, SM, Bielak, LF, Nygaard, M, Giannelis, A, Willoughby, EA, Reynolds, CA, Balbona, JV, Andreassen, OA, Ask, H, Baras, A, Bauer, CR, Boomsma, DI, Campbell, A, Campbell, H, Chen, Z, Christofidou, P, Corfield, E, Dahm, CC, Dokuru, DR, Evans, LM, de Geus, EJC, Giddaluru, S, Gordon, SD, Harden, KP, Hill, WD, Hughes, A, Kerr, SM, Kim, Y, Kweon, H, Latvala, A, Lawlor, DA, Li, L, Lin, K, Magnus, P, Magnusson, PKE, Mallard, TT, Martikainen, P, Mills, MC, Njolstad, PR, Overton, JD, Pedersen, NL, Porteous, DJ, Reid, J, Silventoinen, K, Southey, MC, Stoltenberg, C, Tucker-Drob, EM, Wright, MJ, Hewitt, JK, Keller, MC, Stallings, MC, Lee, JJ, Christensen, K, Kardia, SLR, Peyser, PA, Smith, JA, Wilson, JF, Hopper, JL, Hagg, S, Spector, TD, Pingault, J-B, Plomin, R, Havdahl, A, Bartels, M, Martin, NG, Oskarsson, S, Justice, AE, Millwood, IY, Hveem, K, Naess, O, Willer, CJ, Asvold, BO, Koellinger, PD, Kaprio, J, Medland, SE, Walters, RG, Benjamin, DJ, Turley, P, Evans, DM, Smith, GD, Hayward, C, Brumpton, B, Hemani, G, and Davies, NM

Abstract

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Published
2022

12. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, A, Malik, R., Hachiya, T., Jürgenson, T., Namba, S., Posner, D.C., Kamanu, F.K., Koido, M., Grand, Q. Le, Shi, M., He, Y., Georgakis, M.K., Caro, I., Krebs, K., Liaw, Y.C., Vaura, F.C., Lin, K., Winsvold, B.S., Srinivasasainagendra, V., Parodi, L., Bae, H.J., Chauhan, G., Chong, M.R., Tomppo, L., Akinyemi, R., Roshchupkin, G.V., Habib, N., Jee, Y.H., Thomassen, J.Q., Abedi, V., Cárcel-Márquez, J., Nygaard, M., Leonard, H.L., Yang, C., Yonova-Doing, E., Knol, M.J., Lewis, A.J., Judy, R.L., Ago, T., Amouyel, P., Armstrong, N.D., Bakker, M.K., Bartz, T.M., Bennett, D.A., Bis, J.C., Bordes, C., Børte, S., Cain, A., Ridker, P.M., Cho, K., Chen, Z., Cruchaga, C., Cole, J.W., Jager, P.L., Cid, R. de, Endres, M., Ferreira, L.E., Geerlings, M.I., Gasca, N.C., Gudnason, V., Hata, J., He, J., Heath, A.K., Ho, Y.L., Havulinna, A.S., Hopewell, J.C., Hyacinth, H.I., Inouye, M., Jacob, M.A., Jeon, C.E., Jern, C., Kamouchi, M., Keene, K.L., Kitazono, T., Kittner, S.J., Konuma, T., Kumar, A., Lacaze, P., Launer, L.J., Lee, K.J., Lepik, K., Li, J, Li, L, Manichaikul, A., Markus, H.S., Marston, N.A., Meitinger, T., Mitchell, B.D., Montellano, F.A., Morisaki, T., Mosley, T.H., Nalls, M.A., Nordestgaard, B.G., O'Donnell, M.J., Okada, Y., Onland-Moret, N.C., Ovbiagele, B., Peters, A., Psaty, B.M., Rich, S.S., Tuladhar, A.M., Leeuw, F.E. de, Dichgans, M., Debette, S., Mishra, A, Malik, R., Hachiya, T., Jürgenson, T., Namba, S., Posner, D.C., Kamanu, F.K., Koido, M., Grand, Q. Le, Shi, M., He, Y., Georgakis, M.K., Caro, I., Krebs, K., Liaw, Y.C., Vaura, F.C., Lin, K., Winsvold, B.S., Srinivasasainagendra, V., Parodi, L., Bae, H.J., Chauhan, G., Chong, M.R., Tomppo, L., Akinyemi, R., Roshchupkin, G.V., Habib, N., Jee, Y.H., Thomassen, J.Q., Abedi, V., Cárcel-Márquez, J., Nygaard, M., Leonard, H.L., Yang, C., Yonova-Doing, E., Knol, M.J., Lewis, A.J., Judy, R.L., Ago, T., Amouyel, P., Armstrong, N.D., Bakker, M.K., Bartz, T.M., Bennett, D.A., Bis, J.C., Bordes, C., Børte, S., Cain, A., Ridker, P.M., Cho, K., Chen, Z., Cruchaga, C., Cole, J.W., Jager, P.L., Cid, R. de, Endres, M., Ferreira, L.E., Geerlings, M.I., Gasca, N.C., Gudnason, V., Hata, J., He, J., Heath, A.K., Ho, Y.L., Havulinna, A.S., Hopewell, J.C., Hyacinth, H.I., Inouye, M., Jacob, M.A., Jeon, C.E., Jern, C., Kamouchi, M., Keene, K.L., Kitazono, T., Kittner, S.J., Konuma, T., Kumar, A., Lacaze, P., Launer, L.J., Lee, K.J., Lepik, K., Li, J, Li, L, Manichaikul, A., Markus, H.S., Marston, N.A., Meitinger, T., Mitchell, B.D., Montellano, F.A., Morisaki, T., Mosley, T.H., Nalls, M.A., Nordestgaard, B.G., O'Donnell, M.J., Okada, Y., Onland-Moret, N.C., Ovbiagele, B., Peters, A., Psaty, B.M., Rich, S.S., Tuladhar, A.M., Leeuw, F.E. de, Dichgans, M., and Debette, S.

Abstract

Item does not contain fulltext, Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022

13. Stroke genetics informs drug discovery and risk prediction across ancestries (vol 611, pg 115, 2022)

Author

Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, IH, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, IH, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, and Debette, S

Published
2022

14. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries (Nature, (2022), 611, 7934, (115-123), 10.1038/s41586-022-05165-3)

Author

Mishra, A, Malik, R, Hachiya, T, Jürgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, YC, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, HJ, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Cárcel-Márquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Børte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, YL, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, KJ, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O’Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Mishra, A, Malik, R, Hachiya, T, Jürgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, YC, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, HJ, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Cárcel-Márquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Børte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, YL, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, KJ, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O’Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, and Rich, SS

Abstract

In the version of this article initially published, the name of the PRECISE4Q Consortium was misspelled as “PRECISEQ” and has now been amended in the HTML and PDF versions of the article. Further, data in the first column of Supplementary Table 55 were mistakenly shifted and have been corrected in the file accompanying the HTML version of the article.

Published
2022

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

Author

McCartney D.L., Min J.L., Richmond R.C., Lu A.T., Sobczyk M.K., Davies G., Broer L., Guo X., Jeong A., Jung J., Kasela S., Katrinli S., Kuo P.-L., Matias-Garcia P.R., Mishra P.P., Nygaard M., Palviainen T., Patki A., Raffield L.M., Ratliff S.M., Richardson T.G., Robinson O., Soerensen M., Sun D., Tsai P.-C., van der Zee M.D., Walker R.M., Wang X., Wang Y., Xia R., Xu Z., Yao J., Zhao W., Correa A., Boerwinkle E., Dugue P.-A., Durda P., Elliott H.R., Gieger C., de Geus E.J.C., Harris S.E., Hemani G., Imboden M., Kahonen M., Kardia S.L.R., Kresovich J.K., Li S., Lunetta K.L., Mangino M., Mason D., McIntosh A.M., Mengel-From J., Moore A.Z., Murabito J.M., Ollikainen M., Pankow J.S., Pedersen N.L., Peters A., Polidoro S., Porteous D.J., Raitakari O., Rich S.S., Sandler D.P., Sillanpaa E., Smith A.K., Southey M.C., Strauch K., Tiwari H., Tanaka T., Tillin T., Uitterlinden A.G., Van Den Berg D.J., van Dongen J., Wilson J.G., Wright J., Yet I., Arnett D., Bandinelli S., Bell J.T., Binder A.M., Boomsma D.I., Chen W., Christensen K., Conneely K.N., Elliott P., Ferrucci L., Fornage M., Hagg S., Hayward C., Irvin M., Kaprio J., Lawlor D.A., Lehtimaki T., Lohoff F.W., Milani L., Milne R.L., Probst-Hensch N., Reiner A.P., Ritz B., Rotter J.I., Smith J.A., Taylor J.A., van Meurs J.B.J., Vineis P., Waldenberger M., Deary I.J., Relton C.L., Horvath S., Marioni R.E., McCartney D.L., Min J.L., Richmond R.C., Lu A.T., Sobczyk M.K., Davies G., Broer L., Guo X., Jeong A., Jung J., Kasela S., Katrinli S., Kuo P.-L., Matias-Garcia P.R., Mishra P.P., Nygaard M., Palviainen T., Patki A., Raffield L.M., Ratliff S.M., Richardson T.G., Robinson O., Soerensen M., Sun D., Tsai P.-C., van der Zee M.D., Walker R.M., Wang X., Wang Y., Xia R., Xu Z., Yao J., Zhao W., Correa A., Boerwinkle E., Dugue P.-A., Durda P., Elliott H.R., Gieger C., de Geus E.J.C., Harris S.E., Hemani G., Imboden M., Kahonen M., Kardia S.L.R., Kresovich J.K., Li S., Lunetta K.L., Mangino M., Mason D., McIntosh A.M., Mengel-From J., Moore A.Z., Murabito J.M., Ollikainen M., Pankow J.S., Pedersen N.L., Peters A., Polidoro S., Porteous D.J., Raitakari O., Rich S.S., Sandler D.P., Sillanpaa E., Smith A.K., Southey M.C., Strauch K., Tiwari H., Tanaka T., Tillin T., Uitterlinden A.G., Van Den Berg D.J., van Dongen J., Wilson J.G., Wright J., Yet I., Arnett D., Bandinelli S., Bell J.T., Binder A.M., Boomsma D.I., Chen W., Christensen K., Conneely K.N., Elliott P., Ferrucci L., Fornage M., Hagg S., Hayward C., Irvin M., Kaprio J., Lawlor D.A., Lehtimaki T., Lohoff F.W., Milani L., Milne R.L., Probst-Hensch N., Reiner A.P., Ritz B., Rotter J.I., Smith J.A., Taylor J.A., van Meurs J.B.J., Vineis P., Waldenberger M., Deary I.J., Relton C.L., Horvath S., and Marioni R.E.

Abstract

Background: Biological 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. Result(s): Leveraging 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. Conclusion(s): This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.Copyright © 2021, The Author(s).

