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1. 27-year time trends in dementia incidence in Europe and the US: the Alzheimer Cohorts Consortium

Author: WOLTERS, F. J., CHIBNIK, L. B., WAZIRY, R., Anderson, R., Berr, C., BEISER, A., BIS, J. C., BLACKER, D., BOS, D., Brayne, C., Dartigues, Jean-Francois, DARWEESH, S. K. L., DAVIS-PLOURDE, K. L., DE WOLF, F., Debette, Stephanie, Dufouil, Carole, FORNAGE, M., GOUDSMIT, J., Grasset, Leslie, GUDNASON, V., HADJICHRYSANTHOU, C., Helmer, Catherine, Ikram, M. A., JOAS, E., Kern, S., KULLER, L. H., LAUNER, L., LOPEZ, O. L., MATTHEWS, F. E., MCRAE-MCKEE, K., MEIRELLES, O., MOSLEY, T. H., Jr., PASE, M. P., PSATY, B. M., SATIZABAL, C. L., SESHADRI, S., SKOOG, I., STEPHAN, B. C. M., WETTERBERG, H., WONG, M. M., ZETTERGREN, A., Hofman, A., Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical Research Council, National Institutes of Health, Department of Health, Social Services and Public Safety, UK Government, National Heart, Lung, and Blood Institute, ANR-06-PNRA-0005,COGINUT,COGINUT : Cognition, anti-oxydants, acides gras: approche interdisciplinaire du rôle de la nutrition dans le vieillissement du cerveau(2006), ANR-07-LVIE-0003,COGICARE,Histoire naturelle du déclin cognitif et du besoin de soins chez le sujet âgé(2007), European Project: 667375,H2020,H2020-PHC-2015-two-stage,CoSTREAM(2015), and European Project: 601055,EC:FP7:ICT,FP7-ICT-2011-9,VPH-DARE@IT(2013)
Subjects: [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: OBJECTIVE: To determine changes in the incidence of dementia between 1988 and 2015. METHODS: This analysis was performed in aggregated data from individuals >65 years in seven population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined non-overlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex. RESULTS: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person years in individuals aged 65-69 years, to 65 per 1,000 person years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% CI: 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] versus 8% [0%-15%]). CONCLUSION: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
Published: 2020

2. Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium

Author: Wolters, F.J. (Frank), Chibnik, L.B. (Lori), Waziry, R. (Reem), Anderson, R. (Roy), Berr, C. (Claudine), Beiser, A. (Alexa), Bis, J.C. (Joshua), Blacker, D. (Deborah), Bos, D. (Daniel), Brayne, C. (Carol), Dartigues, J.-F., Darweesh, S.K.L. (Sirwan), Davis-Plourde, K.L. (Kendra L.), de Wolf, F. (Frank), Debette, S. (Stéphanie), Dufouil, C. (Carole), Fornage, M. (Myriam), Goudsmit, J. (Jaap), Grasset, L. (Leslie), Gudnason, V. (Vilmundur), Hadjichrysanthou, C. (Christoforos), Helmer, C. (Catherine), Ikram, M.A. (Arfan), Ikram, M.K. (Kamran), Joas, E. (Erik), Kern, S. (Silke), Kuller, L.H. (Lewis), Launer, L.J. (Lenore), Lopez, O.L. (Oscar), Matthews, F.E. (Fiona), McRae-McKee, K. (Kevin), Meirelles, O., Mosley, T.H. (Thomas H.), Pase, M.P. (Matthew P.), Psaty, B.M. (Bruce), Satizabal, C.L. (Claudia), Seshadri, S. (Sudha), Skoog, I., Stephan, B.C.M., Wetterberg, H. (Hanna), Wong, M.M. (Mei Mei), Zettergren, A. (Anna), Hofman, A. (Albert), Wolters, F.J. (Frank), Chibnik, L.B. (Lori), Waziry, R. (Reem), Anderson, R. (Roy), Berr, C. (Claudine), Beiser, A. (Alexa), Bis, J.C. (Joshua), Blacker, D. (Deborah), Bos, D. (Daniel), Brayne, C. (Carol), Dartigues, J.-F., Darweesh, S.K.L. (Sirwan), Davis-Plourde, K.L. (Kendra L.), de Wolf, F. (Frank), Debette, S. (Stéphanie), Dufouil, C. (Carole), Fornage, M. (Myriam), Goudsmit, J. (Jaap), Grasset, L. (Leslie), Gudnason, V. (Vilmundur), Hadjichrysanthou, C. (Christoforos), Helmer, C. (Catherine), Ikram, M.A. (Arfan), Ikram, M.K. (Kamran), Joas, E. (Erik), Kern, S. (Silke), Kuller, L.H. (Lewis), Launer, L.J. (Lenore), Lopez, O.L. (Oscar), Matthews, F.E. (Fiona), McRae-McKee, K. (Kevin), Meirelles, O., Mosley, T.H. (Thomas H.), Pase, M.P. (Matthew P.), Psaty, B.M. (Bruce), Satizabal, C.L. (Claudia), Seshadri, S. (Sudha), Skoog, I., Stephan, B.C.M., Wetterberg, H. (Hanna), Wong, M.M. (Mei Mei), Zettergren, A. (Anna), and Hofman, A. (Albert)
Abstract: OBJECTIVE: To determine changes in the incidence of dementia between 1988 and 2015. METHODS: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex. RESULTS: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]). CONCLUSION: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
Published: 2020
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3. Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies.

Author: Ding, J, Davis-Plourde, KL, Sedaghat, S, Tully, PJ, Wang, W, Phillips, C, Pase, MP, Himali, JJ, Gwen Windham, B, Griswold, M, Gottesman, R, Mosley, TH, White, L, Guðnason, V, Debette, S, Beiser, AS, Seshadri, S, Ikram, MA, Meirelles, O, Tzourio, C, Launer, LJ, Ding, J, Davis-Plourde, KL, Sedaghat, S, Tully, PJ, Wang, W, Phillips, C, Pase, MP, Himali, JJ, Gwen Windham, B, Griswold, M, Gottesman, R, Mosley, TH, White, L, Guðnason, V, Debette, S, Beiser, AS, Seshadri, S, Ikram, MA, Meirelles, O, Tzourio, C, and Launer, LJ
Abstract: BACKGROUND: Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia. METHODS: We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses. RESULTS: Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), ther
Published: 2020

4. Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium

Author: Wolters, Frank, Chibnik, LB, Waziry, R, Anderson, R, Berr, C, Beiser, A, Bis, JCM, Blacker, D, Bos, Daniel, Brayne, C, Dartigues, JF, Darweesh, Sirwan, Davis-Plourde, KL, de Wolf, F, Debette, S, Dufouil, C, Fornage, M, Goudsmit, J, Grasset, L, Gudnason, V, Hadjichrysanthou, C, Helmer, C, Ikram, Arfan, Ikram, Kamran, Joas, E, Kern, Sandra, Kuller, LH, Launer, L, Lopez, OL, Matthews, FE, McRae-McKee, K, Meirelles, O, Mosley, TH, Jr, Pase, MP, Psaty, BM, Satizabal, CL, Seshadri, S, Skoog, I, Stephan, BC, Wetterberg, H, Wong, MM, Zettergren, A, Hofman, Bert, Wolters, Frank, Chibnik, LB, Waziry, R, Anderson, R, Berr, C, Beiser, A, Bis, JCM, Blacker, D, Bos, Daniel, Brayne, C, Dartigues, JF, Darweesh, Sirwan, Davis-Plourde, KL, de Wolf, F, Debette, S, Dufouil, C, Fornage, M, Goudsmit, J, Grasset, L, Gudnason, V, Hadjichrysanthou, C, Helmer, C, Ikram, Arfan, Ikram, Kamran, Joas, E, Kern, Sandra, Kuller, LH, Launer, L, Lopez, OL, Matthews, FE, McRae-McKee, K, Meirelles, O, Mosley, TH, Jr, Pase, MP, Psaty, BM, Satizabal, CL, Seshadri, S, Skoog, I, Stephan, BC, Wetterberg, H, Wong, MM, Zettergren, A, and Hofman, Bert
Published: 2020

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

Author: Chibnik, L.B. (Lori), Wolters, F.J. (Frank), Bäckman, K. (Kristoffer), Beiser, A. (Alexa), Berr, C. (Claudine), Bis, J.C. (Joshua), Boerwinkle, E. (Eric), Bos, D. (Daniel), Brayne, C. (Carol), Dartigues, J.-F., Darweesh, S.K.L. (Sirwan), Debette, S. (Stéphanie), Davis-Plourde, K.L. (Kendra L.), Dufouil, C. (Carole), Fornage, M. (Myriam), Grasset, L. (Leslie), Gudnason, V. (Vilmundur), Hadjichrysanthou, C. (Christoforos), Helmer, C. (Catherine), Ikram, M.K. (Kamran), Kern, S. (Silke), Kuller, L.H. (Lewis), Launer, L.J. (Lenore), Lopez, O.L. (Oscar), Matthews, F. (Fiona), Meirelles, O., Mosley, T.H. (Thomas H.), Ower, A. (Alison), Psaty, B.M. (Bruce M.), Satizabal, C.L. (Claudia), Seshadri, S. (Sudha), Skoog, I., Stephan, B.C.M., Tzourio, C. (Christophe), Waziry, R. (Reem), Wong, M.M. (Mei Mei), Zettergren, A. (Anna), Hofman, A. (Albert), Chibnik, L.B. (Lori), Wolters, F.J. (Frank), Bäckman, K. (Kristoffer), Beiser, A. (Alexa), Berr, C. (Claudine), Bis, J.C. (Joshua), Boerwinkle, E. (Eric), Bos, D. (Daniel), Brayne, C. (Carol), Dartigues, J.-F., Darweesh, S.K.L. (Sirwan), Debette, S. (Stéphanie), Davis-Plourde, K.L. (Kendra L.), Dufouil, C. (Carole), Fornage, M. (Myriam), Grasset, L. (Leslie), Gudnason, V. (Vilmundur), Hadjichrysanthou, C. (Christoforos), Helmer, C. (Catherine), Ikram, M.K. (Kamran), Kern, S. (Silke), Kuller, L.H. (Lewis), Launer, L.J. (Lenore), Lopez, O.L. (Oscar), Matthews, F. (Fiona), Meirelles, O., Mosley, T.H. (Thomas H.), Ower, A. (Alison), Psaty, B.M. (Bruce M.), Satizabal, C.L. (Claudia), Seshadri, S. (Sudha), Skoog, I., Stephan, B.C.M., Tzourio, C. (Christophe), Waziry, R. (Reem), Wong, M.M. (Mei Mei), Zettergren, A. (Anna), and Hofman, A. (Albert)
Abstract: Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
Published: 2017
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6. Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium

Author: Chibnik, LB, Wolters, Frank, Backman, K, Beiser, A, Berr, C, Bis, JC, Boerwinkle, E, Bos, Daniel, Brayne, C, Dartigues, JF, Darweesh, Sirwan, Debette, S, Davis-Plourde, KL, Dufouil, C, Fornage, M, Grasset, L, Gudnason, V, Hadjichrysanthou, C, Helmer, C, Ikram, Arfan, Ikram, Kamran, Kern, S, Kuller, LH, Launer, L, Lopez, OL, Matthews, F, Meirelles, O, Mosley, T, Ower, A, Psaty, BM, Satizabal, CL, Seshadri, S, Skoog, I, Stephan, BCM, Tzourio, C, Waziry, R, Wong, MM, Zettergren, A, Hofman, Bert, Chibnik, LB, Wolters, Frank, Backman, K, Beiser, A, Berr, C, Bis, JC, Boerwinkle, E, Bos, Daniel, Brayne, C, Dartigues, JF, Darweesh, Sirwan, Debette, S, Davis-Plourde, KL, Dufouil, C, Fornage, M, Grasset, L, Gudnason, V, Hadjichrysanthou, C, Helmer, C, Ikram, Arfan, Ikram, Kamran, Kern, S, Kuller, LH, Launer, L, Lopez, OL, Matthews, F, Meirelles, O, Mosley, T, Ower, A, Psaty, BM, Satizabal, CL, Seshadri, S, Skoog, I, Stephan, BCM, Tzourio, C, Waziry, R, Wong, MM, Zettergren, A, and Hofman, Bert
Published: 2017

7. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author: Ehret, G.B. Ferreira, T. Chasman, D.I. Jackson, A.U. Schmidt, E.M. Johnson, T. Thorleifsson, G. Luan, J. Donnelly, L.A. Kanoni, S. Petersen, A.-K. Pihur, V. Strawbridge, R.J. Shungin, D. Hughes, M.F. Meirelles, O. Kaakinen, M. Bouatia-Naji, N. Kristiansson, K. Shah, S. Kleber, M.E. Guo, X. Lyytikäinen, L.-P. Fava, C. Eriksson, N. Nolte, I.M. Magnusson, P.K. Salfati, E.L. Rallidis, L.S. Theusch, E. Smith, A.J.P. Folkersen, L. Witkowska, K. Pers, T.H. Joehanes, R. Kim, S.K. Lataniotis, L. Jansen, R. Johnson, A.D. Warren, H. Kim, Y.J. Zhao, W. Wu, Y. Tayo, B.O. Bochud, M. Absher, D. Adair, L.S. Amin, N. Arking, D.E. Axelsson, T. Baldassarre, D. Balkau, B. Bandinelli, S. Barnes, M.R. Barroso, I. Bevan, S. Bis, J.C. Bjornsdottir, G. Boehnke, M. Boerwinkle, E. Bonnycastle, L.L. Boomsma, D.I. Bornstein, S.R. Brown, M.J. Burnier, M. Cabrera, C.P. Chambers, J.C. Chang, I.-S. Cheng, C.-Y. Chines, P.S. Chung, R.-H. Collins, F.S. Connell, J.M. Döring, A. Dallongeville, J. Danesh, J. De Faire, U. Delgado, G. Dominiczak, A.F. Doney, A.S.F. Drenos, F. Edkins, S. Eicher, J.D. Elosua, R. Enroth, S. Erdmann, J. Eriksson, P. Esko, T. Evangelou, E. Evans, A. Fall, T. Farrall, M. Felix, J.F. Ferrières, J. Ferrucci, L. Fornage, M. Forrester, T. Franceschini, N. Franco, O.H. Franco-Cereceda, A. Fraser, R.M. Ganesh, S.K. Gao, H. Gertow, K. Gianfagna, F. Gigante, B. Giulianini, F. Goel, A. Goodall, A.H. Goodarzi, M.O. Gorski, M. Gräßler, J. Groves, C.J. Gudnason, V. Gyllensten, U. Hallmans, G. Hartikainen, A.-L. Hassinen, M. Havulinna, A.S. Hayward, C. Hercberg, S. Herzig, K.-H. Hicks, A.A. Hingorani, A.D. Hirschhorn, J.N. Hofman, A. Holmen, J. Holmen, O.L. Hottenga, J.-J. Howard, P. Hsiung, C.A. Hunt, S.C. Ikram, M.A. Illig, T. Iribarren, C. Jensen, R.A. Kähönen, M. Kang, H.M. Kathiresan, S. Keating, B.J. Khaw, K.-T. Kim, Y.K. Kim, E. Kivimaki, M. Klopp, N. Kolovou, G. Komulainen, P. Kooner, J.S. Kosova, G. Krauss, R.M. Kuh, D. Kutalik, Z. Kuusisto, J. Kvaløy, K. Lakka, T.A. Lee, N.R. Lee, I.-T. Lee, W.-J. Levy, D. Li, X. Liang, K.-W. Lin, H. Lin, L. Lindström, J. Lobbens, S. Männistö, S. Müller, G. Müller-Nurasyid, M. Mach, F. Markus, H.S. Marouli, E. McCarthy, M.I. McKenzie, C.A. Meneton, P. Menni, C. Metspalu, A. Mijatovic, V. Moilanen, L. Montasser, M.E. Morris, A.D. Morrison, A.C. Mulas, A. Nagaraja, R. Narisu, N. Nikus, K. O'Donnell, C.J. O'Reilly, P.F. Ong, K.K. Paccaud, F. Palmer, C.D. Parsa, A. Pedersen, N.L. Penninx, B.W. Perola, M. Peters, A. Poulter, N. Pramstaller, P.P. Psaty, B.M. Quertermous, T. Rao, D.C. Rasheed, A. Rayner, N.W. Renström, F. Rettig, R. Rice, K.M. Roberts, R. Rose, L.M. Rossouw, J. Samani, N.J. Sanna, S. Saramies, J. Schunkert, H. Sebert, S. Sheu, W.H.-H. Shin, Y.-A. Sim, X. Smit, J.H. Smith, A.V. Sosa, M.X. Spector, T.D. Stančáková, A. Stanton, A.V. Stirrups, K.E. Stringham, H.M. Sundstrom, J. Swift, A.J. Syvänen, A.-C. Tai, E.-S. Tanaka, T. Tarasov, K.V. Teumer, A. Thorsteinsdottir, U. Tobin, M.D. Tremoli, E. Uitterlinden, A.G. Uusitupa, M. Vaez, A. Vaidya, D. Van Duijn, C.M. Van Iperen, E.P.A. Vasan, R.S. Verwoert, G.C. Virtamo, J. Vitart, V. Voight, B.F. Vollenweider, P. Wagner, A. Wain, L.V. Wareham, N.J. Watkins, H. Weder, A.B. Westra, H.-J. Wilks, R. Wilsgaard, T. Wilson, J.F. Wong, T.Y. Yang, T.-P. Yao, J. Yengo, L. Zhang, W. Zhao, J.H. Zhu, X. Bovet, P. Cooper, R.S. Mohlke, K.L. Saleheen, D. Lee, J.-Y. Elliott, P. Gierman, H.J. Willer, C.J. Franke, L. Hovingh, G.K. Taylor, K.D. Dedoussis, G. Sever, P. Wong, A. Lind, L. Assimes, T.L. Njølstad, I. Schwarz, P.E.H. Langenberg, C. Snieder, H. Caulfield, M.J. Melander, O. Laakso, M. Saltevo, J. Rauramaa, R. Tuomilehto, J. Ingelsson, E. Lehtimäki, T. Hveem, K. Palmas, W. März, W. Kumari, M. Salomaa, V. Chen, Y.-D.I. Rotter, J.I. Froguel, P. Jarvelin, M.-R. Lakatta, E.G. Kuulasmaa, K. Franks, P.W. Hamsten, A. Wichmann, H.-E. Palmer, C.N.A. Stefansson, K. Ridker, P.M. Loos, R.J.F. Chakravarti, A. Deloukas, P. Morris, A.P. Newton-Cheh, C. Munroe, P.B.
Abstract: To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation. © 2016 Nature America, Inc. All rights reserved.
Published: 2016

8. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author: Ehret, G.B. (Georg), Ferreira, T. (Teresa), Chasman, D.I. (Daniel), Jackson, A.U. (Anne), Schmidt, E.M. (Ellen), Johnson, T. (Toby), Thorleifsson, G. (Gudmar), Luan, J. (Jian'An), Donnelly, L.A. (Louise), Kanoni, S. (Stavroula), Petersen, A.K., Pihur, V. (Vasyl), Strawbridge, R.J. (Rona), Shungin, D. (Dmitry), Hughes, M.F. (Maria F.), Meirelles, O., Kaakinen, M. (Marika), Bouatia-Naji, N. (Nabila), Kristiansson, K. (Kati), Shah, S. (Sonia), Kleber, M.E. (Marcus), Guo, X. (Xiuqing), Lyytikäinen, L.-P. (Leo-Pekka), Fava, C. (Cristiano), Eriksson, N. (Niclas), Nolte, I.M. (Ilja), Magnusson, P.K. (Patrik), Salfati, E. (Elias), Rallidis, L.S. (Loukianos), Theusch, E. (Elizabeth), Smith, A.J. (Andrew), Folkersen, L. (Lasse), Witkowska, H.E. (Ewa), Pers, T.H. (Tune), Joehanes, R. (Roby), Kim, S.K. (Stuart K.), Lataniotis, L. (Lazaros), Jansen, R., Johnson, A.D. (Andrew), Warren, H. (Helen), Kim, Y.J., Zhao, W. (Wei), Wu, Y. (Ying), Tayo, B. (Bamidele), Bochud, M. (Murielle), Absher, D. (Devin), Adair, L.S. (Linda), Amin, N. (Najaf), Arking, D.E. (Dan), Axelsson, T. (Tomas), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Bandinelli, S. (Stefania), Barnes, M.J. (Michael), Barroso, I.E. (Inês), Bevan, S. (Stephen), Bis, J.C. (Joshua), Bjornsdottir, G. (Gyda), Boehnke, M. (Michael), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Boomsma, D.I. (Dorret), Bornstein, S.R. (Stefan), Brown, M.J. (Morris), Burnier, M. (Michel), Cabrera, C.P. (Claudia P.), Chambers, J.C. (John), Chang, I.-S. (I-Shou), Cheng, C.-Y. (Ching-Yu), Chines, P.S. (Peter), Chung, R.-H. (Ren-Hua), Collins, F.S. (Francis), Connell, J.M. (John M.), Döring, A. (Angela), Dallongeville, J., Danesh, J. (John), Faire, U. (Ulf) de, Delgado, G., Dominiczak, A. (Anna), Doney, A.S.F. (Alex), Drenos, F. (Fotios), Edkins, T. (Ted), Eicher, J.D. (John D.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erdmann, J. (Jeanette), Eriksson, P. (Per), Esko, T. (Tõnu), Evangelou, E. (Evangelos), Evans, A. (Alun), Fall, M. (Magnus), Farrall, M. (Martin), Felix, J.F. (Janine), Ferrieres, J. (Jean), Ferrucci, L. (Luigi), Fornage, M. (Myriam), Forrester, T. (Terrence), Franceschini, N. (Nora), Franco, O.H. (Oscar), Franco-Cereceda, A. (Anders), Fraser, R.M. (Ross), Ganesh, S.K. (Santhi), Gao, H. (He), Gertow, K. (Karl), Gianfagna, F. (Francesco), Gigante, B. (Bruna), Giulianini, F. (Franco), Goel, A. (Anuj), Goodall, A.H. (Alison), Goodarzi, M. (Mark), Gorski, M. (Mathias), Gräßler, J. (Jürgen), Groves, C.J. (Christopher), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hallmans, G. (Göran), Hartikainen, A.L., Hassinen, M. (Maija), Havulinna, A.S. (Aki), Hayward, C. (Caroline), Hercberg, S. (Serge), Herzig, K.H., Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hirschhorn, J.N. (Joel), Hofman, A. (Albert), Holmen, J. (Jostein), Holmen, O.L. (Oddgeir), Hottenga, J.J. (Jouke Jan), Howard, P. (Philip), Hsiung, C.A. (Chao A.), Hunt, S.C. (Steven), Ikram, M.K. (Kamran), Illig, T. (Thomas), Iribarren, C. (Carlos), Jensen, R.A. (Richard A.), Kähönen, M. (Mika), Kang, H.M. (Hyun Min), Kathiresan, S. (Sekar), Keating, J. (John), Khaw, K.T., Kim, Y.K. (Yun Kyoung), Kim, E. (Eric), Kivimaki, M. (Mika), Klopp, N. (Norman), Kolovou, G. (Genovefa), Komulainen, P. (Pirjo), Kooner, J.S. (Jaspal S.), Kosova, G. (Gulum), Krauss, R.M. (Ronald), Kuh, D. (Diana), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Kvaløy, K. (Kirsti), Lakka, T.A. (Timo), Lee, N.R. (Nanette), Lee, I.T., Lee, W.-J. (Wen-Jane), Levy, D. (Daniel), Li, X. (Xiaohui), Liang, K.-W. (Kae-Woei), Lin, H. (Honghuang), Lin, L. (Li), Lindström, J. (Jaana), Lobbens, S. (Stéphane), Männistö, S. (Satu), Müller, G. (Gabriele), Müller-Nurasyid, M. (Martina), MacH, F. (François), Markus, H.S. (Hugh), Marouli, E. (Eirini), McCarthy, M.I. (Mark), McKenzie, C.A. (Colin), Meneton, P. (Pierre), Menni, C. (Cristina), Metspalu, A. (Andres), Mijatovic, V. (Vladan), Moilanen, L. (Leena), Montasser, M.E. (May E.), Morris, A.D. (Andrew), Morrison, A.C. (Alanna), Mulas, A. (Antonella), Nagaraja, R. (Ramaiah), Narisu, N. (Narisu), Nikus, K. (Kjell), O'Donnell, C.J. (Christopher), O'Reilly, P.F. (Paul), Ong, K.K. (Ken), Paccaud, F. (Fred), Palmer, C. (Cameron), Parsa, A. (Afshin), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Quertermous, T. (Thomas), Rao, D.C. (Dabeeru C.), Rasheed, A. (Asif), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rettig, R. (Rainer), Rice, K.M. (Kenneth), Roberts, R. (Robert), Rose, L.M. (Lynda), Rossouw, J. (Jacques), Samani, N.J. (Nilesh), Sanna, S. (Serena), Saramies, J. (Jouko), Schunkert, H. (Heribert), Sebert, S. (Sylvain), Sheu, W.H.-H. (Wayne H.-H.), Shin, Y.-A. (Young-Ah), Sim, X. (Xueling), Smith, A.V. (Davey), Smith, A.V. (Albert Vernon), Sosa, M.X. (Maria X.), Spector, T.D. (Timothy), Stancáková, A. (Alena), Stanton, A. (Alice), Stirrups, K. (Kathy), Stringham, H.M. (Heather), Sundstrom, J. (Johan), Swift, A.J. (Amy), Syvänen, A.C., Tai, E.-S. (E-Shyong), Tanaka, T. (Toshiko), Tarasov, K.V. (Kirill), Teumer, A. (Alexander), Thorsteinsdottir, U. (Unnur), Tobin, M.D. (Martin), Tremoli, E. (Elena), Uitterlinden, A.G. (Andre G.), Uusitupa, M. (Matti), Vaez, A. (Ahmad), Vaidya, D. (Dhananjay), Van Duijn, C.M. (Cornelia M.), Iperen, E.P.A. (Erik) van, Vasan, R.S. (Ramachandran S.), Verwoert, G.C. (Germaine), Virtamo, J. (Jarmo), Vitart, V. (Veronique), Voight, B.F. (Benjamin), Vollenweider, P. (Peter), Wagner, A. (Aline), Wain, L.V. (Louise V.), Wareham, N.J. (Nick), Watkins, H. (Hugh), Weder, A.B. (Alan), Westra, H.J. (Harm-Jan), Wilks, R. (Rainford), Wilsgaard, T. (Tom), Wilson, J.F. (James F.), Wong, T.Y. (Tien Y.), Yang, T.-P. (Tsun-Po), Yao, J. (Jiefen), Yengo, L. (Loic), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Zhu, X. (Xiaofeng), Bovet, P. (Pascal), Cooper, R.S. (Richard S.), Mohlke, K.L. (Karen), Saleheen, D. (Danish), Lee, J.-Y. (Jong-Young), Elliott, P. (Paul), Gierman, L.M. (Lobke), Willer, C.J. (Cristen), Franke, L. (Lude), Hovingh, G.K. (Kees), Taylor, K.D. (Kent), Dedoussis, G.V. (George), Sever, P. (Peter), Wong, A. (Andrew), Kao, W.H.L. (Wen), Assimes, T.L. (Themistocles), Njølstad, I. (Inger), Schwarz, P.E.H. (Peter), Langenberg, C. (Claudia), Snieder, H. (Harold), Caulfield, M. (Mark), Melander, O. (Olle), Laakso, M. (Markku), Saltevo, J. (Juha), Rauramaa, R. (Rainer), Tuomilehto, J. (Jaakko), Ingelsson, E. (Erik), Lehtimäki, T. (Terho), Hveem, K. (Kristian), Palmas, W. (Walter), März, W. (Winfried), Kumari, M. (Meena), Salomaa, V. (Veikko), Chen, Y.D. (Y.), Rotter, J.I. (Jerome I.), Froguel, P. (Philippe), Jarvelin, M.-R. (Marjo-Riitta), Lakatta, E. (Edward), Kuulasmaa, K. (Kari), Franks, P.W. (Paul), Hamsten, A. (Anders), Wichmann, H.E. (Heinz Erich), Palmer, C.N.A. (Colin), Stefansson, K. (Kari), Ridker, P.M. (Paul), Loos, R.J.F. (Ruth), Chakravarti, A. (Aravinda), Deloukas, P. (Panagiotis), Morris, A.P. (Andrew), Newton-Cheh, C. (C.), Munroe, P. (Patricia), Ehret, G.B. (Georg), Ferreira, T. (Teresa), Chasman, D.I. (Daniel), Jackson, A.U. (Anne), Schmidt, E.M. (Ellen), Johnson, T. (Toby), Thorleifsson, G. (Gudmar), Luan, J. (Jian'An), Donnelly, L.A. (Louise), Kanoni, S. (Stavroula), Petersen, A.K., Pihur, V. (Vasyl), Strawbridge, R.J. (Rona), Shungin, D. (Dmitry), Hughes, M.F. (Maria F.), Meirelles, O., Kaakinen, M. (Marika), Bouatia-Naji, N. (Nabila), Kristiansson, K. (Kati), Shah, S. (Sonia), Kleber, M.E. (Marcus), Guo, X. (Xiuqing), Lyytikäinen, L.-P. (Leo-Pekka), Fava, C. (Cristiano), Eriksson, N. (Niclas), Nolte, I.M. (Ilja), Magnusson, P.K. (Patrik), Salfati, E. (Elias), Rallidis, L.S. (Loukianos), Theusch, E. (Elizabeth), Smith, A.J. (Andrew), Folkersen, L. (Lasse), Witkowska, H.E. (Ewa), Pers, T.H. (Tune), Joehanes, R. (Roby), Kim, S.K. (Stuart K.), Lataniotis, L. (Lazaros), Jansen, R., Johnson, A.D. (Andrew), Warren, H. (Helen), Kim, Y.J., Zhao, W. (Wei), Wu, Y. (Ying), Tayo, B. (Bamidele), Bochud, M. (Murielle), Absher, D. (Devin), Adair, L.S. (Linda), Amin, N. (Najaf), Arking, D.E. (Dan), Axelsson, T. (Tomas), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Bandinelli, S. (Stefania), Barnes, M.J. (Michael), Barroso, I.E. (Inês), Bevan, S. (Stephen), Bis, J.C. (Joshua), Bjornsdottir, G. (Gyda), Boehnke, M. (Michael), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Boomsma, D.I. (Dorret), Bornstein, S.R. (Stefan), Brown, M.J. (Morris), Burnier, M. (Michel), Cabrera, C.P. (Claudia P.), Chambers, J.C. (John), Chang, I.-S. (I-Shou), Cheng, C.-Y. (Ching-Yu), Chines, P.S. (Peter), Chung, R.-H. (Ren-Hua), Collins, F.S. (Francis), Connell, J.M. (John M.), Döring, A. (Angela), Dallongeville, J., Danesh, J. (John), Faire, U. (Ulf) de, Delgado, G., Dominiczak, A. (Anna), Doney, A.S.F. (Alex), Drenos, F. (Fotios), Edkins, T. (Ted), Eicher, J.D. (John D.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erdmann, J. (Jeanette), Eriksson, P. (Per), Esko, T. (Tõnu), Evangelou, E. (Evangelos), Evans, A. (Alun), Fall, M. (Magnus), Farrall, M. (Martin), Felix, J.F. (Janine), Ferrieres, J. (Jean), Ferrucci, L. (Luigi), Fornage, M. (Myriam), Forrester, T. (Terrence), Franceschini, N. (Nora), Franco, O.H. (Oscar), Franco-Cereceda, A. (Anders), Fraser, R.M. (Ross), Ganesh, S.K. (Santhi), Gao, H. (He), Gertow, K. (Karl), Gianfagna, F. (Francesco), Gigante, B. (Bruna), Giulianini, F. (Franco), Goel, A. (Anuj), Goodall, A.H. (Alison), Goodarzi, M. (Mark), Gorski, M. (Mathias), Gräßler, J. (Jürgen), Groves, C.J. (Christopher), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hallmans, G. (Göran), Hartikainen, A.L., Hassinen, M. (Maija), Havulinna, A.S. (Aki), Hayward, C. (Caroline), Hercberg, S. (Serge), Herzig, K.H., Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hirschhorn, J.N. (Joel), Hofman, A. (Albert), Holmen, J. (Jostein), Holmen, O.L. (Oddgeir), Hottenga, J.J. (Jouke Jan), Howard, P. (Philip), Hsiung, C.A. (Chao A.), Hunt, S.C. (Steven), Ikram, M.K. (Kamran), Illig, T. (Thomas), Iribarren, C. (Carlos), Jensen, R.A. (Richard A.), Kähönen, M. (Mika), Kang, H.M. (Hyun Min), Kathiresan, S. (Sekar), Keating, J. (John), Khaw, K.T., Kim, Y.K. (Yun Kyoung), Kim, E. (Eric), Kivimaki, M. (Mika), Klopp, N. (Norman), Kolovou, G. (Genovefa), Komulainen, P. (Pirjo), Kooner, J.S. (Jaspal S.), Kosova, G. (Gulum), Krauss, R.M. (Ronald), Kuh, D. (Diana), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Kvaløy, K. (Kirsti), Lakka, T.A. (Timo), Lee, N.R. (Nanette), Lee, I.T., Lee, W.-J. (Wen-Jane), Levy, D. (Daniel), Li, X. (Xiaohui), Liang, K.-W. (Kae-Woei), Lin, H. (Honghuang), Lin, L. (Li), Lindström, J. (Jaana), Lobbens, S. (Stéphane), Männistö, S. (Satu), Müller, G. (Gabriele), Müller-Nurasyid, M. (Martina), MacH, F. (François), Markus, H.S. (Hugh), Marouli, E. (Eirini), McCarthy, M.I. (Mark), McKenzie, C.A. (Colin), Meneton, P. (Pierre), Menni, C. (Cristina), Metspalu, A. (Andres), Mijatovic, V. (Vladan), Moilanen, L. (Leena), Montasser, M.E. (May E.), Morris, A.D. (Andrew), Morrison, A.C. (Alanna), Mulas, A. (Antonella), Nagaraja, R. (Ramaiah), Narisu, N. (Narisu), Nikus, K. (Kjell), O'Donnell, C.J. (Christopher), O'Reilly, P.F. (Paul), Ong, K.K. (Ken), Paccaud, F. (Fred), Palmer, C. (Cameron), Parsa, A. (Afshin), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Quertermous, T. (Thomas), Rao, D.C. (Dabeeru C.), Rasheed, A. (Asif), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rettig, R. (Rainer), Rice, K.M. (Kenneth), Roberts, R. (Robert), Rose, L.M. (Lynda), Rossouw, J. (Jacques), Samani, N.J. (Nilesh), Sanna, S. (Serena), Saramies, J. (Jouko), Schunkert, H. (Heribert), Sebert, S. (Sylvain), Sheu, W.H.-H. (Wayne H.-H.), Shin, Y.-A. (Young-Ah), Sim, X. (Xueling), Smith, A.V. (Davey), Smith, A.V. (Albert Vernon), Sosa, M.X. (Maria X.), Spector, T.D. (Timothy), Stancáková, A. (Alena), Stanton, A. (Alice), Stirrups, K. (Kathy), Stringham, H.M. (Heather), Sundstrom, J. (Johan), Swift, A.J. (Amy), Syvänen, A.C., Tai, E.-S. (E-Shyong), Tanaka, T. (Toshiko), Tarasov, K.V. (Kirill), Teumer, A. (Alexander), Thorsteinsdottir, U. (Unnur), Tobin, M.D. (Martin), Tremoli, E. (Elena), Uitterlinden, A.G. (Andre G.), Uusitupa, M. (Matti), Vaez, A. (Ahmad), Vaidya, D. (Dhananjay), Van Duijn, C.M. (Cornelia M.), Iperen, E.P.A. (Erik) van, Vasan, R.S. (Ramachandran S.), Verwoert, G.C. (Germaine), Virtamo, J. (Jarmo), Vitart, V. (Veronique), Voight, B.F. (Benjamin), Vollenweider, P. (Peter), Wagner, A. (Aline), Wain, L.V. (Louise V.), Wareham, N.J. (Nick), Watkins, H. (Hugh), Weder, A.B. (Alan), Westra, H.J. (Harm-Jan), Wilks, R. (Rainford), Wilsgaard, T. (Tom), Wilson, J.F. (James F.), Wong, T.Y. (Tien Y.), Yang, T.-P. (Tsun-Po), Yao, J. (Jiefen), Yengo, L. (Loic), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Zhu, X. (Xiaofeng), Bovet, P. (Pascal), Cooper, R.S. (Richard S.), Mohlke, K.L. (Karen), Saleheen, D. (Danish), Lee, J.-Y. (Jong-Young), Elliott, P. (Paul), Gierman, L.M. (Lobke), Willer, C.J. (Cristen), Franke, L. (Lude), Hovingh, G.K. (Kees), Taylor, K.D. (Kent), Dedoussis, G.V. (George), Sever, P. (Peter), Wong, A. (Andrew), Kao, W.H.L. (Wen), Assimes, T.L. (Themistocles), Njølstad, I. (Inger), Schwarz, P.E.H. (Peter), Langenberg, C. (Claudia), Snieder, H. (Harold), Caulfield, M. (Mark), Melander, O. (Olle), Laakso, M. (Markku), Saltevo, J. (Juha), Rauramaa, R. (Rainer), Tuomilehto, J. (Jaakko), Ingelsson, E. (Erik), Lehtimäki, T. (Terho), Hveem, K. (Kristian), Palmas, W. (Walter), März, W. (Winfried), Kumari, M. (Meena), Salomaa, V. (Veikko), Chen, Y.D. (Y.), Rotter, J.I. (Jerome I.), Froguel, P. (Philippe), Jarvelin, M.-R. (Marjo-Riitta), Lakatta, E. (Edward), Kuulasmaa, K. (Kari), Franks, P.W. (Paul), Hamsten, A. (Anders), Wichmann, H.E. (Heinz Erich), Palmer, C.N.A. (Colin), Stefansson, K. (Kari), Ridker, P.M. (Paul), Loos, R.J.F. (Ruth), Chakravarti, A. (Aravinda), Deloukas, P. (Panagiotis), Morris, A.P. (Andrew), Newton-Cheh, C. (C.), and Munroe, P. (Patricia)
Abstract: To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
Published: 2016