Published
2021

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

Author

McCartney, DL, Min, JL, Richmond, RC, Lu, AT, Sobczyk, MK, Davies, G, Broer, L, Guo, X, Jeong, A, Jung, J, Kasela, S, Katrinli, S, Kuo, P-L, Matias-Garcia, PR, Mishra, PP, Nygaard, M, Palviainen, T, Patki, A, Raffield, LM, Ratliff, SM, Richardson, TG, Robinson, O, Soerensen, M, Sun, D, Tsai, P-C, van der Zee, MD, Walker, RM, Wang, X, Wang, Y, Xia, R, Xu, Z, Yao, J, Zhao, W, Correa, A, Boerwinkle, E, Dugue, P-A, Durda, P, Elliott, HR, Gieger, C, de Geus, EJC, Harris, SE, Hemani, G, Imboden, M, Kahonen, M, Kardia, SLR, Kresovich, JK, Li, S, Lunetta, KL, Mangino, M, Mason, D, McIntosh, AM, Mengel-From, J, Moore, AZ, Murabito, JM, Ollikainen, M, Pankow, JS, Pedersen, NL, Peters, A, Polidoro, S, Porteous, DJ, Raitakari, O, Rich, SS, Sandler, DP, Sillanpaa, E, Smith, AK, Southey, MC, Strauch, K, Tiwari, H, Tanaka, T, Tillin, T, Uitterlinden, AG, van den Berg, DJ, van Dongen, J, Wilson, JG, Wright, J, Yet, I, Arnett, D, Bandinelli, S, Bell, JT, Binder, AM, Boomsma, DI, Chen, W, Christensen, K, Conneely, KN, Elliott, P, Ferrucci, L, Fornage, M, Hagg, S, Hayward, C, Irvin, M, Kaprio, J, Lawlor, DA, Lehtimaki, T, Lohoff, FW, Milani, L, Milne, RL, Probst-Hensch, N, Reiner, AP, Ritz, B, Rotter, JI, Smith, JA, Taylor, JA, van Meurs, JBJ, Vineis, P, Waldenberger, M, Deary, IJ, Relton, CL, Horvath, S, Marioni, RE, McCartney, DL, Min, JL, Richmond, RC, Lu, AT, Sobczyk, MK, Davies, G, Broer, L, Guo, X, Jeong, A, Jung, J, Kasela, S, Katrinli, S, Kuo, P-L, Matias-Garcia, PR, Mishra, PP, Nygaard, M, Palviainen, T, Patki, A, Raffield, LM, Ratliff, SM, Richardson, TG, Robinson, O, Soerensen, M, Sun, D, Tsai, P-C, van der Zee, MD, Walker, RM, Wang, X, Wang, Y, Xia, R, Xu, Z, Yao, J, Zhao, W, Correa, A, Boerwinkle, E, Dugue, P-A, Durda, P, Elliott, HR, Gieger, C, de Geus, EJC, Harris, SE, Hemani, G, Imboden, M, Kahonen, M, Kardia, SLR, Kresovich, JK, Li, S, Lunetta, KL, Mangino, M, Mason, D, McIntosh, AM, Mengel-From, J, Moore, AZ, Murabito, JM, Ollikainen, M, Pankow, JS, Pedersen, NL, Peters, A, Polidoro, S, Porteous, DJ, Raitakari, O, Rich, SS, Sandler, DP, Sillanpaa, E, Smith, AK, Southey, MC, Strauch, K, Tiwari, H, Tanaka, T, Tillin, T, Uitterlinden, AG, van den Berg, DJ, van Dongen, J, Wilson, JG, Wright, J, Yet, I, Arnett, D, Bandinelli, S, Bell, JT, Binder, AM, Boomsma, DI, Chen, W, Christensen, K, Conneely, KN, Elliott, P, Ferrucci, L, Fornage, M, Hagg, S, Hayward, C, Irvin, M, Kaprio, J, Lawlor, DA, Lehtimaki, T, Lohoff, FW, Milani, L, Milne, RL, Probst-Hensch, N, Reiner, AP, Ritz, B, Rotter, JI, Smith, JA, Taylor, JA, van Meurs, JBJ, Vineis, P, Waldenberger, M, Deary, IJ, Relton, CL, Horvath, S, and Marioni, RE

Abstract

BACKGROUND: Biological 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. RESULTS: Leveraging 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. CONCLUSION: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Published
2021

20. COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA)

Author

Pagano, L., Salmanton-Garcia, J., Marchesi, F., Busca, A., Corradini, P., Hoenigl, M., Klimko, N., Koehler, P., Pagliuca, A., Passamonti, F., Verga, L., Visek, B., Ilhan, O., Nadali, G., Weinbergerova, B., Cordoba-Mascunano, R., Marchetti, M., Collins, G. P., Farina, F., Cattaneo, C., Cabirta, A., Gomes-Silva, M., Itri, F., van Doesum, J., Ledoux, M. -P., Cernan, M., Jaksic, O., Duarte, R. F., Magliano, G., Omrani, A. S., Fracchiolla, N. S., Kulasekararaj, A., Valkovic, T., Poulsen, C. B., Machado, M., Glenthoj, A., Stoma, I., Racil, Z., Piukovics, K., Navratil, M., Emarah, Z., Sili, U., Maertens, J., Blennow, O., Bergantim, R., Garcia-Vidal, C., Prezioso, L., Guidetti, A., del Principe, M. I., Popova, M., de Jonge, N., Ormazabal-Velez, I., Fernandez, N., Falces-Romero, I., Cuccaro, A., Meers, S., Buquicchio, C., Antic, D., Al-Khabori, M., Garcia-Sanz, R., Biernat, M. M., Tisi, M. C., Sal, E., Rahimli, L., Colovic, N., Schonlein, M., Calbacho, M., Tascini, C., Miranda-Castillo, C., Khanna, N., Mendez, G. -A., Petzer, V., Novak, J., Besson, C., Dulery, R., Lamure, S., Nucci, M., Zambrotta, G., Zak, P., Seval, G. C., Bonuomo, V., Mayer, J., Lopez-Garcia, A., Sacchi, M. V., Booth, S., Ciceri, F., Oberti, M., Salvini, M., Izuzquiza, M., Nunes-Rodrigues, R., Ammatuna, E., Obr, A., Herbrecht, R., Nunez-Martin-Buitrago, L., Mancini, V., Shwaylia, H., Sciume, M., Essame, J., Nygaard, M., Batinic, J., Gonzaga, Y., Regalado-Artamendi, I., Karlsson, L. K., Shapetska, M., Hanakova, M., El-Ashwah, S., Borbenyi, Z., Colak, G. M., Nordlander, A., Dragonetti, G., Maraglino, A. M. E., Rinaldi, A., De Ramon-Sanchez, C., Cornely, O. A., Finizio, O., Fazzi, R., Sapienza, G., Chauchet, A., Van Praet, J., Prattes, J., Dargenio, M., Rossi, C., Shirinova, A., Malak, S., Tafuri, A., Ommen, H. -B., Bologna, S., Khedr, R. A., Choquet, S., Joly, B., Ceesay, M. M., Philippe, L., Kho, C. S., Desole, M., Tsirigotis, P., Otasevic, V., Borducchi, D. M. M., Antoniadou, A., Gaziev, J., Almaslamani, M. A., Garcia-Pouton, N., Paterno, G., Torres-Lopez, A., Tarantini, G., Mellinghoff, S., Grafe, S., Borschel, N., Passweg, J., Merelli, M., Barac, A., Wolf, D., Shaikh, M. U., Thieblemont, C., Bernard, S., Funke, V. A. M., Daguindau, E., Khostelidi, S., Nucci, F. M., Martin-Gonzalez, J. -A., Landau, M., Soussain, C., Laureana, C., Lacombe, K., Kohn, M., Aliyeva, G., Piedimonte, M., Fouquet, G., Rego, M., Hoell-Neugebauer, B., Cartron, G., Pinto, F., Alburquerque, A. M., Passos, J., Yilmaz, A. F., Redondo-Izal, A. -M., Altuntas, F., Heath, C., Kolditz, M., Schalk, E., Guolo, F., Karthaus, M., Della Pepa, R., Vinh, D., Noel, N., Deau Fischer, B., Drenou, B., Mitra, M. E., Meletiadis, J., Bilgin, Y. M., Jindra, P., Espigado, I., Drgona, L., Serris, A., Di Blasi, R., Ali, N., Pagano L. (ORCID:0000-0001-8287-928X), Dragonetti G., Pagano, L., Salmanton-Garcia, J., Marchesi, F., Busca, A., Corradini, P., Hoenigl, M., Klimko, N., Koehler, P., Pagliuca, A., Passamonti, F., Verga, L., Visek, B., Ilhan, O., Nadali, G., Weinbergerova, B., Cordoba-Mascunano, R., Marchetti, M., Collins, G. P., Farina, F., Cattaneo, C., Cabirta, A., Gomes-Silva, M., Itri, F., van Doesum, J., Ledoux, M. -P., Cernan, M., Jaksic, O., Duarte, R. F., Magliano, G., Omrani, A. S., Fracchiolla, N. S., Kulasekararaj, A., Valkovic, T., Poulsen, C. B., Machado, M., Glenthoj, A., Stoma, I., Racil, Z., Piukovics, K., Navratil, M., Emarah, Z., Sili, U., Maertens, J., Blennow, O., Bergantim, R., Garcia-Vidal, C., Prezioso, L., Guidetti, A., del Principe, M. I., Popova, M., de Jonge, N., Ormazabal-Velez, I., Fernandez, N., Falces-Romero, I., Cuccaro, A., Meers, S., Buquicchio, C., Antic, D., Al-Khabori, M., Garcia-Sanz, R., Biernat, M. M., Tisi, M. C., Sal, E., Rahimli, L., Colovic, N., Schonlein, M., Calbacho, M., Tascini, C., Miranda-Castillo, C., Khanna, N., Mendez, G. -A., Petzer, V., Novak, J., Besson, C., Dulery, R., Lamure, S., Nucci, M., Zambrotta, G., Zak, P., Seval, G. C., Bonuomo, V., Mayer, J., Lopez-Garcia, A., Sacchi, M. V., Booth, S., Ciceri, F., Oberti, M., Salvini, M., Izuzquiza, M., Nunes-Rodrigues, R., Ammatuna, E., Obr, A., Herbrecht, R., Nunez-Martin-Buitrago, L., Mancini, V., Shwaylia, H., Sciume, M., Essame, J., Nygaard, M., Batinic, J., Gonzaga, Y., Regalado-Artamendi, I., Karlsson, L. K., Shapetska, M., Hanakova, M., El-Ashwah, S., Borbenyi, Z., Colak, G. M., Nordlander, A., Dragonetti, G., Maraglino, A. M. E., Rinaldi, A., De Ramon-Sanchez, C., Cornely, O. A., Finizio, O., Fazzi, R., Sapienza, G., Chauchet, A., Van Praet, J., Prattes, J., Dargenio, M., Rossi, C., Shirinova, A., Malak, S., Tafuri, A., Ommen, H. -B., Bologna, S., Khedr, R. A., Choquet, S., Joly, B., Ceesay, M. M., Philippe, L., Kho, C. S., Desole, M., Tsirigotis, P., Otasevic, V., Borducchi, D. M. M., Antoniadou, A., Gaziev, J., Almaslamani, M. A., Garcia-Pouton, N., Paterno, G., Torres-Lopez, A., Tarantini, G., Mellinghoff, S., Grafe, S., Borschel, N., Passweg, J., Merelli, M., Barac, A., Wolf, D., Shaikh, M. U., Thieblemont, C., Bernard, S., Funke, V. A. M., Daguindau, E., Khostelidi, S., Nucci, F. M., Martin-Gonzalez, J. -A., Landau, M., Soussain, C., Laureana, C., Lacombe, K., Kohn, M., Aliyeva, G., Piedimonte, M., Fouquet, G., Rego, M., Hoell-Neugebauer, B., Cartron, G., Pinto, F., Alburquerque, A. M., Passos, J., Yilmaz, A. F., Redondo-Izal, A. -M., Altuntas, F., Heath, C., Kolditz, M., Schalk, E., Guolo, F., Karthaus, M., Della Pepa, R., Vinh, D., Noel, N., Deau Fischer, B., Drenou, B., Mitra, M. E., Meletiadis, J., Bilgin, Y. M., Jindra, P., Espigado, I., Drgona, L., Serris, A., Di Blasi, R., Ali, N., Pagano L. (ORCID:0000-0001-8287-928X), and Dragonetti G.

Abstract

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. Ho

Published
2021

21. 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 (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

Author

van der Lee, S. J., Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernandez, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleo, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., Mengel-From, J., Moreno-Grau, S., Wagner, M., Fortea, J., Keogh, M. J., Blennow, K., Skoog, I., Friese, M. A., Pletnikova, O., Zulaica, M., Lage, C., de Rojas, I., Riedel-Heller, S., Illan-Gala, I., Wei, W., Jeune, B., Orellana, A., Then Bergh, F., Wang, X., Hulsman, M., Beker, N., Tesi, N., Morris, C. M., Indakoetxea, B., Collij, L. E., Scherer, M., Morenas-Rodriguez, E., Ironside, J. W., van Berckel, B. N. M., Alcolea, D., Wiendl, H., Strickland, S. L., Pastor, P., Rodriguez Rodriguez, E., Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldo, M., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, B. F., Petersen, R. C., Ferman, T. J., van Gerpen, J. A., Reinders, M. J. T., Uitti, R. J., Tarraga, L., Maier, W., Dols-Icardo, O., Kawalia, A., Dalmasso, M. C., Boada, M., Zettl, U. K., van Schoor, N. M., Beekman, M., Allen, M., Masliah, E., de Munain, A. L., Pantelyat, A., Wszolek, Z. K., Ross, O. A., Dickson, D. W., Graff-Radford, N. R., Knopman, D., Rademakers, R., Lemstra, A. W., Pijnenburg, Y. A. L., Scheltens, P., Gasser, T., Chinnery, P. F., Hemmer, B., Huisman, M. A., Troncoso, J., Moreno, F., Nohr, E. A., Sorensen, T. I. A., Heutink, P., Sanchez-Juan, P., Posthuma, D., Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., Decarli, C., Geschwind, D. H., Clarimon, J., Christensen, K., Ertekin-Taner, N., Scholz, S. W., Ramirez, A., Ruiz, A., Slagboom, E., van der Flier, W. M., Holstege, H., Neurology, Epidemiology and Data Science, Human genetics, APH - Societal Participation & Health, APH - Aging & Later Life, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, and APH - Methodology

Subjects
education
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

22. 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 (vol 138, pg 237, 2019)

Author

van der Lee, SJ, Conway, OJ, Jansen, I, Carrasquillo, MM, Kleineidam, L, van den Akker, E, Hernandez, I, van Eijk, KR, Stringa, N, Chen, JSA, Zettergren, A, Andlauer, TFM, Diez-Fairen, M, Simon-Sanchez, J, Lleo, A, Zetterberg, H, Nygaard, M, Blauwendraat, C, Savage, JE, Mengel-From, J, Moreno-Grau, S, Wagner, M, Fortea, J, Keogh, MJ, Blennow, K, Skoog, I, Friese, MA, Pletnikova, O, Zulaica, M, Lage, C, de Rojas, I, Riedel-Heller, S, Illan-Gala, I, Wei, W, Jeune, B, Orellana, A, Bergh, FT, Wang, X, Hulsman, M, Beker, N, Tesi, N, Morris, CM, Indakoetxea, B, Collij, LE, Scherer, M, Morenas-Rodriguez, E, Ironside, JW, van Berckel, BNM, Alcolea, D, Wiendl, H, Strickland, SL, Pastor, P, Rodriguez, ER, Boeve, BF, Petersen, RC, Ferman, TJ, van Gerpen, JA, Reinders, MJT, Uitti, RJ, Tarraga, L, Maier, W, Dols-Icardo, O, Kawalia, A, Dalmasso, MC, Boada, M, Zettl, UK, van Schoor, NM, Beekman, M, Allen, M, Masliah, E, de Munain, AL, Pantelyat, A, Wszolek, ZK, Ross, OA, Dickson, DW, Graff-Radford, NR, Knopman, D, Rademakers, R, Lemstra, AW, Pijnenburg, YAL, Scheltens, P, Gasser, T, Chinnery, PF, Hemmer, B, Huisman, MA, Troncoso, J, Moreno, F, Nohr, EA, Sorensen, TIA, Heutink, P, Sanchez-Juan, P, Posthuma, D, Clarim?on, J, Christensen, K, Ertekin-Taner, N, Scholz, SW, Ramirez, A, Ruiz, A, Slagboom, E, van der Flier, WM, and Holstege, H

Subjects
education
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

25. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author

Savage, J.E. Jansen, P.R. Stringer, S. Watanabe, K. Bryois, J. De Leeuw, C.A. Nagel, M. Awasthi, S. Barr, P.B. Coleman, J.R.I. Grasby, K.L. Hammerschlag, A.R. Kaminski, J.A. Karlsson, R. Krapohl, E. Lam, M. Nygaard, M. Reynolds, C.A. Trampush, J.W. Young, H. Zabaneh, D. Hägg, S. Hansell, N.K. Karlsson, I.K. Linnarsson, S. Montgomery, G.W. Muñoz-Manchado, A.B. Quinlan, E.B. Schumann, G. Skene, N.G. Webb, B.T. White, T. Arking, D.E. Avramopoulos, D. Bilder, R.M. Bitsios, P. Burdick, K.E. Cannon, T.D. Chiba-Falek, O. Christoforou, A. Cirulli, E.T. Congdon, E. Corvin, A. Davies, G. Deary, I.J. Derosse, P. Dickinson, D. Djurovic, S. Donohoe, G. Conley, E.D. Eriksson, J.G. Espeseth, T. Freimer, N.A. Giakoumaki, S. Giegling, I. Gill, M. Glahn, D.C. Hariri, A.R. Hatzimanolis, A. Keller, M.C. Knowles, E. Koltai, D. Konte, B. Lahti, J. Le Hellard, S. Lencz, T. Liewald, D.C. London, E. Lundervold, A.J. Malhotra, A.K. Melle, I. Morris, D. Need, A.C. Ollier, W. Palotie, A. Payton, A. Pendleton, N. Poldrack, R.A. Räikkönen, K. Reinvang, I. Roussos, P. Rujescu, D. Sabb, F.W. Scult, M.A. Smeland, O.B. Smyrnis, N. Starr, J.M. Steen, V.M. Stefanis, N.C. Straub, R.E. Sundet, K. Tiemeier, H. Voineskos, A.N. Weinberger, D.R. Widen, E. Yu, J. Abecasis, G. Andreassen, O.A. Breen, G. Christiansen, L. Debrabant, B. Dick, D.M. Heinz, A. Hjerling-Leffler, J. Ikram, M.A. Kendler, K.S. Martin, N.G. Medland, S.E. Pedersen, N.L. Plomin, R. Polderman, T.J.C. Ripke, S. Van Der Sluis, S. Sullivan, P.F. Vrieze, S.I. Wright, M.J. Posthuma, D.

Abstract

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders. © 2018 The Author(s).

Published
2018

26. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author

Savage, J. E., Jansen, P. R., Stringer, S., Watanabe, K., Bryois, J., De Leeuw, C. A., Nagel, M., Awasthi, S., Barr, P. B., Coleman, J. R. I., Grasby, K. L., Hammerschlag, A. R., Kaminski, J. A., Karlsson, R., Krapohl, E., Lam, M., Nygaard, M., Reynolds, C. A., Trampush, J. W., Young, H., Zabaneh, D., Hägg, S., Hansell, N. K., Karlsson, Ida K., Linnarsson, S., Montgomery, G. W., Muñoz-Manchado, A. B., Quinlan, E. B., Schumann, G., Skene, N. G., Webb, B. T., White, T., Arking, D. E., Avramopoulos, D., Bilder, R. M., Bitsios, P., Burdick, K. E., Cannon, T. D., Chiba-Falek, O., Christoforou, A., Cirulli, E. T., Congdon, E., Corvin, A., Davies, G., Deary, I. J., Derosse, P., Dickinson, D., Djurovic, S., Donohoe, G., Conley, E. D., Eriksson, J. G., Espeseth, T., Freimer, N. A., Giakoumaki, S., Giegling, I., Gill, M., Glahn, D. C., Hariri, A. R., Hatzimanolis, A., Keller, M. C., Knowles, E., Koltai, D., Konte, B., Lahti, J., Le Hellard, S., Lencz, T., Liewald, D. C., London, E., Lundervold, A. J., Malhotra, A. K., Melle, I., Morris, D., Need, A. C., Ollier, W., Palotie, A., Payton, A., Pendleton, N., Poldrack, R. A., Räikkönen, K., Reinvang, I., Roussos, P., Rujescu, D., Sabb, F. W., Scult, M. A., Smeland, O. B., Smyrnis, N., Starr, J. M., Steen, V. M., Stefanis, N. C., Straub, R. E., Sundet, K., Tiemeier, H., Voineskos, A. N., Weinberger, D. R., Widen, E., Yu, J., Abecasis, G., Andreassen, O. A., Breen, G., Christiansen, L., Debrabant, B., Dick, D. M., Heinz, A., Hjerling-Leffler, J., Ikram, M. A., Kendler, K. S., Martin, N. G., Medland, S. E., Pedersen, N. L., Plomin, R., Polderman, T. J. C., Ripke, S., Van Der Sluis, S., Sullivan, P. F., Vrieze, S. I., Wright, M. J., Posthuma, D., Savage, J. E., Jansen, P. R., Stringer, S., Watanabe, K., Bryois, J., De Leeuw, C. A., Nagel, M., Awasthi, S., Barr, P. B., Coleman, J. R. I., Grasby, K. L., Hammerschlag, A. R., Kaminski, J. A., Karlsson, R., Krapohl, E., Lam, M., Nygaard, M., Reynolds, C. A., Trampush, J. W., Young, H., Zabaneh, D., Hägg, S., Hansell, N. K., Karlsson, Ida K., Linnarsson, S., Montgomery, G. W., Muñoz-Manchado, A. B., Quinlan, E. B., Schumann, G., Skene, N. G., Webb, B. T., White, T., Arking, D. E., Avramopoulos, D., Bilder, R. M., Bitsios, P., Burdick, K. E., Cannon, T. D., Chiba-Falek, O., Christoforou, A., Cirulli, E. T., Congdon, E., Corvin, A., Davies, G., Deary, I. J., Derosse, P., Dickinson, D., Djurovic, S., Donohoe, G., Conley, E. D., Eriksson, J. G., Espeseth, T., Freimer, N. A., Giakoumaki, S., Giegling, I., Gill, M., Glahn, D. C., Hariri, A. R., Hatzimanolis, A., Keller, M. C., Knowles, E., Koltai, D., Konte, B., Lahti, J., Le Hellard, S., Lencz, T., Liewald, D. C., London, E., Lundervold, A. J., Malhotra, A. K., Melle, I., Morris, D., Need, A. C., Ollier, W., Palotie, A., Payton, A., Pendleton, N., Poldrack, R. A., Räikkönen, K., Reinvang, I., Roussos, P., Rujescu, D., Sabb, F. W., Scult, M. A., Smeland, O. B., Smyrnis, N., Starr, J. M., Steen, V. M., Stefanis, N. C., Straub, R. E., Sundet, K., Tiemeier, H., Voineskos, A. N., Weinberger, D. R., Widen, E., Yu, J., Abecasis, G., Andreassen, O. A., Breen, G., Christiansen, L., Debrabant, B., Dick, D. M., Heinz, A., Hjerling-Leffler, J., Ikram, M. A., Kendler, K. S., Martin, N. G., Medland, S. E., Pedersen, N. L., Plomin, R., Polderman, T. J. C., Ripke, S., Van Der Sluis, S., Sullivan, P. F., Vrieze, S. I., Wright, M. J., and Posthuma, D.

Abstract

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Published
2018
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27. Novel loci and pathways significantly associated with longevity.

Author

Zeng, Y, Nie, C, Min, J, Liu, X, Li, M, Chen, H, Xu, H, Wang, M, Ni, T, Li, Y, Yan, H, Zhang, J-P, Song, C, Chi, L-Q, Wang, H-M, Dong, J, Zheng, G-Y, Lin, L, Qian, F, Qi, Y, Cao, H, Wang, Y, Zhang, L, Li, Z, Zhou, Y, Lu, J, Li, J, Qi, M, Bolund, L, Yashin, A, Land, KC, Gregory, S, Yang, Z, Gottschalk, W, Tao, W, Wang, J, Xu, X, Bae, H, Nygaard, M, Christiansen, L, Christensen, K, Franceschi, C, Lutz, MW, Gu, J, Tan, Q, Perls, T, Sebastiani, P, Deelen, J, Slagboom, E, Hauser, E, Tian, X-L, Yang, H, Vaupel, JW, Zeng, Y, Nie, C, Min, J, Liu, X, Li, M, Chen, H, Xu, H, Wang, M, Ni, T, Li, Y, Yan, H, Zhang, J-P, Song, C, Chi, L-Q, Wang, H-M, Dong, J, Zheng, G-Y, Lin, L, Qian, F, Qi, Y, Cao, H, Wang, Y, Zhang, L, Li, Z, Zhou, Y, Lu, J, Li, J, Qi, M, Bolund, L, Yashin, A, Land, KC, Gregory, S, Yang, Z, Gottschalk, W, Tao, W, Wang, J, Xu, X, Bae, H, Nygaard, M, Christiansen, L, Christensen, K, Franceschi, C, Lutz, MW, Gu, J, Tan, Q, Perls, T, Sebastiani, P, Deelen, J, Slagboom, E, Hauser, E, Tian, X-L, Yang, H, and Vaupel, JW

Abstract

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.