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9. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author: Ehret, G. B. (Georg B.), Ferreira, T. (Teresa), Chasman, D. I. (Daniel I.), Jackson, A. U. (Anne U.), Schmidt, E. M. (Ellen M.), Johnson, T. (Toby), Thorleifsson, G. (Gudmar), Luan, J. (Jian'an), Donnelly, L. A. (Louise A.), Kanoni, S. (Stavroula), Petersen, A. -. (Ann -Kristin), Pihurl, V. (Vasyl), Strawbridge, R. J. (Rona J.), Shungin, D. (Dmitry), Hughes, M. F. (Maria F.), Meirelles, O. (Osorio), Kaakinen, M. (Marika), Bouatia-Naji, N. (Nabila), Kristiansson, K. (Kati), Shah, S. (Sonia), Kleber, M. E. (Marcus E.), Guo, X. (Xiuqing), Lyytikainen, L.-P. (Leo-Pekka), Fava, C. (Cristiano), Eriksson, N. (Nidas), Nolte, I. M. (Ilja M.), Magnusson, P. K. (Patrik K.), Salfati, E. L. (Elias L.), Rallidis, L. S. (Loukianos S.), Theusch, E. (Elizabeth), Smith, A. J. (Andrew J. P.), Folkersen, L. (Lasse), Witkowska, K. (Kate), Pers, T. H. (Tune H.), Joehanes, R. (Roby), Kim, S. K. (Stuart K.), Lataniotis, L. (Lazaros), Jansen, R. (Rick), Johnson, A. D. (Andrew D.), Warren, H. (Helen), Kim, Y. J. (Young Jin), Zhao, W. (Wei), Wu, Y. (Ying), Tayo, B. O. (Bamidele O.), Bochud, M. (Murielle), Absher, D. (Devin), Adair, L. S. (Linda S.), Amin, N. (Najaf), Arkingl, D. E. (Dan E.), Axelsson, T. (Tomas), Baldassarre, D. (Damian), Balkau, B. (Beverley), Bandinelli, S. (Stefania), Barnes, M. R. (Michael R.), Barroso, I. (Ines), Bevan, S. (Stephen), Bis, J. C. (Joshua C.), Bjornsdottir, G. (Gyda), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Bonnycastle, L. L. (Lori L.), Boomsma, D. I. (Dorret I.), Bornstein, S. R. (Stefan R.), Brown, M. J. (Morris J.), Burnier, M. (Michel), Cabrera, C. P. (Claudia P.), Chambers, J. C. (John C.), Chang, I.-S. (I-Shou), Cheng, C.-Y. (Ching-Yu), Chines, P. S. (Peter S.), Chung, R.-H. (Ren-Hua), Collins, F. S. (Francis S.), Connell, J. M. (John M.), Doring, A. (Angela), Dallongeville, J. (Jean), Danesh, J. (John), de Faire, U. (Ulf), Delgado, G. (Graciela), Dominiczak, A. F. (Anna F.), Doney, A. S. (Alex S. F.), Drenos, F. (Fotios), Edkins, S. (Sarah), Eicher, J. D. (John D.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erdmann, J. (Jeanette), Eriksson, P. (Per), Esko, T. (Tonu), Evangelou, E. (Evangelos), Evans, A. (Alun), Fai, T. (Tove), Farra, M. (Martin), Felixl, J. F. (Janine F.), Ferrieres, J. (Jean), Ferrucci, L. (Luigi), Fornage, M. (Myriam), Forrester, T. (Terrence), Franceschinil, N. (Nora), Franco, O. H. (Oscar H.), Franco-Cereceda, A. (Anders), Fraser, R. M. (Ross M.), Ganesh, S. K. (Santhi K.), Gao, H. (He), Gertow, K. (Karl), Gianfagna, F. (Francesco), Gigante, B. (Bruna), Giulianini, F. (Franco), Goe, A. (Anuj), Goodall, A. H. (Alison H.), Goodarzi, M. (Mark), Gorski, M. (Mathias), Grassler, J. (Jurgen), Groves, C. J. (Christopher J.), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hallmans, G. (Goran), Hartikainen, A.-L. (Anna-Liisa), Hassinen, M. (Maija), Havulinna, A. S. (Aki S.), Hayward, C. (Caroline), Hercberg, S. (Serge), Herzig, K.-H. (Karl-Heinz), Hicks, A. A. (Andrew A.), Hingorani, A. D. (Aroon D.), Hirschhorn, J. N. (Joel N.), Hofmanl, A. (Albert), Holmen, J. (Jostein), Holmen, O. L. (Oddgeir Lingaas), Hottenga, J.-J. (Jouke-Jan), Howard, P. (Phil), Hsiung, C. A. (Chao A.), Hunt, S. C. (Steven C.), Ikram, M. A. (M. Arfan), Illig, T. (Thomas), Iribarren, C. (Carlos), Jensen, R. A. (Richard A.), Kahonen, M. (Mika), Kang, H. M. (Hyun Min), Kathiresan, S. (Sekar), Keating, B. J. (Brendan J.), Khaw, K.-T. (Kay-Tee), Kim, Y. K. (Yun Kyoung), Kim, E. (Eric), Kivimaki, M. (Mika), Klopp, N. (Norman), Kolovou, G. (Genovefa), Komulainen, P. (Pirjo), Kooner, J. S. (Jaspal S.), Kosova, G. (Gulum), Krauss, R. M. (Ronald M.), Kuh, D. (Diana), Kutalik, Z. (Zoltan), Kuusisto, J. (Johanna), Kvaloy, K. (Kirsti), Lakka, T. A. (Timo A.), Lee, N. R. (Nanette R.), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Levy, D. (Daniel), Li, X. (Xiaohui), Liang, K.-W. (Kae-Woei), Lin, H. (Honghuang), Lin, L. (Li), Lindstrom, J. (Jaana), Lobbens, S. (Stephane), Mannisto, S. (Satu), Muller, G. (Gabriele), Muller-Nurasyid, M. (Martina), Mach, F. (Francois), Markus, H. S. (Hugh S.), Marouli, E. (Eirini), McCarthy, M. I. (Mark I.), McKenzie, C. A. (Colin A.), Meneton, P. (Pierre), Menni, C. (Cristina), Metspalu, A. (Andres), Mijatovic, V. (Vladan), Moilanen, L. (Leena), Montasser, M. E. (May E.), Morris, A. D. (Andrew D.), Morrison, A. C. (Alanna C.), Mulas, A. (Antonella), Nagaraja, R. (Ramaiah), Narisu, N. (Narisu), Nikus, K. (Kjell), O'Donnell, C. J. (Christopher J.), O'Reilly, P. F. (Paul F.), Ong, K. K. (Ken K.), Paccaud, F. (Fred), Palmer, C. D. (Cameron D.), Parsa, A. (Afshin), Pedersen, N. L. (Nancy L.), Penninx, B. W. (Brenda W.), Perola, M. (Markus), Peters, A. (Annette), Poulter, N. (Neil), Pramstaller, P. P. (Peter P.), Psaty, B. M. (Bruce M.), Quertermous, T. (Thomas), Rao, D. C. (Dabeeru C.), Rasheed, A. (Asif), Rayner, N. W. (N. William), Renstrom, F. (Frida), Rettig, R. (Rainer), Rice, K. M. (Kenneth M.), Roberts, R. (Robert), Rose, L. M. (Lynda M.), Rossouw, J. (Jacques), Samani, N. J. (Nilesh J.), Sanna, S. (Serena), Saramies, J. (Jouko), Schunkert, H. (Heribert), Sebert, S. (Sylvain), Sheu, W. H. (Wayne H-H), Shin, Y.-A. (Young-Ah), Sim, X. (Xueling), Smit, J. H. (Johannes H.), Smith, A. V. (Albert V.), Sosa, M. X. (Maria X.), Spector, T. D. (Tim D.), Stancakova, A. (Alena), Stanton, A. V. (Alice V.), Stirrups, K. E. (Kathleen E.), Stringham, H. M. (Heather M.), Sundstrom, J. (Johan), Swift, A. J. (Amy J.), Syvanen, A.-C. (Ann-Christine), Tai, E.-S. (E-Shyong), Tanaka, T. (Toshiko), Tarasov, K. V. (Kirill V.), Teumer, A. (Alexander), Thorsteinsdottir, U. (Unnur), Tobin, M. D. (Martin D.), Tremoli, E. (Elena), Uitterlinden, A. G. (Andre G.), Uusitupa, M. (Matti), Vaez, A. (Ahmad), Vaidya, D. (Dhananjay), van Duijn, C. M. (Cornelia M.), van Iperen, E. P. (Erik P. A.), Vasan, R. S. (Ramachandran S.), Verwoert, G. C. (Germaine C.), Virtamo, J. (Jarmo), Vitart, V. (Veronique), Voight, B. F. (Benjamin F.), Vollenweider, P. (Peter), Wagner, A. (Aline), Wain, L. V. (Louise V.), Wareham, N. J. (Nicholas J.), Watldns, H. (Hugh), Weder, A. B. (Alan B.), Westra, H. J. (Harm Jan), Wilks, R. (Rainford), Wilsgaard, T. (Tom), Wilson, J. F. (James F.), Wong, T. Y. (Tien Y.), Yang, T.-P. (Tsun-Po), Yao, J. (Jie), Yengo, L. (Loic), Zhang, W. (Weihua), Zhao, J. H. (Jing Hua), Zhu, X. (Xiaofeng), Bovet, P. (Pascal), Cooper, R. S. (Richard S.), Mohlke, K. L. (Karen L.), Saleheen, D. (Danish), Lee, J.-Y. (Jong-Young), Elliott, P. (Paul), Gierman, H. J. (Hinco J.), Willer, C. J. (Cristen J.), Franke, L. (Lude), Hovingh, G. K. (G. Kees), Taylor, K. D. (Kent D.), Dedoussis, G. (George), Sever, P. (Peter), Wong, A. (Andrew), Lind, L. (Lars), Assimes, T. L. (Themistocles L.), Njolstad, I. (Inger), Schwarz, P. E. (Peter E. H.), Langenberg, C. (Claudia), Snieder, H. (Harold), Caulfield, M. J. (Mark J.), Melander, E. (E.), Laakso, M. (Markku), Saltevo, J. (Juha), Rauramaa, R. (Rainer), Tuomilehto, J. (Jaakko), Ingelsson, E. (Erik), Lehtimaki, T. (Terho), Hveem, K. (Kristian), Palmas, W. (Walter), Marz, W. (Winfried), Kumar, M. (Meena), Salomaa, V. (Veikko), Chen, Y. I. (Yii-Der I.), Rotter, J. I. (Jerome I.), Froguel, P. (Philippe), Jarvelin, M.-R. (Marjo-Riitta), Lakatta, E. G. (Edward G.), Kuulasmaa, K. (Kari), Franks, P. W. (Paul W.), Hamsten, A. (Anders), Wichmann, H.-E. (H-Erich), Palmer, C. N. (Colin N. A.), Stefansson, K. (Kari), Ridker, P. M. (Paul M.), Loos, R. J. (Ruth J. F.), Chalcravarti, A. (Aravinda), Deloukas, P. (Panos), Morris, A. P. (Andrew P.), Newton-Cheh, C. (Christopher), Munroe, P. B. (Patricia B.), Ehret, G. B. (Georg B.), Ferreira, T. (Teresa), Chasman, D. I. (Daniel I.), Jackson, A. U. (Anne U.), Schmidt, E. M. (Ellen M.), Johnson, T. (Toby), Thorleifsson, G. (Gudmar), Luan, J. (Jian'an), Donnelly, L. A. (Louise A.), Kanoni, S. (Stavroula), Petersen, A. -. (Ann -Kristin), Pihurl, V. (Vasyl), Strawbridge, R. J. (Rona J.), Shungin, D. (Dmitry), Hughes, M. F. (Maria F.), Meirelles, O. (Osorio), Kaakinen, M. (Marika), Bouatia-Naji, N. (Nabila), Kristiansson, K. (Kati), Shah, S. (Sonia), Kleber, M. E. (Marcus E.), Guo, X. (Xiuqing), Lyytikainen, L.-P. (Leo-Pekka), Fava, C. (Cristiano), Eriksson, N. (Nidas), Nolte, I. M. (Ilja M.), Magnusson, P. K. (Patrik K.), Salfati, E. L. (Elias L.), Rallidis, L. S. (Loukianos S.), Theusch, E. (Elizabeth), Smith, A. J. (Andrew J. P.), Folkersen, L. (Lasse), Witkowska, K. (Kate), Pers, T. H. (Tune H.), Joehanes, R. (Roby), Kim, S. K. (Stuart K.), Lataniotis, L. (Lazaros), Jansen, R. (Rick), Johnson, A. D. (Andrew D.), Warren, H. (Helen), Kim, Y. J. (Young Jin), Zhao, W. (Wei), Wu, Y. (Ying), Tayo, B. O. (Bamidele O.), Bochud, M. (Murielle), Absher, D. (Devin), Adair, L. S. (Linda S.), Amin, N. (Najaf), Arkingl, D. E. (Dan E.), Axelsson, T. (Tomas), Baldassarre, D. (Damian), Balkau, B. (Beverley), Bandinelli, S. (Stefania), Barnes, M. R. (Michael R.), Barroso, I. (Ines), Bevan, S. (Stephen), Bis, J. C. (Joshua C.), Bjornsdottir, G. (Gyda), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Bonnycastle, L. L. (Lori L.), Boomsma, D. I. (Dorret I.), Bornstein, S. R. (Stefan R.), Brown, M. J. (Morris J.), Burnier, M. (Michel), Cabrera, C. P. (Claudia P.), Chambers, J. C. (John C.), Chang, I.-S. (I-Shou), Cheng, C.-Y. (Ching-Yu), Chines, P. S. (Peter S.), Chung, R.-H. (Ren-Hua), Collins, F. S. (Francis S.), Connell, J. M. (John M.), Doring, A. (Angela), Dallongeville, J. (Jean), Danesh, J. (John), de Faire, U. (Ulf), Delgado, G. (Graciela), Dominiczak, A. F. (Anna F.), Doney, A. S. (Alex S. F.), Drenos, F. (Fotios), Edkins, S. (Sarah), Eicher, J. D. (John D.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erdmann, J. (Jeanette), Eriksson, P. (Per), Esko, T. (Tonu), Evangelou, E. (Evangelos), Evans, A. (Alun), Fai, T. (Tove), Farra, M. (Martin), Felixl, J. F. (Janine F.), Ferrieres, J. (Jean), Ferrucci, L. (Luigi), Fornage, M. (Myriam), Forrester, T. (Terrence), Franceschinil, N. (Nora), Franco, O. H. (Oscar H.), Franco-Cereceda, A. (Anders), Fraser, R. M. (Ross M.), Ganesh, S. K. (Santhi K.), Gao, H. (He), Gertow, K. (Karl), Gianfagna, F. (Francesco), Gigante, B. (Bruna), Giulianini, F. (Franco), Goe, A. (Anuj), Goodall, A. H. (Alison H.), Goodarzi, M. (Mark), Gorski, M. (Mathias), Grassler, J. (Jurgen), Groves, C. J. (Christopher J.), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hallmans, G. (Goran), Hartikainen, A.-L. (Anna-Liisa), Hassinen, M. (Maija), Havulinna, A. S. (Aki S.), Hayward, C. (Caroline), Hercberg, S. (Serge), Herzig, K.-H. (Karl-Heinz), Hicks, A. A. (Andrew A.), Hingorani, A. D. (Aroon D.), Hirschhorn, J. N. (Joel N.), Hofmanl, A. (Albert), Holmen, J. (Jostein), Holmen, O. L. (Oddgeir Lingaas), Hottenga, J.-J. (Jouke-Jan), Howard, P. (Phil), Hsiung, C. A. (Chao A.), Hunt, S. C. (Steven C.), Ikram, M. A. (M. Arfan), Illig, T. (Thomas), Iribarren, C. (Carlos), Jensen, R. A. (Richard A.), Kahonen, M. (Mika), Kang, H. M. (Hyun Min), Kathiresan, S. (Sekar), Keating, B. J. (Brendan J.), Khaw, K.-T. (Kay-Tee), Kim, Y. K. (Yun Kyoung), Kim, E. (Eric), Kivimaki, M. (Mika), Klopp, N. (Norman), Kolovou, G. (Genovefa), Komulainen, P. (Pirjo), Kooner, J. S. (Jaspal S.), Kosova, G. (Gulum), Krauss, R. M. (Ronald M.), Kuh, D. (Diana), Kutalik, Z. (Zoltan), Kuusisto, J. (Johanna), Kvaloy, K. (Kirsti), Lakka, T. A. (Timo A.), Lee, N. R. (Nanette R.), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Levy, D. (Daniel), Li, X. (Xiaohui), Liang, K.-W. (Kae-Woei), Lin, H. (Honghuang), Lin, L. (Li), Lindstrom, J. (Jaana), Lobbens, S. (Stephane), Mannisto, S. (Satu), Muller, G. (Gabriele), Muller-Nurasyid, M. (Martina), Mach, F. (Francois), Markus, H. S. (Hugh S.), Marouli, E. (Eirini), McCarthy, M. I. (Mark I.), McKenzie, C. A. (Colin A.), Meneton, P. (Pierre), Menni, C. (Cristina), Metspalu, A. (Andres), Mijatovic, V. (Vladan), Moilanen, L. (Leena), Montasser, M. E. (May E.), Morris, A. D. (Andrew D.), Morrison, A. C. (Alanna C.), Mulas, A. (Antonella), Nagaraja, R. (Ramaiah), Narisu, N. (Narisu), Nikus, K. (Kjell), O'Donnell, C. J. (Christopher J.), O'Reilly, P. F. (Paul F.), Ong, K. K. (Ken K.), Paccaud, F. (Fred), Palmer, C. D. (Cameron D.), Parsa, A. (Afshin), Pedersen, N. L. (Nancy L.), Penninx, B. W. (Brenda W.), Perola, M. (Markus), Peters, A. (Annette), Poulter, N. (Neil), Pramstaller, P. P. (Peter P.), Psaty, B. M. (Bruce M.), Quertermous, T. (Thomas), Rao, D. C. (Dabeeru C.), Rasheed, A. (Asif), Rayner, N. W. (N. William), Renstrom, F. (Frida), Rettig, R. (Rainer), Rice, K. M. (Kenneth M.), Roberts, R. (Robert), Rose, L. M. (Lynda M.), Rossouw, J. (Jacques), Samani, N. J. (Nilesh J.), Sanna, S. (Serena), Saramies, J. (Jouko), Schunkert, H. (Heribert), Sebert, S. (Sylvain), Sheu, W. H. (Wayne H-H), Shin, Y.-A. (Young-Ah), Sim, X. (Xueling), Smit, J. H. (Johannes H.), Smith, A. V. (Albert V.), Sosa, M. X. (Maria X.), Spector, T. D. (Tim D.), Stancakova, A. (Alena), Stanton, A. V. (Alice V.), Stirrups, K. E. (Kathleen E.), Stringham, H. M. (Heather M.), Sundstrom, J. (Johan), Swift, A. J. (Amy J.), Syvanen, A.-C. (Ann-Christine), Tai, E.-S. (E-Shyong), Tanaka, T. (Toshiko), Tarasov, K. V. (Kirill V.), Teumer, A. (Alexander), Thorsteinsdottir, U. (Unnur), Tobin, M. D. (Martin D.), Tremoli, E. (Elena), Uitterlinden, A. G. (Andre G.), Uusitupa, M. (Matti), Vaez, A. (Ahmad), Vaidya, D. (Dhananjay), van Duijn, C. M. (Cornelia M.), van Iperen, E. P. (Erik P. A.), Vasan, R. S. (Ramachandran S.), Verwoert, G. C. (Germaine C.), Virtamo, J. (Jarmo), Vitart, V. (Veronique), Voight, B. F. (Benjamin F.), Vollenweider, P. (Peter), Wagner, A. (Aline), Wain, L. V. (Louise V.), Wareham, N. J. (Nicholas J.), Watldns, H. (Hugh), Weder, A. B. (Alan B.), Westra, H. J. (Harm Jan), Wilks, R. (Rainford), Wilsgaard, T. (Tom), Wilson, J. F. (James F.), Wong, T. Y. (Tien Y.), Yang, T.-P. (Tsun-Po), Yao, J. (Jie), Yengo, L. (Loic), Zhang, W. (Weihua), Zhao, J. H. (Jing Hua), Zhu, X. (Xiaofeng), Bovet, P. (Pascal), Cooper, R. S. (Richard S.), Mohlke, K. L. (Karen L.), Saleheen, D. (Danish), Lee, J.-Y. (Jong-Young), Elliott, P. (Paul), Gierman, H. J. (Hinco J.), Willer, C. J. (Cristen J.), Franke, L. (Lude), Hovingh, G. K. (G. Kees), Taylor, K. D. (Kent D.), Dedoussis, G. (George), Sever, P. (Peter), Wong, A. (Andrew), Lind, L. (Lars), Assimes, T. L. (Themistocles L.), Njolstad, I. (Inger), Schwarz, P. E. (Peter E. H.), Langenberg, C. (Claudia), Snieder, H. (Harold), Caulfield, M. J. (Mark J.), Melander, E. (E.), Laakso, M. (Markku), Saltevo, J. (Juha), Rauramaa, R. (Rainer), Tuomilehto, J. (Jaakko), Ingelsson, E. (Erik), Lehtimaki, T. (Terho), Hveem, K. (Kristian), Palmas, W. (Walter), Marz, W. (Winfried), Kumar, M. (Meena), Salomaa, V. (Veikko), Chen, Y. I. (Yii-Der I.), Rotter, J. I. (Jerome I.), Froguel, P. (Philippe), Jarvelin, M.-R. (Marjo-Riitta), Lakatta, E. G. (Edward G.), Kuulasmaa, K. (Kari), Franks, P. W. (Paul W.), Hamsten, A. (Anders), Wichmann, H.-E. (H-Erich), Palmer, C. N. (Colin N. A.), Stefansson, K. (Kari), Ridker, P. M. (Paul M.), Loos, R. J. (Ruth J. F.), Chalcravarti, A. (Aravinda), Deloukas, P. (Panos), Morris, A. P. (Andrew P.), Newton-Cheh, C. (Christopher), and Munroe, P. B. (Patricia B.)
Abstract: To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure–associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure–related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
Published: 2016