Published
2016

29. COVID-19 infection in adult patients with hematological malignancies:a European Hematology Association Survey (EPICOVIDEHA)

Author

Pagano, Livio, Salmanton-García, Jon, Marchesi, Francesco, Busca, Alessandro, Corradini, Paolo, Hoenigl, Martin, Klimko, Nikolai, Koehler, Philipp, Pagliuca, Antonio, Passamonti, Francesco, Verga, Luisa, Víšek, Benjamin, Ilhan, Osman, Nadali, Gianpaolo, Weinbergerová, Barbora, Córdoba-Mascuñano, Raúl, Marchetti, Monia, Collins, Graham P., Farina, Francesca, Cattaneo, Chiara, Cabirta, Alba, Gomes-Silva, Maria, Itri, Federico, van Doesum, Jaap, Ledoux, Marie-Pierre, Čerňan, Martin, Jakšić, Ozren, Duarte, Rafael F., Magliano, Gabriele, Omrani, Ali S., Fracchiolla, Nicola S., Kulasekararaj, Austin, Valković, Toni, Poulsen, Christian Bjørn, Machado, Marina, Glenthøj, Andreas, Stoma, Igor, Ráčil, Zdeněk, Piukovics, Klára, Navrátil, Milan, Emarah, Ziad, Sili, Uluhan, Maertens, Johan, Blennow, Ola, Bergantim, Rui, García-Vidal, Carolina, Prezioso, Lucia, Guidetti, Anna, del Principe, Maria Ilaria, Popova, Marina, de Jonge, Nick, Ormazabal-Vélez, Irati, Fernández, Noemí, Falces-Romero, Iker, Cuccaro, Annarosa, Meers, Stef, Buquicchio, Caterina, Antić, Darko, Al-Khabori, Murtadha, García-Sanz, Ramón, Biernat, Monika M., Tisi, Maria Chiara, Sal, Ertan, Rahimli, Laman, Čolović, Natasa, Schönlein, Martin, Calbacho, Maria, Tascini, Carlo, Miranda-Castillo, Carolina, Khanna, Nina, Méndez, Gustavo-Adolfo, Petzer, Verena, Novák, Jan, Besson, Caroline, Duléry, Rémy, Lamure, Sylvain, Nucci, Marcio, Zambrotta, Giovanni, Žák, Pavel, Seval, Guldane Cengiz, Bonuomo, Valentina, Mayer, Jiří, López-García, Alberto, Sacchi, Maria Vittoria, Booth, Stephen, Ciceri, Fabio, Oberti, Margherita, Salvini, Marco, Izuzquiza, Macarena, Nunes-Rodrigues, Raquel, Ammatuna, Emanuele, Obr, Aleš, Herbrecht, Raoul, Núñez-Martín-Buitrago, Lucía, Mancini, Valentina, Shwaylia, Hawraa, Sciumè, Mariarita, Essame, Jenna, Nygaard, Marietta, Batinić, Josip, Gonzaga, Yung, Regalado-Artamendi, Isabel, Karlsson, Linda Katharina, Shapetska, Maryia, Hanakova, Michaela, El-Ashwah, Shaimaa, Borbényi, Zita, Çolak, Gökçe Melis, Nordlander, Anna, Dragonetti, Giulia, Maraglino, Alessio Maria Edoardo, Rinaldi, Amelia, De Ramón-Sánchez, Cristina, Cornely, Oliver A., Finizio, Olimpia, Fazzi, Rita, Sapienza, Giuseppe, Chauchet, Adrien, Van Praet, Jens, Prattes, Juergen, Dargenio, Michelina, Rossi, Cédric, Shirinova, Ayten, Malak, Sandra, Tafuri, Agostino, Ommen, Hans-Beier, Bologna, Serge, Khedr, Reham Abdelaziz, Choquet, Sylvain, Joly, Bertrand, Ceesay, M. Mansour, Philippe, Laure, Kho, Chi Shan, Desole, Maximilian, Tsirigotis, Panagiotis, Otašević, Vladimir, Borducchi, Davimar M. M., Antoniadou, Anastasia, Gaziev, Javid, Almaslamani, Muna A., García-Poutón, Nicole, Paterno, Giovangiacinto, Torres-López, Andrea, Tarantini, Giuseppe, Mellinghoff, Sibylle, Gräfe, Stefanie, Börschel, Niklas, Passweg, Jakob, Merelli, Maria, Barać, Aleksandra, Wolf, Dominik, Shaikh, Mohammad Usman, Thiéblemont, Catherine, Bernard, Sophie, Funke, Vaneuza Araújo Moreira, Daguindau, Etienne, Khostelidi, Sofya, Nucci, Fabio Moore, Martín-González, Juan-Alberto, Landau, Marianne, Soussain, Carole, Laureana, Cécile, Lacombe, Karine, Kohn, Milena, Aliyeva, Gunay, Piedimonte, Monica, Fouquet, Guillemette, Rêgo, Mayara, Hoell-Neugebauer, Baerbel, Cartron, Guillaume, Pinto, Fernando, Alburquerque, Ana Munhoz, Passos, Juliana, Yilmaz, Asu Fergun, Redondo-Izal, Ana-Margarita, Altuntaş, Fevzi, Heath, Christopher, Kolditz, Martin, Schalk, Enrico, Guolo, Fabio, Karthaus, Meinolf, Della Pepa, Roberta, Vinh, Donald, Noël, Nicolas, Deau Fischer, Bénédicte, Drenou, Bernard, Mitra, Maria Enza, Meletiadis, Joseph, Bilgin, Yavuz M., Jindra, Pavel, Espigado, Ildefonso, Drgoňa, Ľuboš, Serris, Alexandra, Di Blasi, Roberta, Ali, Natasha, EPICOVIDEHA working group, [missing], Pagano, Livio, Salmanton-Garcia, Jon, Marchesi, Francesco, Busca, Alessandro, Corradini, Paolo, Hoenigl, Martin, Klimko, Nikolai, Koehler, Philipp, Pagliuca, Antonio, Passamonti, Francesco, Verga, Luisa, Visek, Benjamin, Ilhan, Osman, Nadali, Gianpaolo, Weinbergerova, Barbora, Cordoba-Mascunano, Raul, Marchetti, Monia, Collins, Graham P., Farina, Francesca, Cattaneo, Chiara, Cabirta, Alba, Gomes-Silva, Maria, Itri, Federico, van Doesum, Jaap, Ledoux, Marie-Pierre, Cernan, Martin, Jaksic, Ozren, Duarte, Rafael F., Magliano, Gabriele, Omrani, Ali S., Fracchiolla, Nicola S., Kulasekararaj, Austin, Valkovic, Toni, Poulsen, Christian Bjorn, Machado, Marina, Glenthoj, Andreas, Stoma, Igor, Racil, Zdenek, Piukovics, Klara, Navratil, Milan, Emarah, Ziad, Sili, Uluhan, Maertens, Johan, Blennow, Ola, Bergantim, Rui, Garcia-Vidal, Carolina, Prezioso, Lucia, Guidetti, Anna, del Principe, Maria Ilaria, Popova, Marina, de Jonge, Nick, Ormazabal-Velez, Irati, Fernandez, Noemi, Falces-Romero, Iker, Cuccaro, Annarosa, Meers, Stef, Buquicchio, Caterina, Antic, Darko, Al-Khabori, Murtadha, Garcia-Sanz, Ramon, Biernat, Monika M., Tisi, Maria Chiara, Sal, Ertan, Rahimli, Laman, Colovic, Natasa, Schonlein, Martin, Calbacho, Maria, Tascini, Carlo, Miranda-Castillo, Carolina, Khanna, Nina, Mendez, Gustavo-Adolfo, Petzer, Verena, Novak, Jan, Besson, Caroline, Dulery, Remy, Lamure, Sylvain, Nucci, Marcio, Zambrotta, Giovanni, Zak, Pavel, Seval, Guldane Cengiz, Bonuomo, Valentina, Mayer, Jiri, Lopez-Garcia, Alberto, Sacchi, Maria Vittoria, Booth, Stephen, Ciceri, Fabio, Oberti, Margherita, Salvini, Marco, Izuzquiza, Macarena, Nunes-Rodrigues, Raquel, Ammatuna, Emanuele, Obr, Ales, Herbrecht, Raoul, Nunez-Martin-Buitrago, Lucia, Mancini, Valentina, Shwaylia, Hawraa, Sciume, Mariarita, Essame, Jenna, Nygaard, Marietta, Batinic, Josip, Gonzaga, Yung, Regalado-Artamendi, Isabel, Karlsson, Linda Katharina, Shapetska, Maryia, Hanakova, Michaela, El-Ashwah, Shaimaa, Borbenyi, Zita, Colak, Gokce Melis, Nordlander, Anna, Dragonetti, Giulia, Maraglino, Alessio Maria Edoardo, Rinaldi, Amelia, De Ramon-Sanchez, Cristina, Cornely, Oliver A., Pagano, L., Salmanton-Garcia, J., Marchesi, F., Busca, A., Corradini, P., Hoenigl, M., Klimko, N., Koehler, P., Pagliuca, A., Passamonti, F., Verga, L., Visek, B., Ilhan, O., Nadali, G., Weinbergerova, B., Cordoba-Mascunano, R., Marchetti, M., Collins, G. P., Farina, F., Cattaneo, C., Cabirta, A., Gomes-Silva, M., Itri, F., van Doesum, J., Ledoux, M. -P., Cernan, M., Jaksic, O., Duarte, R. F., Magliano, G., Omrani, A. S., Fracchiolla, N. S., Kulasekararaj, A., Valkovic, T., Poulsen, C. B., Machado, M., Glenthoj, A., Stoma, I., Racil, Z., Piukovics, K., Navratil, M., Emarah, Z., Sili, U., Maertens, J., Blennow, O., Bergantim, R., Garcia-Vidal, C., Prezioso, L., Guidetti, A., del Principe, M. I., Popova, M., de Jonge, N., Ormazabal-Velez, I., Fernandez, N., Falces-Romero, I., Cuccaro, A., Meers, S., Buquicchio, C., Antic, D., Al-Khabori, M., Garcia-Sanz, R., Biernat, M. M., Tisi, M. C., Sal, E., Rahimli, L., Colovic, N., Schonlein, M., Calbacho, M., Tascini, C., Miranda-Castillo, C., Khanna, N., Mendez, G. -A., Petzer, V., Novak, J., Besson, C., Dulery, R., Lamure, S., Nucci, M., Zambrotta, G., Zak, P., Seval, G. C., Bonuomo, V., Mayer, J., Lopez-Garcia, A., Sacchi, M. V., Booth, S., Ciceri, F., Oberti, M., Salvini, M., Izuzquiza, M., Nunes-Rodrigues, R., Ammatuna, E., Obr, A., Herbrecht, R., Nunez-Martin-Buitrago, L., Mancini, V., Shwaylia, H., Sciume, M., Essame, J., Nygaard, M., Batinic, J., Gonzaga, Y., Regalado-Artamendi, I., Karlsson, L. K., Shapetska, M., Hanakova, M., El-Ashwah, S., Borbenyi, Z., Colak, G. M., Nordlander, A., Dragonetti, G., Maraglino, A. M. E., Rinaldi, A., De Ramon-Sanchez, C., Cornely, O. A., Finizio, O., Fazzi, R., Sapienza, G., Chauchet, A., Van Praet, J., Prattes, J., Dargenio, M., Rossi, C., Shirinova, A., Malak, S., Tafuri, A., Ommen, H. -B., Bologna, S., Khedr, R. A., Choquet, S., Joly, B., Ceesay, M. M., Philippe, L., Kho, C. S., Desole, M., Tsirigotis, P., Otasevic, V., Borducchi, D. M. M., Antoniadou, A., Gaziev, J., Almaslamani, M. A., Garcia-Pouton, N., Paterno, G., Torres-Lopez, A., Tarantini, G., Mellinghoff, S., Grafe, S., Borschel, N., Passweg, J., Merelli, M., Barac, A., Wolf, D., Shaikh, M. U., Thieblemont, C., Bernard, S., Funke, V. A. M., Daguindau, E., Khostelidi, S., Nucci, F. M., Martin-Gonzalez, J. -A., Landau, M., Soussain, C., Laureana, C., Lacombe, K., Kohn, M., Aliyeva, G., Piedimonte, M., Fouquet, G., Rego, M., Hoell-Neugebauer, B., Cartron, G., Pinto, F., Alburquerque, A. M., Passos, J., Yilmaz, A. F., Redondo-Izal, A. -M., Altuntas, F., Heath, C., Kolditz, M., Schalk, E., Guolo, F., Karthaus, M., Della Pepa, R., Vinh, D., Noel, N., Deau Fischer, B., Drenou, B., Mitra, M. E., Meletiadis, J., Bilgin, Y. M., Jindra, P., Espigado, I., Drgona, L., Serris, A., Di Blasi, R., Ali, N., Stem Cell Aging Leukemia and Lymphoma (SALL), Salvy-Córdoba, Nathalie, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University Hospital of Cologne [Cologne], Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, IFO - Istituto Nazionale Tumori Regina Elena [Roma] (IRE), Città della Salute e della Scienza University-Hospital, IRCCS Istituto Nazionale dei Tumori [Milano], University of California [San Diego] (UC San Diego), University of California (UC), Medical University of Graz, Odessa National I.I.Mechnikov University, Faculty of Medicine [Cologne], University Hospital of Cologne [Cologne]-University of Cologne, King's College Hospital (KCH), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Dipartimento di Medicina e Chirurgia = School of Medicine and Surgery [Monza], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Faculty of Medicine in Hradec Kralove [Republique Tchèque], Charles University [Prague] (CU), Ankara University School of Medicine [Turkey], Azienda Ospedaliera Universitaria Integrata of Verona, Masaryk University [Brno] (MUNI), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Ospedale SS Antonio e Biagio e Cesare Arrigo, Churchill Hospital Oxford Centre for Haematology, IRCCS San Raffaele Scientific Institute [Milan, Italie], ASST Spedali Civili of Brescia, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Universitat Autònoma de Barcelona (UAB), Instituto Português de Oncologia de Lisboa Francisco Gentil, Ospedale San Luigi Gonzaga, University Medical Center Groningen [Groningen] (UMCG), Institut de Cancérologie de Strasbourg Europe (ICANS), Palacky University Olomouc, Zagreb School of Medicine [Zagreb, Croatia] (Dubrava University Hospital), University of Zagreb, Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], ASST Great Metropolitan Niguarda / ASST Grande Ospedale Metropolitano Niguarda [Milan, Italia], Hamad Medical Corporation [Doha, Qatar], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Rijeka, Croatian Cooperative Group for Hematological Diseases (CROHEM), Zealand University Hospital [Roskilde, Denmark], Hospital General Universitario 'Gregorio Marañón' [Madrid], Department of Clinical Microbiology [Rigshospitalet], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Homieĺ State Medical University (GSMU), Institute of Hematology and Blood Transfusion [Prague, Czech Republic], University of Szeged [Szeged], University Hospital Ostrava, Mansoura University [Egypt], Marmara University [Kadıköy - İstanbul], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Karolinska University Hospital [Stockholm], Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Hospital de São João [Porto], Faculdade de Medicina da Universidade do Porto (FMUP), Clinic Barcelona Hospital Universitari, Department of Public Health and Cell Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy, Pavlov First Saint Petersburg State Medical University [St. Petersburg], Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), Complejo Hospitalario de Navarra, Hospital Universitario Marqués de Valdecilla [Santander], La Paz University Hospital, Azienda Usl Toscana centro [Firenze], AZ Klina, Clinical Center of Serbia (KCS), University of Belgrade [Belgrade], Sultan Qaboos University Hospital, Partenaires INRAE, Hospital Universitario de Salamanca, Servicio de Haematologia, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), University of Wrocław [Poland] (UWr), San Bortolo Hospital, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospital Universitario 12 de Octubre [Madrid], Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Universidad Rey Juan Carlos [Madrid] (URJC), University of Basel (Unibas), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Hospital Kralovské Vinohrady, Centre Hospitalier de Versailles André Mignot (CHV), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département Hématologie biologique [CHRU Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universidade Federal do Estado do Rio de Janeiro (UNIRIO), San Gerardo Hospital of Monza, Oxford NIHR Biomedical Research Centre, IRCCS Ospedale San Raffaele [Milan, Italy], Assi Sette Llaghi Varese, Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), University Hospital Olomouc [Czech Republic], ASST Grande Ospedale Metropolitano Niguarda, University Hospital Centre Zagreb, Instituto Nacional do Câncer, Copenhagen University Hospital, Republican Scientific and Practical Center (RSPC) for organ and Tissue Transplantation, Minsk, Republican Scientific and Practical Center (RSPC) for Organ and Transplantation, German Centre for Infection Research (DZIF), Gilead Sciences, Pagano, Livio [0000-0001-8287-928X], Salmanton-García, Jon [0000-0002-6766-8297], Marchesi, Francesco [0000-0001-6353-2272], Busca, Alessandro [0000-0001-5361-5613], Corradini, Paolo [0000-0002-9186-1353], Hoenigl, Martin [0000-0002-1653-2824], Klimko, Nikolay [0000-0001-6095-7531], Koehler, Philipp [0000-0002-7386-7495], Pagliuca, Antonio [0000-0003-2519-0333], Passamonti, Francesco [0000-0001-8068-5289], Verga, Luisa [0000-0003-1142-8435], Víšek, Benjamin [0000-0001-8268-452X], Ilhan, Osman [0000-0003-1665-372X], Weinbergerová, Barbora [0000-0001-6460-2471], Córdoba, Raúl [0000-0002-7654-8836], Marchetti, Monia [0000-0001-7615-0572], Farina, Francesca [0000-0002-5124-6970], Cattaneo, Chiara [0000-0003-0031-3237], Cabirta, Alba [0000-0001-7198-8894], Gomes-Silva, Maria [0000-0002-6993-2450], Itri, Federico [0000-0002-3532-5281], Doesum, Jaap van [0000-0003-0214-3219], Ledoux, Marie-Pierre [0000-0002-3261-3616], Čerňan, Martin [0000-0003-2345-1229], Jakšić, Ozren [0000-0003-4026-285X], Magliano, Gabriel [0000-0002-9129-1530], Omrani, Ali S. [0000-0001-5309-6358], Fracchiolla, Nicola S. [0000-0002-8982-8079], Kulasekararaj, Austin G. [0000-0003-3180-3570], Valković, Toni [0000-0001-6083-8815], Poulsen, Christian Bjørn [0000-0001-9785-1378], Machado, Marina [0000-0002-8370-2248], Glenthøj, Andrea [0000-0003-2082-0738], Stoma, Igor [0000-0003-0483-7329], Ráčil, Zdeněk [0000-0003-3511-4596], Piukovics, Klára [0000-0003-4480-3131], Emarah, Ziad [0000-0003-0622-2598], Sili, Uluhan [0000-0002-9939-9298], Maertens, Johan [0000-0003-4257-5980], Bergantim, Rui [0000-0002-7811-9509], García-Vidal, Carolina [0000-0002-8915-0683], Prezioso, Lucia [0000-0003-1660-4960], Principe, Maria Ilaria del [0000-0002-3958-0669], Popova, Marina [0000-0001-8536-5495], Jonge, Nick de [0000-0002-9901-0887], Ormazabal-Vélez, Irati [0000-0003-1141-5546], Falces-Romero, Iker [0000-0001-5888-7706], Cuccaro, Annarosa [0000-0002-0237-1839], Meers, Stef [0000-0003-1754-2175], Buquicchio, Caterina [0000-0002-3683-5953], Antić, Darko [0000-0002-2608-1342], Al-Khabori, Murtadha [0000-0002-2937-8838], García-Sanz, Ramón [0000-0003-4120-2787], Biernat, Monika [0000-0003-3161-3398], Tisi, Maria Chiara [0000-0001-8231-6700], Sal, Ertan [0000-0003-2761-2675], Rahimli, Laman [0000-0003-2266-445X], Schönlein, Martin [0000-0002-1010-0975], Calbacho, María [0000-0001-8106-4863], Tascini, Carlo [0000-0001-9625-6024], Miranda-Castillo, Carolina [0000-0001-8763-9576], Khanna, Nina [0000-0002-2642-419X], Méndez, Gustavo-Adolfo [0000-0003-0514-7004], Petzer, Verena [0000-0002-9205-1440], Besson, Caroline [0000-0003-4364-7173], Duléry, Rémy [0000-0002-5024-1713], Lamure, Sylvain [0000-0001-5980-305X], Nucci, Marcio [0000-0003-4867-0014], Zambrotta, Giovanni [0000-0002-8612-2994], Žák, Pavel [0000-0003-4465-5343], Cengiz Seval, Guldane [0000-0001-9433-2054], Bonuomo, Valentina [0000-0001-6491-8337], Mayer, Jiří [0000-0003-0567-9887], López-García, Alberto [0000-0002-5354-5261], Sacchi, Maria Vittoria [0000-0001-8133-3357], Booth, Stephen [0000-0003-2687-0234], Ciceri, Fabio [0000-0003-0873-0123], Nunes-Rodrigues, Raquel [0000-0002-8347-4281], Ammatuna, Emanuele [0000-0001-8247-4901], Obr, Aleš [0000-0002-6758-3074], Herbrecht, Raoul [0000-0002-9381-4876], Shwaylia, Hawraa [0000-0002-4098-6092], Sciumè, Mariarita [0000-0001-7958-4966], Essame, Jenna [0000-0003-0926-5577], Batinić, Josip [0000-0001-5595-9911], Gonzaga, Yung [0000-0003-1416-2118], Regalado-Artamendi, Isabel [0000-0002-9673-9015], Karlsson, Linda Katharina [0000-0003-3317-7550], Shapetska, Maryia [0000-0002-1223-9161], El-Ashwah, Shaimaa [0000-0003-2210-1534], Çolak, Gökçe Melis [0000-0002-7662-7454], Dragonetti, Giulia [0000-0003-1775-6333], Rinaldi, Amelia [0000-0002-8211-5076], Ramón, Cristina de [0000-0002-8167-6410], Cornely, Oliver A. [0000-0001-9599-3137], Institut Català de la Salut, [Pagano L] Hematology, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS – Università Cattolica del Sacro Cuore, Rome, Italy. Università Cattolica del Sacro Cuore, Rome, Italy. [Salmanton-García J] Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Excellence Center for Medical Mycology (ECMM), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. Cologne Excellence Cluster On Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. [Marchesi F] Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy. [Busca A] Stem Cell Transplant Center, AOU Citta’ Della Salute E Della Scienza, Turin, Italy. [Corradini P] University of Milan and Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy. [Hoenigl M] Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, San Diego, CA, USA. Clinical and Translational Fungal Working Group, University of California San Diego, La Jolla, CA, USA. Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, Graz, Austria. [Cabirta A, Izuzquiza M] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Hematology, Salmanton-García, Jon, Klimko, Nikolay, Víšek, Benjamin, Weinbergerová, Barbora, Córdoba, Raúl, Doesum, Jaap van, Čerňan, Martin, Jakšić, Ozren, Magliano, Gabriel, Kulasekararaj, Austin G., Valković, Toni, Poulsen, Christian Bjørn, Glenthøj, Andrea, Ráčil, Zdeněk, Piukovics, Klára, García-Vidal, Carolina, Principe, Maria Ilaria del, Jonge, Nick de, Ormazabal-Vélez, Irati, Antić, Darko, García-Sanz, Ramón, Biernat, Monika, Schönlein, Martin, Calbacho, María, Méndez, Gustavo-Adolfo, Duléry, Rémy, Žák, Pavel, Cengiz Seval, Guldane, Mayer, Jiří, López-García, Alberto, Obr, Aleš, Sciumè, Mariarita, Batinić, Josip, Çolak, Gökçe Melis, Ramón, Cristina de, and Universidad de Sevilla. Departamento de Medicina