10. Morphology of mucosa-associated lymphoid tissue in odontocetes

Author: Silva, Fernanda M. O., primary, Guimarães, Juliana P., additional, Vergara-Parente, Jociery E., additional, Carvalho, Vitor L., additional, Carolina, Ana, additional, Meirelles, O., additional, Marmontel, Miriam, additional, Oliveira, Bruno S. S. P., additional, Santos, Silvanise M., additional, Becegato, Estella Z., additional, Evangelista, Janaina S. A. M., additional, and Miglino, Maria Angelica, additional
Published: 2016
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11. A genome-wide association study of depressive symptoms

Author: Hek, K, Demirkan, A, Lahti, J, Terracciano, A, Teumer, A, Cornelis, MC, Amin, N, Bakshis, E, Baumert, J, Ding, J, Liu, Y, Marciante, K, Meirelles, O, Nalls, MA, Sun, YV, Vogelzangs, N, Yu, L, Bandinelli, S, Benjamin, EJ, Bennett, DA, Boomsma, D, Cannas, A, Coker, LH, De Geus, E, De Jager, PL, Diez-Roux, AV, Purcell, S, Hu, FB, Rimm, EB, Hunter, DJ, Jensen, MK, Curhan, G, Rice, K, Penman, AD, Rotter, JI, Sotoodehnia, N, Emeny, R, Eriksson, JG, Evans, DA, Ferrucci, L, Fornage, M, Gudnason, V, Hofman, A, Illig, T, Kardia, S, Kelly-Hayes, M, Koenen, K, Kraft, P, Kuningas, M, Massaro, JM, Melzer, D, Mulas, A, Mulder, CL, Murray, A, Oostra, BA, Palotie, A, Penninx, B, Petersmann, A, Pilling, LC, Psaty, B, Rawal, R, Reiman, EM, Schulz, A, Shulman, JM, Singleton, AB, Smith, AV, Sutin, AR, and Uitterlinden, AG
Abstract: Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p
Published: 2013

12. GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

Author: LifeLines Cohort Study, Rietveld, C.A., Medland, S.E., Derringer, J., Yang, J., Esko, T., Martin, N.W., Westra, H.J., Shakhbazov, K., Abdellaoui, A., Agrawal, A., Albrecht, E., Alizadeh, B.Z., Amin, N., Barnard, J., Baumeister, S.E., Benke, K.S., Bielak, L.F., Boatman, J.A., Boyle, P.A., Davies, G., de Leeuw, C., Eklund, N., Evans, D.S., Ferhmann, R., Fischer, K., Gieger, C., Gjessing, H.K., Hägg, S., Harris, J.R., Hayward, C., Holzapfel, C., Ibrahim-Verbaas, C.A., Ingelsson, E., Jacobsson, B., Joshi, P.K., Jugessur, A., Kaakinen, M., Kanoni, S., Karjalainen, J., Kolcic, I., Kristiansson, K., Kutalik, Z., Lahti, J., Lee, S.H., Lin, P., Lind, P.A., Liu, Y., Lohman, K., Loitfelder, M., McMahon, G., Vidal, P.M., Meirelles, O., Milani, L., Myhre, R., Nuotio, M.L., Oldmeadow, C.J., Petrovic, K.E., Peyrot, W.J., Polasek, O., Quaye, L., Reinmaa, E., Rice, J.P., Rizzi, T.S., Schmidt, H., Schmidt, R., Smith, A.V., Smith, J.A., Tanaka, T., Terracciano, A., van der Loos, M.J., Vitart, V., Völzke, H., Wellmann, J., Yu, L., Zhao, W., Allik, J., Attia, J.R., Bandinelli, S., Bastardot, F., Beauchamp, J., Bennett, D.A., Berger, K., Bierut, L.J., Boomsma, D.I., Bültmann, U., Campbell, H., Chabris, C.F., Cherkas, L., Chung, M.K., Cucca, F., de Andrade, M., De Jager, P.L., De Neve, J.E., Deary, I.J., Dedoussis, G.V., Deloukas, P., Dimitriou, M., Eiríksdóttir, G., Elderson, M.F., Eriksson, J.G., Evans, D.M., Faul, J.D., Ferrucci, L., Garcia, M.E., Grönberg, H., Guðnason, V., Hall, P., Harris, J.M., Harris, T.B., Hastie, N.D., Heath, A.C., Hernandez, D.G., Hoffmann, W., Hofman, A., Holle, R., Holliday, E.G., Hottenga, J.J., Iacono, W.G., Illig, T., Järvelin, M.R., Kähönen, M., Kaprio, J., Kirkpatrick, R.M., Kowgier, M., Latvala, A., Launer, L.J., Lawlor, D.A., Lehtimäki, T., Li, J., Lichtenstein, P., Lichtner, P., Liewald, D.C., Madden, P.A., Magnusson, P.K., Mäkinen, T.E., Masala, M., McGue, M., Metspalu, A., Mielck, A., Miller, M.B., Montgomery, G.W., Mukherjee, S., Nyholt, D.R., Oostra, B.A., Palmer, L.J., Palotie, A., Penninx, B.W., Perola, M., Peyser, P.A., Preisig, M., Räikkönen, K., Raitakari, O.T., Realo, A., Ring, S.M., Ripatti, S., Rivadeneira, F., Rudan, I., Rustichini, A., Salomaa, V., Sarin, A.P., Schlessinger, D., Scott, R.J., Snieder, H., St Pourcain, B., Starr, J.M., Sul, J.H., Surakka, I., Svento, R., Teumer, A., Tiemeier, H., van Rooij, F.J., Van Wagoner, D.R., Vartiainen, E., Viikari, J., Vollenweider, P., Vonk, J.M., Waeber, G., Weir, D.R., Wichmann, H.E., Widen, E., Willemsen, G., Wilson, J.F., Wright, A.F., Conley, D., Davey-Smith, G., Franke, L., Groenen, P.J., Johannesson, M., Kardia, S.L., Krueger, R.F., Laibson, D., Martin, N.G., Meyer, M.N., Posthuma, D., Thurik, A.R., Timpson, N.J., Uitterlinden, A.G., van Duijn, C.M., Visscher, P.M., Benjamin, D.J., Cesarini, D., Koellinger, P.D., LifeLines Cohort Study, Rietveld, C.A., Medland, S.E., Derringer, J., Yang, J., Esko, T., Martin, N.W., Westra, H.J., Shakhbazov, K., Abdellaoui, A., Agrawal, A., Albrecht, E., Alizadeh, B.Z., Amin, N., Barnard, J., Baumeister, S.E., Benke, K.S., Bielak, L.F., Boatman, J.A., Boyle, P.A., Davies, G., de Leeuw, C., Eklund, N., Evans, D.S., Ferhmann, R., Fischer, K., Gieger, C., Gjessing, H.K., Hägg, S., Harris, J.R., Hayward, C., Holzapfel, C., Ibrahim-Verbaas, C.A., Ingelsson, E., Jacobsson, B., Joshi, P.K., Jugessur, A., Kaakinen, M., Kanoni, S., Karjalainen, J., Kolcic, I., Kristiansson, K., Kutalik, Z., Lahti, J., Lee, S.H., Lin, P., Lind, P.A., Liu, Y., Lohman, K., Loitfelder, M., McMahon, G., Vidal, P.M., Meirelles, O., Milani, L., Myhre, R., Nuotio, M.L., Oldmeadow, C.J., Petrovic, K.E., Peyrot, W.J., Polasek, O., Quaye, L., Reinmaa, E., Rice, J.P., Rizzi, T.S., Schmidt, H., Schmidt, R., Smith, A.V., Smith, J.A., Tanaka, T., Terracciano, A., van der Loos, M.J., Vitart, V., Völzke, H., Wellmann, J., Yu, L., Zhao, W., Allik, J., Attia, J.R., Bandinelli, S., Bastardot, F., Beauchamp, J., Bennett, D.A., Berger, K., Bierut, L.J., Boomsma, D.I., Bültmann, U., Campbell, H., Chabris, C.F., Cherkas, L., Chung, M.K., Cucca, F., de Andrade, M., De Jager, P.L., De Neve, J.E., Deary, I.J., Dedoussis, G.V., Deloukas, P., Dimitriou, M., Eiríksdóttir, G., Elderson, M.F., Eriksson, J.G., Evans, D.M., Faul, J.D., Ferrucci, L., Garcia, M.E., Grönberg, H., Guðnason, V., Hall, P., Harris, J.M., Harris, T.B., Hastie, N.D., Heath, A.C., Hernandez, D.G., Hoffmann, W., Hofman, A., Holle, R., Holliday, E.G., Hottenga, J.J., Iacono, W.G., Illig, T., Järvelin, M.R., Kähönen, M., Kaprio, J., Kirkpatrick, R.M., Kowgier, M., Latvala, A., Launer, L.J., Lawlor, D.A., Lehtimäki, T., Li, J., Lichtenstein, P., Lichtner, P., Liewald, D.C., Madden, P.A., Magnusson, P.K., Mäkinen, T.E., Masala, M., McGue, M., Metspalu, A., Mielck, A., Miller, M.B., Montgomery, G.W., Mukherjee, S., Nyholt, D.R., Oostra, B.A., Palmer, L.J., Palotie, A., Penninx, B.W., Perola, M., Peyser, P.A., Preisig, M., Räikkönen, K., Raitakari, O.T., Realo, A., Ring, S.M., Ripatti, S., Rivadeneira, F., Rudan, I., Rustichini, A., Salomaa, V., Sarin, A.P., Schlessinger, D., Scott, R.J., Snieder, H., St Pourcain, B., Starr, J.M., Sul, J.H., Surakka, I., Svento, R., Teumer, A., Tiemeier, H., van Rooij, F.J., Van Wagoner, D.R., Vartiainen, E., Viikari, J., Vollenweider, P., Vonk, J.M., Waeber, G., Weir, D.R., Wichmann, H.E., Widen, E., Willemsen, G., Wilson, J.F., Wright, A.F., Conley, D., Davey-Smith, G., Franke, L., Groenen, P.J., Johannesson, M., Kardia, S.L., Krueger, R.F., Laibson, D., Martin, N.G., Meyer, M.N., Posthuma, D., Thurik, A.R., Timpson, N.J., Uitterlinden, A.G., van Duijn, C.M., Visscher, P.M., Benjamin, D.J., Cesarini, D., and Koellinger, P.D.
Abstract: A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
Published: 2013