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Cancer Research, MESH: Registries, Epidemiology, MESH: Hospitalization, Hematological malignancies, Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], MESH: Aged, 80 and over, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Risk Factors, Malalties - Factors de risc, Risk of mortality, Medicine and Health Sciences, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], 80 and over, Medicine, MESH: COVID-19, Registries, Sang - Malalties - Complicacions, RC254-282, Cause of death, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Interna medicina, MESH: Aged, Aged, 80 and over, Hematology, MESH: Middle Aged, Mortality rate, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Myeloid leukemia, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, CANCER, Europe, Hospitalization, Intensive Care Units, Oncology, MESH: Young Adult, Hematologic Neoplasms, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Infektologija, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, COVID-19, EHA, Pandemic, Aged, Humans, SARS-CoV-2, Young Adult, técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], [SDV.CAN] Life Sciences [q-bio]/Cancer, Intensive care, Internal medicine, Diseases of the blood and blood-forming organs, MESH: SARS-CoV-2, neoplasias::neoplasias por localización::neoplasias hematológicas [ENFERMEDADES], Molecular Biology, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Internal Medicine, pandemic, hematological malignancies, epidemiology, MESH: Humans, Science & Technology, business.industry, Myelodysplastic syndromes, Research, MESH: Adult, Neoplasms::Neoplasms by Site::Hematologic Neoplasms [DISEASES], medicine.disease, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Infectology, Settore MED/15, MESH: Male, Settore MED/15 - MALATTIE DEL SANGUE, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, COVID-19 (Malaltia) - Diagnòstic, MESH: Intensive Care Units, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], MESH: Europe, RC633-647.5, business, MESH: Female, Other subheadings::Other subheadings::/complications [Other subheadings], MESH: Hematologic Neoplasms
Abstract

Background Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value, EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

Published
2021

30. Mosaic loss of Y chromosome and the association to mortality in Danish men aged 56-100 years.

Author

Hozakowska-Roszkowska DM, Mengel-From J, Hristozova TK, Pedersen JK, Jeune B, Andersen-Ranberg K, Hjelmborg JVB, Christensen K, Röttger R, and Nygaard M

Abstract

Mosaic loss of the Y chromosome (mLOY) is a common somatic mutation in the blood of elderly men and several studies have found mLOY in blood cells to be associated with an increased risk of various diseases and mortality. However, most of these studies have focused on middle-aged and older adults, meaning that mLOY in extremely old individuals like centenarians is understudied. To explore mLOY across a wider age range compared to earlier studies and to specifically focus on centenarians, mLOY was estimated in 917 Danish men aged 56-100 years. We found that the percentage of men with LOY increased with age until age 85, after which it plateaued at around 40 %. Consistently, a longitudinal comparison of mLOY revealed that mLOY predominantly increased with age, although inter-individual variation was seen. Using a twin sub-sample, the broad-sense heritability of mLOY was estimated at 72 %, indicating a substantial genetic influence. Supporting previous findings, mLOY was found to associate with increased mortality across all study participants and in men younger than 80 years. In centenarians, however, a higher level of mLOY associated with better survival, most likely due to selection, although confirmation of our findings in larger studies is needed., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2024
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31. Maternal glucose homeostasis during pregnancy in women with overweight or obesity and offspring metabolic health.

Author

Mogensen CS, Nygaard M, Kampmann U, Mølgaard C, Magkos F, and Geiker NRW

Subjects
Humans, Female, Pregnancy, Adult, Diabetes, Gestational metabolism, Diabetes, Gestational blood, Infant, Newborn, Child, Preschool, Insulin blood, Insulin metabolism, C-Peptide blood, Fasting blood, Pregnancy Complications metabolism, Pregnancy Complications blood, Blood Glucose metabolism, Homeostasis, Obesity metabolism, Obesity blood, Body Mass Index, Glucose Tolerance Test, Overweight metabolism, Overweight blood
Abstract

Gestational diabetes mellitus (GDM) adversely affects offspring glucose homeostasis and risk of developing obesity. Here, we examined the association between glycemia in pregnant women with overweight or obesity without GDM and offspring metabolic health. Maternal fasting glucose concentrations and glucose 2-h after an oral glucose tolerance test (OGTT) were measured in 208 women with a pre-pregnancy body mass index (BMI) of 28-45 kg/m 2 without GDM. Offspring outcomes were collected at birth, 3, and 5 years of age. Linear mixed models with time as fixed factor and subject ID as random effects were used for analysis. No associations were found between maternal fasting or 2-h glucose concentrations with offspring glucose and insulin concentrations from birth to 5 years of age. However, maternal fasting glucose in GW 28 and 36, and 2-h OGTT glucose in GW 28 were positively associated with C-peptide concentration at birth. Maternal fasting glucose concentrations in GW 28 and 36 were positively associated with weight-for-length, and maternal fasting glucose in GW 36 was associated with BMI z-score at birth. In summary, blood glucose in pregnant women with overweight or obesity is positively associated with offspring C-peptide concentration, weight-for-length, and BMI z-score at birth, even in the absence of GDM., (© 2024. The Author(s).)

Published
2024
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32. FOXO-regulated OSER1 reduces oxidative stress and extends lifespan in multiple species.

Author

Song J, Li Z, Zhou L, Chen X, Sew WQG, Herranz H, Ye Z, Olsen JV, Li Y, Nygaard M, Christensen K, Tong X, Bohr VA, Rasmussen LJ, and Dai F

Subjects
Animals, Humans, Bombyx genetics, Bombyx metabolism, Bombyx physiology, Drosophila melanogaster genetics, Mitochondria metabolism, Mitochondria genetics, Reactive Oxygen Species metabolism, Gene Expression Regulation, Longevity genetics, Caenorhabditis elegans genetics, Caenorhabditis elegans physiology, Caenorhabditis elegans metabolism, Oxidative Stress, Drosophila Proteins metabolism, Drosophila Proteins genetics, Forkhead Transcription Factors metabolism, Forkhead Transcription Factors genetics, Caenorhabditis elegans Proteins metabolism, Caenorhabditis elegans Proteins genetics
Abstract

FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging., (© 2024. The Author(s).)

Published
2024
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33. Factors associated with teenage pregnancy in the Scandinavian countries.

Author

Bennetsen AKK, Faber MT, Nygaard M, Sundström K, Hansen BT, Thomsen LT, Munk C, Frederiksen K, and Kjaer SK

Subjects
Humans, Female, Pregnancy, Adolescent, Cross-Sectional Studies, Young Adult, Adult, Scandinavian and Nordic Countries epidemiology, Middle Aged, Risk Factors, Alcohol Drinking epidemiology, Alcohol Drinking psychology, Contraception Behavior statistics & numerical data, Surveys and Questionnaires, Pregnancy in Adolescence statistics & numerical data, Smoking epidemiology
Abstract

Aims: Teenage pregnancy may have negative consequences for the mother and the infant. The aim of the study was to examine whether selected individual factors occurring early in life were associated with teenage pregnancy., Methods: In a population-based, cross-sectional questionnaire study among 34,455 women from Denmark, Norway, and Sweden aged 20-45 years, who had first sexual intercourse (FSI) at age 13-19 years, we assessed the association between early smoking and drinking initiation (i.e., before the age of 13), contraceptive use at FSI, and teenage pregnancy. Log-linear binary regression models were fitted to estimate the relative risk (RR) with 95% confidence intervals (CIs) of teenage pregnancy according to the three exposure variables, overall and by age at FSI. Furthermore, the outcomes of the teenage pregnancies were examined according to age at FSI., Results: Teenage pregnancy occurred in 11% of the population. Both early smoking initiation (RR: 1.6; 95% CI: 1.4-1.8), early drinking initiation (RR: 1.2; 95% CI: 1.0-1.4), and non-use of contraceptives at FSI (RR: 1.9; 95% CI: 1.8-2.0) were associated with teenage pregnancy. The associations for early smoking initiation and non-use of contraceptives remained when analyses were stratified by age at FSI. Almost 60% of all teenage pregnant women had an induced abortion and less than 30% gave birth., Conclusions: Individual factors, including early smoking and drinking initiation, and non-use of contraceptives at FSI, were associated with teenage pregnancy regardless of age at FSI. This emphasizes the necessity of focusing on early risk-taking behavior as a potential modifier to prevent teenage pregnancy., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2024
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34. Prospective Effects of Self-Rated Health on Dementia Risk in Two Twin Studies of Aging.

Author

Pilgrim MJD, Beam CR, Nygaard M, and Finkel D

Subjects
Humans, Female, Male, Sweden, Denmark, Aged, Risk Factors, Health Status, Middle Aged, Aged, 80 and over, Twins, Monozygotic genetics, Prospective Studies, Twins, Dizygotic genetics, Self Report, Dementia genetics, Aging genetics
Abstract

Subjective health ratings are associated with dementia risk such that those who rate their health more poorly have increased risk for dementia. The genetic and environmental mechanisms underlying this association are unclear, as prior research cannot rule out whether the association is due to genetic confounds. The current study addresses this gap in two samples of twins, one from Sweden (N = 548) and one from Denmark (N = 4,373). Using genetically-informed, bivariate regression models, we assessed whether additive genetic effects explained the association between subjective health and dementia risk as indexed by a latent variable proxy measure. Age at intake, sex, education, depressive symptomatology, and follow-up time between subjective health and dementia risk assessments were included as covariates. Results indicate that genetic variance and other sources of confounding accounted for the majority of the effect of subjective health ratings on dementia risk. After adjusting for genetic confounding and other covariates, a small correlation was observed between subjective health and latent dementia risk in the Danish sample (r E  = - .09, p < .05). The results provide further support for the genetic association between subjective health and dementia risk, and also suggest that subjective ratings of health measures may be useful for predicting dementia risk., (© 2024. The Author(s).)

Published
2024
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35. Cognitively high-performing oldest old individuals are physically active and have strong motor skills-A study of the Danish 1905 and 1915 birth cohorts.

Author

Hermansen M, Nygaard M, Tan Q, Jeune B, Semkovska M, Christensen K, Thinggaard M, and Mengel-From J

Subjects
Humans, Denmark, Male, Female, Aged, 80 and over, Exercise psychology, Hand Strength physiology, Cohort Studies, Aging physiology, Aging psychology, Life Style, Cognition physiology, Activities of Daily Living, Motor Skills physiology
Abstract

Preserving cognitive function with age or super-aging greatly contributes to successful aging. Super-aging nonagenarians born in Denmark in either year 1905 or 1915 were classified as Cognitively High-Performing Oldest Old individuals with a five item cognitive composite score, equivalent to or better than mean middle-aged subjects. Cognitively high-performers were more physically active and had a better physical performance on e.g., Activity of Daily Living (p-value < 0.01), gait speed (p-value < 0.01) and grip strength (p-value < 0.05) compared with age-matched peers. Cognitive high-performing was also linked to lower depression symptomatology. When comparing super-agers with semi super-agers classified by Mini Mental State Examination > 27, super-agers were still more physically active and had a better physical performance (p-value < 0.05). Results suggests that physical activity is a lifestyle factor strongly associated with both semi and full cognitive super-aging., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Published
2024
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36. Age and Sex Differences in the Genetic Architecture of Measures of Subjective Health: Relationships With Physical Health, Depressive Symptoms, and Episodic Memory.

Author

Finkel D, Gatz M, Franz CE, Catts VS, Christensen K, Kremen W, Nygaard M, Plassman BL, Sachdev PS, Whitfield K, and Pedersen NL

Subjects
Humans, Female, Aged, Male, Middle Aged, Adult, Aged, 80 and over, Sex Factors, Age Factors, Aging psychology, Aging genetics, Diagnostic Self Evaluation, Memory, Episodic, Depression genetics, Depression psychology, Health Status
Abstract

Objectives: Subjective health (SH) is not just an indicator of physical health, but also reflects active cognitive processing of information about one's own health and has been associated with emotional health measures, such as neuroticism and depression. Behavior genetic approaches investigate the genetic architecture of SH, that is, genetic and environmental influences on individual differences in SH and associations with potential components such as physical, cognitive, and emotional health. Previous twin analyses have been limited by sex, sample size, age range, and focus on single covariates., Methods: The current analysis used data from 24,173 adults ranging in age from 40 to 90 years from the international Interplay of Genes and Environment across Multiple Studies consortium to investigate the genetic architecture of 3 measures of SH: self-rated health, health compared to others, and impact of health on activities. Independent pathways model of SH included physical health, depressive symptoms, and episodic memory, with age, sex, and country included as covariates., Results: Most or all of the genetic variance for SH measures were shared with physical health, depressive symptoms, and episodic memory. Genetic architecture of SH differed across measures, age groups (40-65, 66-90), and sexes. Age comparisons indicated stronger correlations with all 3 covariates in older adults, often resulting from greater shared genetic variance., Discussion: The predictive value of SH has been amply demonstrated. The higher genetic contributions to associations between SH and its components in older adults support the increasing conceptualization with age of SH as an intuitive summation of one's vital reserve., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2024
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37. Epigenome-wide analysis of frailty: Results from two European twin cohorts.

Author

Mak JKL, Skovgaard AC, Nygaard M, Kananen L, Reynolds CA, Wang Y, Kuja-Halkola R, Karlsson IK, Pedersen NL, Hägg S, Soerensen M, and Jylhävä J

Subjects
Humans, Male, Female, Aged, Genome-Wide Association Study, Cohort Studies, CpG Islands genetics, Aging genetics, Longitudinal Studies, Epigenesis, Genetic, Aged, 80 and over, Frailty genetics, Epigenome genetics, DNA Methylation genetics
Abstract

Epigenetics plays an important role in the aging process, but it is unclear whether epigenetic factors also influence frailty, an age-related state of physiological decline. In this study, we performed a meta-analysis of epigenome-wide association studies in four samples drawn from the Swedish Adoption/Twin Study of Aging (SATSA) and the Longitudinal Study of Aging Danish Twins (LSADT) to explore the association between DNA methylation and frailty. Frailty was defined using the frailty index (FI), and DNA methylation levels were measured in whole blood using Illumina's Infinium HumanMethylation450K and MethylationEPIC arrays. In the meta-analysis consisting of a total of 829 participants, we identified 589 CpG sites that were statistically significantly associated with either the continuous or categorical FI (false discovery rate <0.05). Many of these CpGs have previously been associated with age and age-related diseases. The identified sites were also largely directionally consistent in a longitudinal analysis using mixed-effects models in SATSA, where the participants were followed up to a maximum of 20 years. Moreover, we identified three differentially methylated regions within the MGRN1, MIR596, and TAPBP genes that have been linked to neuronal aging, tumor growth, and immune functions. Furthermore, our meta-analysis results replicated 34 of the 77 previously reported frailty-associated CpGs at p < 0.05. In conclusion, our findings demonstrate robust associations between frailty and DNA methylation levels in 589 novel CpGs, previously unidentified for frailty, and strengthen the role of neuronal/brain pathways in frailty., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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

Author

Tan Q, Li W, Nygaard M, An P, Feitosa M, Wojczynski MK, Zmuda J, Arbeev K, Ukraintseva S, Yashin A, Christensen K, and Mengel-From J

Subjects
Humans, Male, Aged, Female, Middle Aged, Semantics, Aged, 80 and over, Gene Regulatory Networks, Genotype, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Epistasis, Genetic
Abstract

Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10 -8 ; rs880179, p = 4.83 × 10 -8 ) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10 -5 < p < 7.35 × 10 -3 ), of which two were replicated ( p < 3.10 × 10 -3 ). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.

Published
2024
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39. Genetics of environmental sensitivity to psychiatric and neurodevelopmental phenotypes: evidence from GWAS of monozygotic twins.

Author

Assary E, Coleman J, Hemani G, van Der Veijer M, Howe L, Palviainen T, Grasby K, Ahlskog R, Nygaard M, Cheesman R, Lim K, Reynolds C, Ordoñana J, Colodro-Conde L, Gordon S, Madrid-Valero J, Thalamuthu A, Hottenga JJ, Mengel-From J, Armstrong NJ, Sachdev P, Lee T, Brodaty H, Trollor J, Wright M, Ames D, Catts V, Latvala A, Vuoksimaa E, Mallard T, Harden K, Tucker-Drob E, Oskarsson S, Hammond C, Christensen K, Taylor M, Lundström S, Larsson H, Karlsson R, Pedersen N, Mather K, Medland S, Boomsma D, Martin N, Plomin R, Bartels M, Lichtenstein P, Kaprio J, Eley T, Davies N, Munroe P, and Keers R

Abstract

Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes. However, environmental sensitivity genetic variants have proven challenging to detect. GWAS of monozygotic twin differences is a family-based variance analysis method, which is more robust to systemic biases that impact population-based methods. We combined data from up to 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct the largest GWAS meta-analysis of monozygotic phenotypic differences in children and adolescents/adults for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder (ADHD) symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism, and wellbeing. The SNP-heritability of variance in these phenotypes were estimated (h2: 0% to 18%), but were imprecise. We identified a total of 13 genome-wide significant associations (SNP, gene, and gene-set), including genes related to stress-reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. Monozygotic twins are an important new source of evidence about the genetics of environmental sensitivity., Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Published
2024
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40. Can social connections become stressful? Exploring the link between social media use and perceived stress in cross-sectional and longitudinal analyses of 25,053 adults.

Author

Nygaard M, Andersen TO, and Rod NH

Abstract

Background: Social media has become a dominant part of daily lives for many, but excessive use may lead to an experience of stress. Only relatively few studies have investigated social media's influence on mental health., Aims: We aimed to investigate whether social media use is associated with perceived stress and changes in perceived stress over 18 months., Methods: The study population consisted of 25,053 adults (mean age 42.8; 62% women) from the SmartSleep Study. Self-reported frequency of social media use, of 10 specific social media platforms, and of perceived stress (the Perceived Stress Scale 4 item) was obtained at baseline and 18-months follow-up ( N  = 1745). The associations were evaluated at baseline and follow-up using multiple linear regression models adjusted for potential confounders., Results: Compared to non-use, high social media use (at least every second hour) was associated with a slightly higher perceived stress level at baseline. No association was found between the frequency of social media use and changes in perceived stress during follow-up. Only small differences in these associations were noted across social media platforms., Conclusions: Further studies are needed to comprehensively explore the relationship between excessive social media use and mental health, recognizing different characteristics across social media platforms.

Published
2024
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41. Cohort profile: The SmartSleep Study , Denmark, combining evidence from survey, clinical and tracking data.

Author

Rod NH, Andersen TO, Severinsen ER, Sejling C, Dissing A, Pham VT, Nygaard M, Schmidt LKH, Drews HJ, Varga T, Freiesleben NC, Nielsen HS, and Jensen AK

Subjects
Humans, Smartphone, Surveys and Questionnaires, Sleep, Denmark epidemiology, Mobile Applications
Abstract

Purpose: The SmartSleep Study is established to comprehensively assess the impact of night-time smartphone use on sleep patterns and health. An innovative combination of large-scale repeated survey information, high-resolution sensor-driven smartphone data, in-depth clinical examination and registry linkage allows for detailed investigations into multisystem physiological dysregulation and long-term health consequences associated with night-time smartphone use and sleep impairment., Participants: The SmartSleep Study consists of three interconnected data samples, which combined include 30 673 individuals with information on smartphone use, sleep and health. Subsamples of the study population also include high-resolution tracking data (n=5927) collected via a customised app and deep clinical phenotypical data (n=245). A total of 7208 participants are followed in nationwide health registries with full data coverage and long-term follow-up., Findings to Date: We highlight previous findings on the relation between smartphone use and sleep in the SmartSleep Study , and we evaluate the interventional potential of the citizen science approach used in one of the data samples. We also present new results from an analysis in which we use 803 000 data points from the high-resolution tracking data to identify clusters of temporal trajectories of night-time smartphone use that characterise distinct use patterns. Based on these objective tracking data, we characterise four clusters of night-time smartphone use., Future Plans: The unprecedented size and coverage of the SmartSleep Study allow for a comprehensive documentation of smartphone activity during the entire sleep span. The study has been expanded by linkage to nationwide registers, which allow for further investigations into the long-term health and social consequences of night-time smartphone use. We also plan new rounds of data collection in the coming years., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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42. A Short-Form Measure of Diabetes Distress Among Adults With Type 1 Diabetes for Use in Clinical Practice: Development and Validation of the T1-DDS-7.

Author

Nygaard M, Willaing I, Joensen LE, Lindgreen P, Stenov V, Hessler D, Nørgaard K, Pedersen-Bjergaard U, and Olesen K

Subjects
Adult, Humans, Reproducibility of Results, Stress, Psychological, Surveys and Questionnaires, Factor Analysis, Statistical, Psychometrics, Diabetes Mellitus, Type 1 therapy
Abstract

Objective: Valid and reliable diabetes distress assessment is essential for identifying adults with elevated levels of concern and to guide targeted support. However, assessing diabetes distress must also be feasible in time-limited settings. We aimed to identify a short-form measure of the 28-item Type 1 Diabetes Distress Scale (T1-DDS-28) representing seven sources of type 1 diabetes distress that would be convenient for use in clinical practice., Research Design and Methods: Based on the evaluation of influence and importance by 14 experts in diabetes care and research, we identified the best-performing item within each of seven sources of diabetes distress included in the T1-DDS-28. To further validate the proposed short-form measure, we used survey data from 2,016 adults living with type 1 diabetes. Validity was examined by exploratory factor analysis, Cronbach's α, test-retest reliability analysis, and correlations with other psychosocial measures., Results: We identified a short-form measure of the T1-DDS-28 consisting of seven items, each representing a source of diabetes distress. These items showed satisfactory reliability (factor loadings > 0.45; α = 0.82; test-retest correlation, r = 0.90) and validity (correlation with T1-DDS-28, r = 0.95; area under the curve = 0.91; sensitivity 93%; specificity 89%) when combined in the short-form scale (T1-DDS-7)., Conclusions: We propose the T1-DDS-7 as a valid and reliable measure for routine screening of diabetes distress among adults with type 1 diabetes. In case of elevated levels of diabetes distress, we recommend that a full-scale assessment and open dialogue follow the short-form measure before determining further treatment., (© 2023 by the American Diabetes Association.)

Published
2023
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43. Remember This: Age Moderation of Genetic and Environmental Contributions to Verbal Episodic Memory from Midlife through Late Adulthood.

Author

Luczak SE, Beam CR, Pahlen S, Lynch M, Pilgrim M, Reynolds CA, Panizzon MS, Catts VS, Christensen K, Finkel D, Franz CE, Kremen WS, Lee T, McGue M, Nygaard M, Plassman BL, Whitfield KE, Pedersen NL, and Gatz M

Abstract

It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium constituted the analytic sample. Verbal episodic memory was assessed with immediate word list recall ( N = 35,204 individuals; 21,792 twin pairs) and prose recall ( N = 3,805 individuals; 2,028 twin pairs), with scores harmonized across studies. Average test performance was lower in successively older age groups for both measures. Twin models found significant age moderation for both measures, with total inter-individual variance increasing significantly with age, although it was not possible definitively to attribute the increase specifically to either genetic or environmental sources. Pooled results across all 12 studies were compared to results where we successively dropped each study (leave-one-out) to assure results were not due to an outlier. We conclude the models indicated an overall increase in variance for verbal episodic memory that was driven by a combination of increases in the genetic and nonshared environmental parameters that were not independently statistically significant. In contrast to reported results for other cognitive domains, differences in environmental exposures are comparatively important for verbal episodic memory, especially word list learning., Competing Interests: Declaration of Competing Interests: None

Published
2023
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44. Identifying genetic variants regulating MGMT gene expression - A study in monozygotic Danish twins.

Author

Mohammadnejad A, Soerensen M, Mengel-From J, Nygaard M, Timofeeva M, He L, Clemmensen SB, Halekoh U, Dahlrot RH, Tan Q, and Hjelmborg JVB

Subjects
Middle Aged, Humans, Genome-Wide Association Study, O(6)-Methylguanine-DNA Methyltransferase genetics, O(6)-Methylguanine-DNA Methyltransferase metabolism, Gene Expression, Denmark, DNA Methylation, Tripartite Motif Proteins genetics, Tripartite Motif Proteins metabolism, Ubiquitin-Protein Ligases genetics, DNA Modification Methylases, Tumor Suppressor Proteins genetics, DNA Repair Enzymes genetics, DNA Repair Enzymes metabolism, Twins, Monozygotic, Glioblastoma genetics, Glioblastoma metabolism
Abstract

Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient's sensitivity to therapeutic alkylating agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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45. Rare genetic variants correlate with better processing speed.