13. GWAS of 126,559 individuals identifies genetic variants associated with educational attainment

Author: Rietveld, C.A. (Niels), Medland, S.E. (Sarah), Derringer, J., Yang, J. (Joanna), Esko, T. (Tõnu), Martin, N.W. (Nicolas), Westra, H.J. (Harm-Jan), Shakhbazov, K. (Konstantin), Abdellaoui, A. (Abdel), Agrawal, A. (Arpana), Albrecht, E. (Eva), Alizadeh, B.Z. (Behrooz), Amin, N. (Najaf), Barnard, J. (John), Baumeister, S.E. (Sebastian), Benke, P.J. (Paul), Bielak, L.F. (Lawrence F.), Boatman, J.A. (Jeffrey), Boyle, P.A. (Patricia), Davies, G. (Gail), Leeuw, C. (Christiaan) de, Eklund, N. (Niina), Evans, D.S. (Daniel), Ferhmann, R. (Rudolf), Fischer, K. (Krista), Gieger, C. (Christian), Gjessing, H.K. (Håkon), Hägg, S. (Sara), Harris, J.R. (Jennifer), Hayward, C. (Caroline), Holzapfel, C. (Christina), Ibrahim-Verbaas, C.A. (Carla), Ingelsson, E. (Erik), Jacobsson, B. (Bo), Joshi, P.K. (Peter), Juqessur, A. (Astanand), Kaakinen, M. (Marika), Kanoni, S. (Stavroula), Karjalainen, J. (Juha), Kolcic, I. (Ivana), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Lee, S.H. (Sang Hong), Lin, P. (Peng), Lind, P.A. (Penelope), Liu, Y. (YongMei), Lohman, K. (Kurt), Loitfelder, M. (Marisa), Mcmahon, G. (George), Marques-Vidal, P. (Pedro), Meirelles, O., Milani, L. (Lili), Myhre, R. (Ronny), Nuotio, M.-L. (Marja-Liisa), Oldmeadow, C. (Christopher), Petrovic, K. (Katja), Peyrot, W.J. (Wouter ), Polasek, O. (Ozren), Quaye, L. (Lydia), Reinmaa, E. (Eva), Rice, J.P. (John), Rizzi, T.S. (Thais), Schmidt, H. (Helena), Schmidt, R. (Reinhold), Smith, A.V. (Davey), Smith, J.A. (Jennifer A), Tanaka, T. (Toshiko), Terracciano, A., Loos, M.J.H.M. (Matthijs) van der, Vitart, V. (Veronique), Völzke, H. (Henry), Wellmann, J. (Jürgen), Yu, L. (Lei), Zhao, W. (Wei), Allik, J., Attia, J. (John), Bandinelli, S. (Stefania), Bastardot, F. (Francois), Beauchamp, J.P. (Jonathan), Bennett, D.A. (David), Berger, K. (Klaus), Bierut, L.J. (Laura), Boomsma, D.I. (Dorret), Bültmann, U. (Ute), Campbell, H. (Harry), Chabris, C.F. (Christopher F.), Cherkas, L. (Lynn), Chung, M.K. (Mina), Cucca, F. (Francesco), Andrade, M. (Mariza) de, Jager, P.L. (Philip) de, Neve, J.E. (Jan-Emmanuel) de, Deary, I.J. (Ian), Dedoussis, G.V. (George), Deloukas, P. (Panagiotis), Dimitriou, M. (Maria), Eiríksdóttir, G. (Guoný), Elderson, M.F. (Martin), Eriksson, J.G. (Johan), Evans, D.M. (David), Faul, J.D. (Jessica), Ferrucci, L. (Luigi), Garcia, M. (Melissa), Grönberg, H. (Henrik), Guonason, V. (Vilmundur), Hall, P. (Per), Harris, J.M. (Juliette), Harris, T.B. (Tamara), Hastie, N. (Nick), Heath, A.C. (Andrew), Hernandez, D.G. (Dena), Hoffmann, W. (Wolfgang), Holle, R. (Rolf), Holliday, E.G. (Elizabeth), Hottenga, J.J. (Jouke Jan), Iacono, W.G. (William), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Kähönen, M. (Mika), Kaprio, J. (Jaakko), Kirkpatrick, R.M. (Robert), Kowgier, M. (Matthew), Latvala, A. (Antti), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lehtimäki, T. (Terho), Li, J. (Jingmei), Lichtenstein, P. (Paul), Lichtner, P. (Peter), Liewald, D.C.M. (David), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Mäkinen, T. (Tuukka), Masala, G. (Giovanna), McGue, M. (Matt), Metspalu, A. (Andres), Mielck, A. (Andreas), Miller, M. (Michael), Montgomery, G.W. (Grant), Mukherjee, S. (Sutapa), Nyholt, D.R. (Dale), Oostra, B.A. (Ben), Palmer, C. (Cameron), Palotie, A. (Aarno), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peyser, P.A. (Patricia A.), Preisig, M. (Martin), Räikkönen, K. (Katri), Raitakari, O. (Olli), Realo, A. (Anu), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Rustichini, A. (Aldo), Salomaa, V. (Veikko), Sarin, A.-P., Schlessinger, D., Scott, R.J. (Rodney), Snieder, H. (Harold), St Pourcain, B. (Beate), Starr, J.M. (John), Sul, J.H. (Jae Hoon), Surakka, I. (Ida), Svento, R. (Rauli), Teumer, A. (Alexander), Tiemeier, H.W. (Henning), Rooij, F.J.A. (Frank) van, Wagoner, D.R. (David) van, Vartiainen, E. (Erkki), Viikari, J. (Jorma), Vollenweider, P. (Peter), Vonk, J.M. (Judith), Waeber, G. (Gérard), Weir, D.R. (David), Wichmann, H.E. (Heinz Erich), Widen, E. (Elisabeth), Willemsen, G.A.H.M. (Gonneke), Wilson, J.F. (James), Wright, A.F. (Alan), Conley, D. (Dalton), Davey-Smith, G. (George), Franke, L. (Lude), Groenen, P.J.F. (Patrick), Hofman, A. (Albert), Johannesson, M. (Magnus), Kardia, S.L.R. (Sharon), Krueger, R.F., Laibson, D. (David), Martin, N.G. (Nicholas), Meyer, M.N. (Michelle), Posthuma, D. (Danielle), Thurik, A.R. (Roy), Timpson, N.J. (Nicholas), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Visscher, P.M. (Peter), Benjamin, D.J. (Daniel J.), Cesarini, D. (David), Koellinger, Ph.D. (Philipp), Rietveld, C.A. (Niels), Medland, S.E. (Sarah), Derringer, J., Yang, J. (Joanna), Esko, T. (Tõnu), Martin, N.W. (Nicolas), Westra, H.J. (Harm-Jan), Shakhbazov, K. (Konstantin), Abdellaoui, A. (Abdel), Agrawal, A. (Arpana), Albrecht, E. (Eva), Alizadeh, B.Z. (Behrooz), Amin, N. (Najaf), Barnard, J. (John), Baumeister, S.E. (Sebastian), Benke, P.J. (Paul), Bielak, L.F. (Lawrence F.), Boatman, J.A. (Jeffrey), Boyle, P.A. (Patricia), Davies, G. (Gail), Leeuw, C. (Christiaan) de, Eklund, N. (Niina), Evans, D.S. (Daniel), Ferhmann, R. (Rudolf), Fischer, K. (Krista), Gieger, C. (Christian), Gjessing, H.K. (Håkon), Hägg, S. (Sara), Harris, J.R. (Jennifer), Hayward, C. (Caroline), Holzapfel, C. (Christina), Ibrahim-Verbaas, C.A. (Carla), Ingelsson, E. (Erik), Jacobsson, B. (Bo), Joshi, P.K. (Peter), Juqessur, A. (Astanand), Kaakinen, M. (Marika), Kanoni, S. (Stavroula), Karjalainen, J. (Juha), Kolcic, I. (Ivana), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Lee, S.H. (Sang Hong), Lin, P. (Peng), Lind, P.A. (Penelope), Liu, Y. (YongMei), Lohman, K. (Kurt), Loitfelder, M. (Marisa), Mcmahon, G. (George), Marques-Vidal, P. (Pedro), Meirelles, O., Milani, L. (Lili), Myhre, R. (Ronny), Nuotio, M.-L. (Marja-Liisa), Oldmeadow, C. (Christopher), Petrovic, K. (Katja), Peyrot, W.J. (Wouter ), Polasek, O. (Ozren), Quaye, L. (Lydia), Reinmaa, E. (Eva), Rice, J.P. (John), Rizzi, T.S. (Thais), Schmidt, H. (Helena), Schmidt, R. (Reinhold), Smith, A.V. (Davey), Smith, J.A. (Jennifer A), Tanaka, T. (Toshiko), Terracciano, A., Loos, M.J.H.M. (Matthijs) van der, Vitart, V. (Veronique), Völzke, H. (Henry), Wellmann, J. (Jürgen), Yu, L. (Lei), Zhao, W. (Wei), Allik, J., Attia, J. (John), Bandinelli, S. (Stefania), Bastardot, F. (Francois), Beauchamp, J.P. (Jonathan), Bennett, D.A. (David), Berger, K. (Klaus), Bierut, L.J. (Laura), Boomsma, D.I. (Dorret), Bültmann, U. (Ute), Campbell, H. (Harry), Chabris, C.F. (Christopher F.), Cherkas, L. (Lynn), Chung, M.K. (Mina), Cucca, F. (Francesco), Andrade, M. (Mariza) de, Jager, P.L. (Philip) de, Neve, J.E. (Jan-Emmanuel) de, Deary, I.J. (Ian), Dedoussis, G.V. (George), Deloukas, P. (Panagiotis), Dimitriou, M. (Maria), Eiríksdóttir, G. (Guoný), Elderson, M.F. (Martin), Eriksson, J.G. (Johan), Evans, D.M. (David), Faul, J.D. (Jessica), Ferrucci, L. (Luigi), Garcia, M. (Melissa), Grönberg, H. (Henrik), Guonason, V. (Vilmundur), Hall, P. (Per), Harris, J.M. (Juliette), Harris, T.B. (Tamara), Hastie, N. (Nick), Heath, A.C. (Andrew), Hernandez, D.G. (Dena), Hoffmann, W. (Wolfgang), Holle, R. (Rolf), Holliday, E.G. (Elizabeth), Hottenga, J.J. (Jouke Jan), Iacono, W.G. (William), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Kähönen, M. (Mika), Kaprio, J. (Jaakko), Kirkpatrick, R.M. (Robert), Kowgier, M. (Matthew), Latvala, A. (Antti), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lehtimäki, T. (Terho), Li, J. (Jingmei), Lichtenstein, P. (Paul), Lichtner, P. (Peter), Liewald, D.C.M. (David), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Mäkinen, T. (Tuukka), Masala, G. (Giovanna), McGue, M. (Matt), Metspalu, A. (Andres), Mielck, A. (Andreas), Miller, M. (Michael), Montgomery, G.W. (Grant), Mukherjee, S. (Sutapa), Nyholt, D.R. (Dale), Oostra, B.A. (Ben), Palmer, C. (Cameron), Palotie, A. (Aarno), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peyser, P.A. (Patricia A.), Preisig, M. (Martin), Räikkönen, K. (Katri), Raitakari, O. (Olli), Realo, A. (Anu), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Rustichini, A. (Aldo), Salomaa, V. (Veikko), Sarin, A.-P., Schlessinger, D., Scott, R.J. (Rodney), Snieder, H. (Harold), St Pourcain, B. (Beate), Starr, J.M. (John), Sul, J.H. (Jae Hoon), Surakka, I. (Ida), Svento, R. (Rauli), Teumer, A. (Alexander), Tiemeier, H.W. (Henning), Rooij, F.J.A. (Frank) van, Wagoner, D.R. (David) van, Vartiainen, E. (Erkki), Viikari, J. (Jorma), Vollenweider, P. (Peter), Vonk, J.M. (Judith), Waeber, G. (Gérard), Weir, D.R. (David), Wichmann, H.E. (Heinz Erich), Widen, E. (Elisabeth), Willemsen, G.A.H.M. (Gonneke), Wilson, J.F. (James), Wright, A.F. (Alan), Conley, D. (Dalton), Davey-Smith, G. (George), Franke, L. (Lude), Groenen, P.J.F. (Patrick), Hofman, A. (Albert), Johannesson, M. (Magnus), Kardia, S.L.R. (Sharon), Krueger, R.F., Laibson, D. (David), Martin, N.G. (Nicholas), Meyer, M.N. (Michelle), Posthuma, D. (Danielle), Thurik, A.R. (Roy), Timpson, N.J. (Nicholas), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Visscher, P.M. (Peter), Benjamin, D.J. (Daniel J.), Cesarini, D. (David), and Koellinger, Ph.D. (Philipp)
Published: 2013
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14. A genome-wide association study of depressive symptoms

Author: Hek, K. (Karin), Demirkan, A. (Ayşe), Lahti, J. (Jari), Terracciano, A., Teumer, A. (Alexander), Cornelis, M. (Marilyn), Amin, N. (Najaf), Bakshis, E. (Erin), Baumert, J. (Jens), Ding, J. (Jingzhong), Liu, Y. (YongMei), Marciante, K. (Kristin), Meirelles, O., Nalls, M.A. (Michael), Sun, Y.V. (Yan), Vogelzangs, N. (Nicole), Yu, L. (Lei), Bandinelli, S. (Stefania), Benjamin, E.J. (Emelia), Bennett, D.A. (David), Boomsma, D.I. (Dorret), Cannas, A., Coker, L.H. (Laura), Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Diez Roux, A.V. (Ana), Purcell, S. (Shaun), Hu, F.B. (Frank), Rimm, E., Hunter, D.J. (David), Jensen, M.K. (Majken), Curhan, G.C. (Gary), Rice, K.M. (Kenneth), Penman, A.D. (Alan), Rotter, J.I. (Jerome), Sotoodehnia, N. (Nona), Emeny, R. (Rebecca), Eriksson, J.G. (Johan), Evans, D.A. (Denis), Ferrucci, L. (Luigi), Fornage, M. (Myriam), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Illig, T. (Thomas), Kardia, S.L.R. (Sharon), Kelly-Hayes, M. (Margaret), Koenen, M.E. (Marjorie), Kraft, P. (Peter), Kuningas, M. (Maris), Massaro, J. (Joseph), Melzer, D. (David), Mulas, A. (Antonella), Mulder, C.L. (Niels), Murray, A. (Anna), Oostra, B.A. (Ben), Palotie, A. (Aarno), Penninx, B.W.J.H. (Brenda), Petersmann, A. (Astrid), Pilling, L.C. (Luke), Psaty, B.M. (Bruce), Rawal, R. (Rajesh), Reiman, E.M. (Eric), Schulz, A. (Ansgar), Shulman, L. (Lee), Singleton, A.B. (Andrew), Smith, A.V. (Davey), Sutin, A.R., Uitterlinden, A.G. (André), Völzke, H. (Henry), Widen, E. (Elisabeth), Yaffe, K. (Kristine), Zonderman, A.B. (Alan), Cucca, F. (Francesco), Harris, T.B. (Tamara), Ladwig, K.-H. (Karl-Heinz), Llewellyn, D.J. (David), Räikkönen, K. (Katri), Tanaka, T. (Toshiko), Duijn, C.M. (Cornelia) van, Grabe, H.J. (Hans Jörgen), Launer, L.J. (Lenore), Lunetta, K.L. (Kathryn), Mosley, T.H. (Thomas), Newman, A.B. (Anne), Tiemeier, H.W. (Henning), Murabito, J. (Joanne), Hek, K. (Karin), Demirkan, A. (Ayşe), Lahti, J. (Jari), Terracciano, A., Teumer, A. (Alexander), Cornelis, M. (Marilyn), Amin, N. (Najaf), Bakshis, E. (Erin), Baumert, J. (Jens), Ding, J. (Jingzhong), Liu, Y. (YongMei), Marciante, K. (Kristin), Meirelles, O., Nalls, M.A. (Michael), Sun, Y.V. (Yan), Vogelzangs, N. (Nicole), Yu, L. (Lei), Bandinelli, S. (Stefania), Benjamin, E.J. (Emelia), Bennett, D.A. (David), Boomsma, D.I. (Dorret), Cannas, A., Coker, L.H. (Laura), Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Diez Roux, A.V. (Ana), Purcell, S. (Shaun), Hu, F.B. (Frank), Rimm, E., Hunter, D.J. (David), Jensen, M.K. (Majken), Curhan, G.C. (Gary), Rice, K.M. (Kenneth), Penman, A.D. (Alan), Rotter, J.I. (Jerome), Sotoodehnia, N. (Nona), Emeny, R. (Rebecca), Eriksson, J.G. (Johan), Evans, D.A. (Denis), Ferrucci, L. (Luigi), Fornage, M. (Myriam), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Illig, T. (Thomas), Kardia, S.L.R. (Sharon), Kelly-Hayes, M. (Margaret), Koenen, M.E. (Marjorie), Kraft, P. (Peter), Kuningas, M. (Maris), Massaro, J. (Joseph), Melzer, D. (David), Mulas, A. (Antonella), Mulder, C.L. (Niels), Murray, A. (Anna), Oostra, B.A. (Ben), Palotie, A. (Aarno), Penninx, B.W.J.H. (Brenda), Petersmann, A. (Astrid), Pilling, L.C. (Luke), Psaty, B.M. (Bruce), Rawal, R. (Rajesh), Reiman, E.M. (Eric), Schulz, A. (Ansgar), Shulman, L. (Lee), Singleton, A.B. (Andrew), Smith, A.V. (Davey), Sutin, A.R., Uitterlinden, A.G. (André), Völzke, H. (Henry), Widen, E. (Elisabeth), Yaffe, K. (Kristine), Zonderman, A.B. (Alan), Cucca, F. (Francesco), Harris, T.B. (Tamara), Ladwig, K.-H. (Karl-Heinz), Llewellyn, D.J. (David), Räikkönen, K. (Katri), Tanaka, T. (Toshiko), Duijn, C.M. (Cornelia) van, Grabe, H.J. (Hans Jörgen), Launer, L.J. (Lenore), Lunetta, K.L. (Kathryn), Mosley, T.H. (Thomas), Newman, A.B. (Anne), Tiemeier, H.W. (Henning), and Murabito, J. (Joanne)
Abstract: Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10-5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10-7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10-3). This 5q21 region reached genome-wide significance (p = 4.78×10-8) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
Published: 2013
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15. Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking

Author: University of Helsinki, Institute of Behavioural Sciences, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Terracciano, A., Esko, T., Sutin, A. R., de Moor, M. H. M., Meirelles, O., Zhu, G., Tanaka, T., Giegling, I., Nutile, T., Realo, A., Allik, J., Hansell, N. K., Wright, M. J., Montgomery, G. W., Willemsen, G., Hottenga, J-J, Friedl, M., Ruggiero, D., Sorice, R., Sanna, S., Cannas, A., Räikkönen, Katri, Widen, E., Palotie, A., Eriksson, J. G., Cucca, F., Krueger, R. F., Lahti, J., Luciano, M., Smoller, J. W., van Duijn, C. M., Abecasis, G. R., Boomsma, D. I., Ciullo, M., Costa, P. T., Ferrucci, L., Martin, N. G., Metspalu, A., Rujescu, D., Schlessinger, D., Uda, M., University of Helsinki, Institute of Behavioural Sciences, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Terracciano, A., Esko, T., Sutin, A. R., de Moor, M. H. M., Meirelles, O., Zhu, G., Tanaka, T., Giegling, I., Nutile, T., Realo, A., Allik, J., Hansell, N. K., Wright, M. J., Montgomery, G. W., Willemsen, G., Hottenga, J-J, Friedl, M., Ruggiero, D., Sorice, R., Sanna, S., Cannas, A., Räikkönen, Katri, Widen, E., Palotie, A., Eriksson, J. G., Cucca, F., Krueger, R. F., Lahti, J., Luciano, M., Smoller, J. W., van Duijn, C. M., Abecasis, G. R., Boomsma, D. I., Ciullo, M., Costa, P. T., Ferrucci, L., Martin, N. G., Metspalu, A., Rujescu, D., Schlessinger, D., and Uda, M.
Published: 2011

16. Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with Excitement-Seeking

Author: Terracciano, A., Esko, T., Sutin, A.R., de Moor, M.H.M., Meirelles, O., Zhu, G., Tanaka, T., Giegling, I., Nutile, T., Realo, A., Allik, J., Hansell, N.K., Wright, M.J., Montgomery, G.W., Willemsen, G., Hottenga, J.J., Friedl, M., Ruggiero, D., Sorice, R., Sanna, S., Deiana, B., Cucca, F., Krueger, R.F., Lahti, A., Luciano, M., Smoller, J.W., van Duijn, C.M., Abecasis, G.R., Boomsma, D.I., Ciullo, M., Costa, P.T., Ferrucci, L., Martin, N.G., Metspalu, A., Rujescu, D., Schlessinger, D., Uda, M., Terracciano, A., Esko, T., Sutin, A.R., de Moor, M.H.M., Meirelles, O., Zhu, G., Tanaka, T., Giegling, I., Nutile, T., Realo, A., Allik, J., Hansell, N.K., Wright, M.J., Montgomery, G.W., Willemsen, G., Hottenga, J.J., Friedl, M., Ruggiero, D., Sorice, R., Sanna, S., Deiana, B., Cucca, F., Krueger, R.F., Lahti, A., Luciano, M., Smoller, J.W., van Duijn, C.M., Abecasis, G.R., Boomsma, D.I., Ciullo, M., Costa, P.T., Ferrucci, L., Martin, N.G., Metspalu, A., Rujescu, D., Schlessinger, D., and Uda, M.
Abstract: The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 × 10
Published: 2011
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17. Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking

Author: Terracciano, A, primary, Esko, T, additional, Sutin, A R, additional, de Moor, M H M, additional, Meirelles, O, additional, Zhu, G, additional, Tanaka, T, additional, Giegling, I, additional, Nutile, T, additional, Realo, A, additional, Allik, J, additional, Hansell, N K, additional, Wright, M J, additional, Montgomery, G W, additional, Willemsen, G, additional, Hottenga, J-J, additional, Friedl, M, additional, Ruggiero, D, additional, Sorice, R, additional, Sanna, S, additional, Cannas, A, additional, Räikkönen, K, additional, Widen, E, additional, Palotie, A, additional, Eriksson, J G, additional, Cucca, F, additional, Krueger, R F, additional, Lahti, J, additional, Luciano, M, additional, Smoller, J W, additional, van Duijn, C M, additional, Abecasis, G R, additional, Boomsma, D I, additional, Ciullo, M, additional, Costa, P T, additional, Ferrucci, L, additional, Martin, N G, additional, Metspalu, A, additional, Rujescu, D, additional, Schlessinger, D, additional, and Uda, M, additional
Published: 2011
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18. Neuroticism, depressive symptoms, and serum BDNF.

Author: Terracciano A, Lobina M, Piras MG, Mulas A, Cannas A, Meirelles O, Sutin AR, Zonderman AB, Uda M, Crisponi L, Schlessinger D, Terracciano, Antonio, Lobina, Monia, Piras, Maria Grazia, Mulas, Antonella, Cannas, Alessandra, Meirelles, Osorio, Sutin, Angelina R, Zonderman, Alan B, and Uda, Manuela
Published: 2011
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19. Electrons in Random Media

Author: NEW MEXICO UNIV ALBUQUERQUE BUREAU OF ENGINEERING RESEARCH, Meirelles,O. C., Byatt,W. J., NEW MEXICO UNIV ALBUQUERQUE BUREAU OF ENGINEERING RESEARCH, Meirelles,O. C., and Byatt,W. J.
Abstract: The question of particle transport in solids is discussed, for which there are available both classical and quantum mechanical formulations. In the past, the classical formulation, especially among engineers, has led to a diffusion theory description of particles in solids. It is the contention of this work that such a description is valid only asymptotically and otherwise suffers from serious deficiencies which are discussed. Starting from the Boltzmann equation for the elastic scattering of electrons in solids, it is shown that when the scattering angles are discretized, the logical outcome is not the diffusion equation, but is, rather, a family of first order partial differential equations. This set of equations is then generalized in both one and two dimensions to include absorption and internal sources, and solutions are written down for a number of cases of some physical interest. (Author)
Published: 1971

20. The association between lower educational attainment and depression owing to shared genetic effects?: Results in ~25,000 subjects

Author: Patricia A. Peyser, Jessica D. Faul, Patrik K. E. Magnusson, Nicholas D. Hastie, Beate St Pourcain, Marcus Ising, Gérard Waeber, Behrooz Z. Alizadeh, Judith M. Vonk, Lawrence F. Bielak, Sang Hong Lee, Wouter J. Peyrot, Thomas Illig, M. M. Weissman, Nicholas J. Timpson, George Dedoussis, Nicholas G. Martin, Tomi E. Mäkinen, Jorma Viikari, Lili Milani, Harold Snieder, Laura J. Bierut, A. C. Heath, Reinhold E. Schmidt, Mariza de Andrade, Vilmundur Gudnason, K. Petrovic, Robert M. Kirkpatrick, Marcela González Gross, William G. Iacono, Michelle N. Meyer, Henry Völzke, Marisa Loitfelder, Maria Dimitriou, Lude Franke, Robert F. Krueger, E. J. C. G. van den Oord, Sven Cichon, Michael Conlon O'Donovan, Ian W. Craig, Shawn N. Murphy, Danielle Posthuma, Brenda W.J.H. Penninx, Aarno Palotie, Roy Thurik, Panos Deloukas, Matt McGue, M. Preisig, Patricia A. Boyle, Osorio Meirelles, Ben A. Oostra, Klaus Berger, G. M. Montgomery, Sharon L.R. Kardia, Peter K. Joshi, K. Stefansson, Paul Lichtenstein, Andrew Heath, Andrea Schulz, Dena G. Hernandez, Debbie A Lawlor, S. P. Hamilton, James B. Potash, Z. Kutalik, Elisabeth Widen, Emil L. Sigurdsson, Rudolf S N Fehrmann, Matthias Nauck, Mikael Landén, Kurt Lohman, S.D. Gordon, Lefkos T. Middleton, Caroline Hayward, Anjali K. Henders, Philipp Koellinger, Jeffrey A. Boatman, G van Grootheest, M. Daly, Jian Yang, Peter Vollenweider, Penelope A. Lind, Stacy Steinberg, Frank J. A. van Rooij, Florian Holsboer, Hkon K. Gjessing, Erkki Vartiainen, Magnus Johannesson, Jingmei Li, David Laibson, Henrik Grönberg, Tõnu Esko, Ivana Kolcic, Niina Eklund, Kelly S. Benke, Henning Tiemeier, Isaac S. Kohane, Nicolas W. Martin, Ronny Myhre, Frans G. Zitman, Arpana Agrawal, James F. Wilson, Michael R. Barnes, Lei Yu, Thorgeir E. Thorgeirsson, Franois Bastardot, Katri Räikkönen, William Lawson, Willem A. Nolen, M. Rietschel, René Breuer, Bertram Müller-Myhsok, James A. Knowles, Grant W. Montgomery, Eva Reinmaa, Rudolf Uher, Andreas Mielck, Luigi Ferrucci, S. E. Medland, Yuri Milaneschi, Philip L. De Jager, Manfred Uhr, A. E. Farmer, Cornelia M. van Duijn, Samuli Ripatti, Marja-Liisa Nuotio, Manuel Mattheisen, Sebastian E. Baumeister, David R. Van Wagoner, Martin Preisig, Fernando Rivadeneira, Peter Lichtner, Christopher Oldmeadow, Hreinn Stefansson, Ian B. Hickie, Darina Czamara, Elizabeth G. Holliday, Astanand Jugessur, Carla A. Ibrahim-Verbaas, Jaime Derringer, Vivian S. Gainer, P. Muglia, Daniel J. Benjamin, Patrick K.E. Magnusson, Patience J. Gallagher, Jennifer A. Smith, Lynn Cherkas, Pamela A. F. Madden, David A. Bennett, Zoltán Kutalik, George Davey-Smith, Gudny Eiriksdottir, Jens Treutlein, N. Craddock, Juliette Harris, Antti Latvala, Roy H. Perlis, Markus M. Noethen, Jan-Emmanuel De Neve, Stanley I. Shyn, J.H. Smit, Dalton Conley, Adriaan Hofman, Jari Lahti, Patrick J. F. Groenen, Jüri Allik, Albert V. Smith, Ozren Polasek, Susan M. Ring, Thomas Bettecken, Michele L. Pergadia, Patrick J. McGrath, Katherine E. Tansey, Stephan Ripke, Hogni Oskarsson, Peng Lin, Douglas F. Levinson, Matthijs J. H. M. van der Loos, Melissa E. Garcia, Jonathan P. Beauchamp, Rodney J. Scott, Zhihong Zhu, Michel Guipponi, Lyle J. Palmer, Alexander Teumer, William Coryell, Stefan Kloiber, Gonneke Willemsen, John Frank, Victor M. Castro, Andrew M. McIntosh, John M. Starr, Antonio Terracciano, Mika Kähönen, Marco Masala, Markus Perola, André G. Uitterlinden, Sutapa Mukherjee, Alexander Viktorin, Lenore J. Launer, Elisabeth B. Binder, William A. Scheftner, Christel M. Middeldorp, D. H. R. Blackwood, I. Jones, Thais S. Rizzi, A. Teumer, Cornelius A. Rietveld, Aldo Rustichini, Guy Lewis, Susan L. Slager, David M. Evans, Dorret I. Boomsma, Harry Campbell, Susanne Churchill, Johan G. Eriksson, Alan F. Wright, Dan V. Iosifescu, W. Maier, Francesco Cucca, Federica Tozzi, David R. Weir, Eva Albrecht, L. Milani, Jennifer R. Harris, Min A. Jhun, Marjo-Riitta Järvelin, Martin F. Elderson, Ute Bültmann, Olli T. Raitakari, Konstantin Shakhbazov, Krista Fischer, Thomas G. Schulze, T. Jung-Ying, P. Lichtenstein, Terho Lethimäki, Jeffrey B. Weilburg, Rolf Holle, Bo Jacobsson, Pedro Marques Vidal, Jordan W. Smoller, Stavroula Kanoni, Kati Kristiansson, Sergey Goryachev, Michael Steffens, Peter M. Visscher, Toshiko Tanaka, Donald J. MacIntyre, Witte J.G. Hoogendijk, David Schlessinger, Ian J. Deary, Harm-Jan Westra, Erik Ingelsson, E.J.C. de Geus, Franziska Degenhardt, Lydia Quaye, John Barnard, David C. Liewald, John P. Rice, Christopher F. Chabris, P. McGuffin, Tamara B. Harris, C. M. Lewis, Gail Davies, Enda M. Byrne, H.-Erich Wichmann, Sara Hägg, David Cesarini, Najaf Amin, Juha Karjalainen, Dale R. Nyholt, Christian Gieger, Per Hall, Ania Korszun, Neale Bm, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Christina Holzapfel, Jae Hoon Sul, Christiaan de Leeuw, Antti-Pekka Sarin, Ida Surakka, Veikko Salomaa, Mina K. Chung, N. L. Pedersen, Gerome Breen, P. A. F. Madden, Martin A. Kohli, J Kaprio, John Attia, Jing Shi, Gibran Hemani, Rauli Svento, Veronique Vitart, Susanne Lucae, L. A. Jones, Jouke-Jan Hottenga, Daniel S. Evans, Hans-Jörgen Grabe, Yongmei Liu, Danyu Lin, Albert Hofman, George McMahon, Naomi R. Wray, Stefan Herms, Stefania Bandinelli, W. Hoffmann, P.F. Sullivan, Susanne Hoefels, Michael B. Miller, Alan W. McLean, Igor Rudan, Jürgen Wellmann, Anu Realo, Maurizio Fava, Matthew Kowgier, Marika Kaakinen, Helena Schmidt, Faculteit Medische Wetenschappen/UMCG, Peyrot, WJ, Lee, SH, Milaneschi, Y, Abdellaoui, A, Penninx, BWJH, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Social Science Genetic Association Consortium, Psychiatry, NCA - Neurobiology of mental health, EMGO - Mental health, Applied Economics, Biological Psychology, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (Corporate Collaborator), Social Science Genetic Association Consortium Corporate Collaborator, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium Corporate Collaborator, Lewis, C.M., Hamilton, S.P., Weissman, M.M., Breen, G., Blackwood, D.H., Cichon, S., Heath, A.C., Holsboer, F., Madden, P.A., McGuffin, P., Muglia, P., Pergadia, M.L., Lin, D., Müller-Myhsok, B., Steinberg, S., Grabe, H.J., Lichtenstein, P., Magnusson, P., Perlis, R.H., Preisig, M., Smoller, J.W., Stefansson, K., Uher, R., Kutalik, Z., Tansey, K.E., Teumer, A., Viktorin, A., Barnes, M.R., Bettecken, T., Binder, E.B., Breuer, R., Castro, V.M., Churchill, S.E., Coryell, W.H., Craddock, N., Craig, I.W., Czamara, D., Degenhardt, F., Farmer, A.E., Fava, M., Frank, J., Gainer, V.S., Gallagher, P.J., Gordon, S.D., Goryachev, S., Gross, M., Guipponi, M., Henders, A.K., Herms, S., Hickie, I.B., Hoefels, S., Hoogendijk, W., Iosifescu, D.V., Ising, M., Jones, I., Jones, L., Jung-Ying, T., Knowles, J.A., Kohane, I.S., Kohli, M.A., Korszun, A., Landen, M., Lawson, W.B., Lewis, G., Macintyre, D., Maier, W., Mattheisen, M., McGrath, P.J., McIntosh, A., McLean, A., Middeldorp, C.M., Middleton, L., Montgomery, G.M., Murphy, S.N., Nauck, M., Nolen, W.A., Nyholt, D.R., O'Donovan, M., Oskarsson, H., Pedersen, N., Scheftner, W.A., Schulz, A., Schulze, T.G., Shyn, S.I., Sigurdsson, E., Slager, S.L., Smit, J.H., Stefansson, H., Steffens, M., Thorgeirsson, T., Tozzi, F., Treutlein, J., Uhr, M., van den Oord, E.J., Van Grootheest, G., Völzke, H., Weilburg, J.B., Willemsen, G., Zitman, F.G., Neale, B., Daly, M., Sullivan, P.F., Agrawal, A., Albrecht, E., Alizadeh, B.Z., Allik, J., Amin, N., Attia, J.R., Bandinelli, S., Barnard, J., Bastardot, F., Baumeister, S.E., Beauchamp, J., Benjamin, D.J., Benke, K.S., Bennett, D.A., Berger, K., Bielak, L.F., Bierut, L.J., Boatman, J.A., Boyle, P.A., Bültmann, U., Campbell, H., Cesarini, D., Chabris, C.F., Cherkas, L., Chung, M.K., Conley, D., Cucca, F., Davey-Smith, G., Davies, G., de Andrade, M., De Jager, P.L., de Leeuw, C., De Neve, J.E., Deary, I.J., Dedoussis, G.V., Deloukas, P., Derringer, J., Dimitriou, M., Eiriksdottir, G., Eklund, N., Elderson, M.F., Eriksson, J.G., Evans, D.S., Evans, D.M., Faul, J.D., Fehrmann, R., Ferrucci, L., Fischer, K., Franke, L., Garcia, M.E., Gieger, C., Gjessing, H.K., Groenen, P.J., Grönberg, H., Gudnason, V., Hägg, S., Hall, P., Harris, J.R., Harris, J.M., Harris, T.B., Hastie, N.D., Hayward, C., Hernandez, D.G., Hoffmann, W., Hofman, A., Holle, R., Holliday, E.G., Holzapfel, C., Iacono, W.G., Ibrahim-Verbaas, C.A., Illig, T., Ingelsson, E., Jacobsson, B., Järvelin, M.R., Jhun, M.A., Johannesson, M., Joshi, P.K., Jugessur, A., Kaakinen, M., Kähönen, M., Kanoni, S., Kaprio, J., Kardia, S.L., Karjalainen, J., Kirkpatrick, R.M., Koellinger, P.D., Kolcic, I., Kowgier, M., Kristiansson, K., Krueger, R.F., Lahti, J., Laibson, D., Latvala, A., Launer, L.J., Lawlor, D.A., Lethimäki, T., Li, J., Lichtner, P.K., Liewald, D.C., Lin, P., Lind, P.A., Liu, Y., Lohman, K., Loitfelder, M., Magnusson, P.K., Mäkinen, T.E., Vidal, P.M., Martin, N.W., Masala, M., McGue, M., McMahon, G., Meirelles, O., Meyer, M.N., Mielck, A., Milani, L., Miller, M.B., Montgomery, G.W., Mukherjee, S., Myhre, R., Nuotio, M.L., Oldmeadow, C.J., Oostra, B.A., Palmer, L.J., Palotie, A., Perola, M., Petrovic, K.E., Peyser, P.A., Polašek, O., Posthuma, D., Quaye, L., Räikkönen, K., Raitakari, O.T., Realo, A., Reinmaa, E., Rice, J.P., Ring, S.M., Ripatti, S., Rivadeneira, F., Rizzi, T.S., Rudan, I., Rustichini, A., Salomaa, V., Sarin, A.P., Schlessinger, D., Schmidt, H., Schmidt, R., Scott, R.J., Shakhbazov, K., Smith, A.V., Smith, J.A., Snieder, H., Pourcain, B.S., Starr, J.M., Sul, J.H., Surakka, I., Svento, R., Tanaka, T., Terracciano, A., Thurik, A.R., Tiemeier, H., Timpson, N.J., Uitterlinden, A.G., van der Loos, M.J., van Duijn, C.M., van Rooij, F.J., Van Wagoner, D.R., Vartiainen, E., Viikari, J., Visscher, P.M., Vitart, V., Vollenweider, P.K., Vonk, J.M., Waeber, G., Weir, D.R., Wellmann, J., Westra, H.J., Wichmann, H.E., Widen, E., Wilson, J.F., Wright, A.F., Yang, J., Yu, L., and Zhao, W.
Subjects: Netherlands Twin Register (NTR), Male, Genome-wide association study, Logistic regression, Cohort Studies, Odds Ratio, pleiotropic genetic effects, Netherlands, Psychiatry, education.field_of_study, Likelihood Functions, Single Nucleotide, Middle Aged, Psychiatry and Mental health, educational attainment, depression, Major depressive disorder, Educational Status, Regression Analysis, Female, Psychology, Adult, Estonia, medicine.medical_specialty, Biochemistry & Molecular Biology, Aged, Depressive Disorder, Major/epidemiology, Depressive Disorder, Major/genetics, Depressive Disorder, Major/psychology, Estonia/epidemiology, Gene-Environment Interaction, Genetic Association Studies, Genotype, Humans, Netherlands/epidemiology, Polymorphism, Single Nucleotide/genetics, Psychiatric Status Rating Scales, Concordance, Population, SNP, Single-nucleotide polymorphism, Genetic correlation, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, mental disorders, medicine, Polymorphism, education, Molecular Biology, Depressive Disorder, Depressive Disorder, Major, major depressive disorder, ta1184, Neurosciences, Major, Odds ratio, medicine.disease, ta3124, Neurosciences & Neurology, polymorphisms, Demography
Abstract: An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on similar to 120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. Refereed/Peer-reviewed
Published: 2015