Author

Song Z, Gurinovich A, Nygaard M, Mengel-From J, Andersen S, Cosentino S, Schupf N, Lee J, Zmuda J, Ukraintseva S, Arbeev K, Christensen K, Perls T, and Sebastiani P

Subjects
Humans, Middle Aged, Longitudinal Studies, Genotype, Haplotypes, Polymorphism, Single Nucleotide genetics, Genome-Wide Association Study, Processing Speed
Abstract

We conducted a genome-wide association study of Digit Symbol Substitution Test scores administered in 4207 family members of the Long Life Family Study (LLFS). Genotype data were imputed to the HRC panel of 64,940 haplotypes resulting in ∼15M genetic variants with a quality score > 0.7. The results were replicated using genetic data imputed to the 1000 Genomes phase 3 reference panel from 2 Danish twin cohorts: the study of Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The genome-wide association study in LLFS discovered 18 rare genetic variants (minor allele frequency (MAF) < 1.0%) that reached genome-wide significance (p-value < 5 × 10 -8 ). Among these, 17 rare variants in chromosome 3 had large protective effects on the processing speed, including rs7623455, rs9821776, rs9821587, rs78704059, which were replicated in the combined Danish twin cohort. These SNPs are located in/near 2 genes, THRB and RARB, that belonged to the thyroid hormone receptors family that may influence the speed of metabolism and cognitive aging. The gene-level tests in LLFS confirmed that these 2 genes are associated with processing speed., Competing Interests: Disclosure statement The authors have no actual or potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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46. Improving Health and Diabetes Self-Management in Immigrants with Type 2 Diabetes Through a Co-Created Diabetes Self-Management Education and Support Intervention.

Author

Hempler NF, Fagt C, Olesen K, Wagner S, Rasmussen LB, Laursen DH, Glümer C, Nygaard M, and Willaing I

Subjects
Humans, Glycated Hemoglobin, Health Behavior, Diabetes Mellitus, Type 2 therapy, Diabetes Mellitus, Type 2 psychology, Self-Management, Emigrants and Immigrants
Abstract

To examine the impact of a co-created culturally sensitive diabetes self-management education and support (DSMES) intervention on the physical and mental health of immigrants with type 2 diabetes (T2D). Pre- and post-test among people with T2D whose primary language was Urdu, Arabic or Turkish (n = 97). Participants were offered a six-week intervention based on a person-centred approach using research-based dialogue tools to facilitate learning and reflection, which was developed in co-creation with immigrants and healthcare professionals. Data were collected at baseline, post-intervention and after 6 months and analysed using paired t-tests, Wilcoxon signed-rank tests, chi-square tests and regression models when appropriate. Several clinical outcomes were improved post-intervention, including HbA1c (P < 0.001), body fat percentage (P = 0.002), self-rated general health (P = 0.05), well-being (P = 0.004) and several self-management behaviours, e.g., physical activity (P < 0.001). Most outcomes remained improved after 6 months, but the effect on HbA1c was no longer statistically significant. Some outcomes were improved only at 6 months, including waist circumference (P < 0.001) and diabetes-related emotional distress (P < 0.001). Fatigue did not change. Attendance at more programme sessions was associated with better outcomes. The DSMES intervention developed in a co-creation process was highly effective in improving the health of immigrants with T2D., (© 2022. The Author(s).)

Published
2023
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47. Signatures of Neuropsychological Test Results in the Long Life Family Study: A Cluster Analysis.

Author

Xiang Q, Andersen SL, Sweigart B, Gunn S, Nygaard M, Perls TT, and Sebastiani P

Subjects
Aged, 80 and over, Female, Humans, Male, Bayes Theorem, Biomarkers, Cardiovascular Diseases, Cognition physiology, Cognitive Dysfunction diagnosis, Cognitive Dysfunction psychology, Dementia, Holistic Health, Multifactorial Inheritance, Skin Neoplasms, Aged, Middle Aged, Cluster Analysis, Cognitive Aging physiology, Cognitive Aging psychology, Family Health, Longevity, Neuropsychological Tests statistics & numerical data
Abstract

Background: Discovering patterns of cognitive domains and characterizing how these patterns associate with other risk factors and biomarkers can improve our understanding of the determinants of cognitive aging., Objective: To discover patterns of cognitive domains using neuropsychological test results in Long Life Family Study (LLFS) and characterize how these patterns associate with aging markers., Methods: 5,086 LLFS participants were administered neuropsychological tests at enrollment. We performed a cluster analysis of six baseline neuropsychological test scores and tested the association between the identified clusters and various clinical variables, biomarkers, and polygenic risk scores using generalized estimating equations and the Chi-square test. We used Cox regression to correlate the clusters with the hazard of various medical events. We investigated whether the cluster information could enhance the prediction of cognitive decline using Bayesian beta regression., Results: We identified 12 clusters with different cognitive signatures that represent profiles of performance across multiple neuropsychological tests. These signatures significantly correlated with 26 variables including polygenic risk scores, physical and pulmonary functions, and blood biomarkers and were associated with the hazard of mortality (p < 0.01), cardiovascular disease (p = 0.03), dementia (p = 0.01), and skin cancer (p = 0.03)., Conclusion: The identified cognitive signatures capture multiple domains simultaneously and provide a holistic vision of cognitive function, showing that different patterns of cognitive function can coexist in aging individuals. Such patterns can be used for clinical intervention and primary care.

Published
2023
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48. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries.

Author

Mishra A, Malik R, Hachiya T, Jürgenson T, Namba S, Posner DC, Kamanu FK, Koido M, Le Grand Q, Shi M, He Y, Georgakis MK, Caro I, Krebs K, Liaw YC, Vaura FC, Lin K, Winsvold BS, Srinivasasainagendra V, Parodi L, Bae HJ, Chauhan G, Chong MR, Tomppo L, Akinyemi R, Roshchupkin GV, Habib N, Jee YH, Thomassen JQ, Abedi V, Cárcel-Márquez J, Nygaard M, Leonard HL, Yang C, Yonova-Doing E, Knol MJ, Lewis AJ, Judy RL, Ago T, Amouyel P, Armstrong ND, Bakker MK, Bartz TM, Bennett DA, Bis JC, Bordes C, Børte S, Cain A, Ridker PM, Cho K, Chen Z, Cruchaga C, Cole JW, de Jager PL, de Cid R, Endres M, Ferreira LE, Geerlings MI, Gasca NC, Gudnason V, Hata J, He J, Heath AK, Ho YL, Havulinna AS, Hopewell JC, Hyacinth HI, Inouye M, Jacob MA, Jeon CE, Jern C, Kamouchi M, Keene KL, Kitazono T, Kittner SJ, Konuma T, Kumar A, Lacaze P, Launer LJ, Lee KJ, Lepik K, Li J, Li L, Manichaikul A, Markus HS, Marston NA, Meitinger T, Mitchell BD, Montellano FA, Morisaki T, Mosley TH, Nalls MA, Nordestgaard BG, O'Donnell MJ, Okada Y, Onland-Moret NC, Ovbiagele B, Peters A, Psaty BM, Rich SS, Rosand J, Sabatine MS, Sacco RL, Saleheen D, Sandset EC, Salomaa V, Sargurupremraj M, Sasaki M, Satizabal CL, Schmidt CO, Shimizu A, Smith NL, Sloane KL, Sutoh Y, Sun YV, Tanno K, Tiedt S, Tatlisumak T, Torres-Aguila NP, Tiwari HK, Trégouët DA, Trompet S, Tuladhar AM, Tybjærg-Hansen A, van Vugt M, Vibo R, Verma SS, Wiggins KL, Wennberg P, Woo D, Wilson PWF, Xu H, Yang Q, Yoon K, Millwood IY, Gieger C, Ninomiya T, Grabe HJ, Jukema JW, Rissanen IL, Strbian D, Kim YJ, Chen PH, Mayerhofer E, Howson JMM, Irvin MR, Adams H, Wassertheil-Smoller S, Christensen K, Ikram MA, Rundek T, Worrall BB, Lathrop GM, Riaz M, Simonsick EM, Kõrv J, França PHC, Zand R, Prasad K, Frikke-Schmidt R, de Leeuw FE, Liman T, Haeusler KG, Ruigrok YM, Heuschmann PU, Longstreth WT, Jung KJ, Bastarache L, Paré G, Damrauer SM, Chasman DI, Rotter JI, Anderson CD, Zwart JA, Niiranen TJ, Fornage M, Liaw YP, Seshadri S, Fernández-Cadenas I, Walters RG, Ruff CT, Owolabi MO, Huffman JE, Milani L, Kamatani Y, Dichgans M, and Debette S

Published
2022
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49. Circulating microRNAs related to lipid metabolism and solid tissue maintenance and morphology associate with mortality in elderly twins.

Author

Mengel-From J, Nielsen KE, Clemmensen SB, Feddersen S, Christensen K, Hjelmborg JVB, Tan Q, and Nygaard M

Subjects
Humans, Aged, Lipid Metabolism genetics, Signal Transduction, Gene Expression Profiling, Circulating MicroRNA genetics, Circulating MicroRNA metabolism, MicroRNAs genetics, MicroRNAs metabolism
Abstract

The lifespan of humans varies greatly between individuals. Here, we aimed to explore what biological roles miRNAs may have on old age mortality-variation. Circulating miRNAs were measured in plasma from 43 monozygotic twin pairs (73-95 years of age) and mortality analyses were applied using Cox regression survival analyses and linear regression analyses of lifespan. In general, nominally significant miRNAs were mainly upregulated with shorter lifespan, both in Cox analysis (72 % upregulated) and in linear regression analysis (81 % upregulated). A total of 29 miRNAs were associated to mortality at a nominal significance level (p < 0.05) in the survival analysis, but no miRNAs passed the FDR adjusted level of significance. Seven of the 29 miRNAs; hsa-miR-140-3p, hsa-miR-16-5p, hsa-miR-487b-3p, hsa-miR-19a-3p, hsa-let-7d-5p, hsa-miR-320a, hsa-miR-375, were nominally significant across two linear twin-paired analyses and the cox analysis. Pathway analyses of the 29 nominally significant miRNAs from the individual level analyses resulted in two nominally significant associated Reactome pathways (unadjusted p < 0.05); 'Negative regulation of FGFR signaling' and 'Neurotransmitter receptor binding and downstream transmission in the postsynaptic cell', and two significantly associated KEGG pathways; 'Linoleic acid metabolism' and 'Toxoplasmosis'. Additional pathway analyses and results of previous studies support that miRNAs linked to mortality at age 70 years or older play a role in lipid metabolism, tissues maintenance and morphology., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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50. Systemic hormone therapy and dementia: A nested case-control and co-twin control study.

Author

Løkkegaard LE, Thinggaard M, Nygaard M, Hallas J, Osler M, and Christensen K

Subjects
Case-Control Studies, Female, Hormones, Humans, Odds Ratio, Registries, Dementia epidemiology, Dementia etiology, Twins
Abstract

Objective: The effect of systemic hormone therapy (HT) on dementia risk is unclear. Our aim was to investigate the association between HT and dementia., Study Design: This register-based study consists of a nested case-control study and a co-twin control design, which controls for familial confounding, including shared genetics., Main Outcome Measures: Through Danish national registries from 1995 to 2011, we identified: a) 2700 female singletons with incident dementia and 13,492 matched controls; b) 288 female twins with incident dementia and co-twins without dementia. Data on HT and education were retrieved, and analyses were performed using conditional logistic regression and McNemar's χ 2 -test. HT use decreased dramatically after the Women's Health Initiative study results were published in 2002, and the analyses were stratified accordingly to account for potentially different HT user characteristics., Results: The odds ratio (OR) for the association between systemic HT and dementia was 1.05, 95% CI = [0.93-1.19] in singletons and 2.10, 95% CI = [0.99-4.46] in twins. A statistically significant association was found for systemic HT before 2003 in both populations, with an OR of 1.14, 95% CI = [1.01-1.28] in singletons and an OR of 2.20, 95% CI = [1.04-4.65] in twins., Conclusion: Using Danish nationwide registries and controlling for education and for familial factors in a subsample, systemic HT was found to be associated with increased dementia risk if used before 2003, when HT was more commonly prescribed., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2022
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