21. Plasma proteomic biomarkers and the association between poor cardiovascular health and incident dementia: The UK Biobank study.

Author: Beydoun MA, Beydoun HA, Hu YH, Maino Vieytes CA, Noren Hooten N, Song M, Georgescu MF, Fanelli-Kuczmarski MT, Meirelles O, Launer LJ, Evans MK, and Zonderman AB
Subjects: Humans, Male, Aged, Female, United Kingdom epidemiology, Middle Aged, Proteome metabolism, Incidence, Risk Factors, Blood Proteins metabolism, Blood Proteins analysis, UK Biobank, Dementia blood, Dementia epidemiology, Proteomics methods, Biological Specimen Banks, Biomarkers blood, Cardiovascular Diseases blood, Cardiovascular Diseases epidemiology
Abstract: Background: The study examined how plasma proteome indicators may explain the link between poor cardiovascular health (CVH) and dementia risk., Methods: The present study involved 28,974 UK Biobank participants aged 50-74y at baseline (2006-2010) who were followed-up for ≤ 15 y for incidence of dementia. CVH was calculated using Life's Essential 8 (LE8) total scores. The scores were standardized and reverse coded to reflect poor CVH (LE8z_rev). OLINK proteomics was available on this sample (k = 1,463 plasma proteins). The study primarily tested the mediating effects of the plasma proteome in LE8z_rev-dementia effect. The total effect was decomposed into "mediation only" or pure indirect effect (PIE), "interaction only" or interaction referent (INTREF), "neither mediation nor interaction" or controlled direct effect (CDE), and "both mediation and interaction" or mediated interaction (INTMED)., Results: The study found poorer CVH assessed by LE8z_rev increased the risk of all-cause dementia by 11 % [per 1 SD, hazard ratio, (HR) = 1.11, 95 % CI: 1.03-1.20, p = 0.005). The study identified 11 plasma proteins with strong mediating effects, with GDF15 having the strongest association with dementia risk (per 1 SD, HR = 1.24, 95 % CI: 1.16, 1.33, P < 0.001 when LE8z_rev is set at its mean value) and the largest proportion mediated combining PIE and INTMED (62.6 %; 48 % of TE is PIE), followed by adrenomedullin or ADM. A first principal component with 10 top mediators (TNFRSF1A, GDF15, FSTL3, COL6A3, PLAUR, ADM, GFRAL, ACVRL1, TNFRSF6B, TGFA) mediated 53.6 % of the LE8z_rev-dementia effect. Using all the significant PIE (k = 526) proteins, we used OLINK Insight pathway analysis to identify key pathways, which revealed the involvement of the immune system, signal transduction, metabolism, disease, protein metabolism, hemostasis, membrane trafficking, extracellular matrix organization, developmental biology, and gene expression among others. STRING analysis revealed that five top consistent proteomic mediators were represented in two larger clusters reflecting numerous interconnected biological gene ontology pathways, most notably cytokine-mediated signaling pathway for GDF15 cluster (GO:0019221) and regulation of peptidyl-tyrosine phosphorylation for the ADM cluster (GO:0050730)., Conclusion: Dementia is linked to poor CVH mediated by GDF15 and ADM among several key proteomic markers which collectively explained ∼ 54 % of the total effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)
Published: 2024
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22. Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and incident dementia: The UK Biobank study.

Author: Beydoun HA, Beydoun MA, Noren Hooten N, Weiss J, Li Z, Georgescu MF, Maino Vieytes CA, Meirelles O, Launer LJ, Evans MK, and Zonderman AB
Subjects: Aged, Female, Humans, Male, Middle Aged, Blood Proteins metabolism, Growth Differentiation Factor 15 blood, Incidence, Oral Health, Proteome metabolism, UK Biobank, United Kingdom epidemiology, Biomarkers blood, Dementia blood, Dementia epidemiology, Proteomics
Abstract: The plasma proteome can mediate poor oral health problems (POHP)'s link to incident dementia. We screened 37,269 UK Biobank participants 50-74 years old (2006-2010) for prevalent POHP, further tested against 1463 plasma proteins and incident dementia over up to 15 years of follow-up. Total effect (TE) of POHP-dementia through plasma proteomic markers was decomposed into pure indirect effect (PIE), interaction referent (INTREF), controlled direct effect (CDE), or mediated interaction (INTMED). POHP increased the risk of all-cause dementia by 17% (P < 0.05). Growth differentiation factor 15 (GDF15) exhibited the strongest mediating effects (PIE > 0, P < 0.001), explaining 28% the total effect of POHP on dementia, as a pure indirect effect. A first principal component encompassing top 4 mediators (GDF15, IL19, MMP12, and ACVRL1), explained 11% of the POHP-dementia effect as a pure indirect effect. Pathway analysis including all mediators (k = 173 plasma proteins) revealed the involvement of the immune system, signal transduction, metabolism, disease, and gene expression, while STRING analysis indicated that top mediators within the first principal component were also represented in the two largest proteomic clusters. The dominant biological GO pathway for the GDF15 cluster was GO:0007169 labeled as "transmembrane receptor protein tyrosine kinase signaling pathway." Dementia is linked to POHP mediated by GDF15 among several proteomic markers., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Published: 2024
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23. The magnitude and direction of the relationship between risk factor and cognition depends on age: a pooled analysis of 5 community-based studies.

Author: Meirelles O, Arnette A, Guðnason V, and Launer LJ
Subjects: Humans, Adult, Middle Aged, Aged, Aged, 80 and over, Prospective Studies, Risk Factors, Body Mass Index, Cognition, Cognitive Dysfunction epidemiology
Abstract: The mixed evidence of the association between high levels of cardiovascular risk factors (CVRF) and the risk for cognitive impairment may be due to confounding of age across studies. We pooled and harmonized individual-level data (30,967 persons, age range 42-96 years) from five prospective cohorts to investigate by 1 year age increments to investigate whether or not there is change in slope describing the association of CVRF to a cognitive outcome (Digit Symbol Substitution Test; DSST). The CVRF included: systolic and diastolic blood pressure, total cholesterol, fasting glucose and body mass index. Linear and quadratic piecewise regression models were fit to the trajectory patterns of these slopes (betas). The pattern of yearly slope changes showed higher CVRF were associated with lower DSST, but associations attenuated toward zero as age increased for all but DBP where 1 year slopes for DBP changed direction from negative to positive from mid- to late-age. Age is not only a driver of cognitive decline-age also modifies the direction and strength of the association of cognitive function to CVRF and cohort age may be one reason why the evidence for CVRF-CD association is mixed., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Published: 2024
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24. Genetic and biomarker modulation of arterial stiffness change in the SardiNIA population cohort.

Author: Asefa NG, Meirelles O, Lakatta E, Fiorillo E, Scuteri A, Cucca F, Marongiu M, Delitala A, Schlessinger D, and Launer LJ
Abstract: Background and Aims: Arterial stiffness (AS), quantified by pulse wave velocity (PWV), arises due to impaired arterial elastic tissue and smooth muscle dysfunction. We aimed to examine the longitudinal association of genetic, lipid and inflammation biomarkers with PWV and how these associations may change with aging., Materials and Methods: We utilized genotype and four time-point biomarker data from the SardiNIA cohort [ n = 6,301; mean baseline age 43.3 (SD 17.3); 58% females]. To investigate the association of PWV with genetic variants, lipid, and inflammation biomarkers, we employed linear mixed modeling, using age as the time scale. Biomarkers exhibiting significant longitudinal associations were categorized into tertiles and individuals within the second tertile or those with heterozygous alleles were excluded, leaving a cohort of 2,000 individuals. This cohort was further divided into four risk groups: low genetic and low biomarker (L-L), low genetic and high biomarker (L-H), high genetic and low biomarker (H-L), and high genetic and high biomarker risk (H-H). Subsequent analyses focused on these risk groups to assess their association to PWV with time., Results: Using the complete dataset, we found a significant longitudinal association of total cholesterol (TC), triglycerides (TG), fibrinogen (FGN), and total white blood cell count (TWBC) with PWV, all with p < 3.33 × 10 -3 . After grouping, individuals with homogeneous risk alleles of SNP rs3742207 and high baseline TG levels (H-H group) exhibited a 1.39-fold higher PWV (m/s) (95% CI, 1.17-1.64, p = 1.21 × 10 -4 ) compared to the L-L group. Similarly, individuals in the H-H group of rs3742207-TWBC combination showed 1.75 times higher PWV (95% CI, 1.48-0.2.07, p = 1.01 × 10 -10 ) compared to the L-L group. Similar patterns were observed for groups based on SNP rs7152623-TWBC risk. Furthermore, these associations became more pronounced with increasing age ( p < 3.33 × 10 -3 )., Conclusion: The longitudinal association of TG and TWBC biomarkers with PWV varied by SNPs rs3742207 and rs7152623 genotype. Further studies are warranted to investigate the function of genetics, lipids, and inflammation biomarkers on PWV change., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors EF, EL declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Asefa, Meirelles, Lakatta, Fiorillo, Scuteri, Cucca, Marongiu, Delitala, Schlessinger and Launer.)
Published: 2024
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25. Infection burden and its association with neurite orientation dispersion and density imaging markers in the UK Biobank.

Author: Beydoun MA, Beydoun HA, Hu YH, Li Z, Wolf C, Meirelles O, Noren Hooten N, Launer LJ, Evans MK, and Zonderman AB
Subjects: Neurites, Biological Specimen Banks, Brain, Diffusion Magnetic Resonance Imaging methods, Diffusion Tensor Imaging methods, White Matter diagnostic imaging
Abstract: Background: Infection burden (IB), although linked to neurodegeneration, including Alzheimer's Disease (AD), has not been examined against neurite orientation, dispersion, and density imaging (NODDI) measures., Methods: Among 38,803 UK Biobank adults (Age:40-70 years), we tested associations of total IB (IB total , 47.5 %) and hospital-treated IB (IB hosp , 9.7 %) with NODDI measures (5-15 years later), including volume fraction of Gaussian isotropic diffusion (ISOVF), intra-cellular volume fraction (ICVF) and orientation dispersion (OD) indices, using multiple linear regression models., Results: Total and hospital-treated infection burdens (IB total and IB hosp ) were associated with increased ISOVF, indicating increased free-water component. IB total was positively associated with OD, indicating that at higher IB total there was greater fanning of neurites. This was more evident in the lower cardiovascular health group. IB hosp was associated with higher OD, and lower ICVF at higher AD polygenic risk. Together, these findings indicate that both total and hospital-treated infections have effects on NODDI outcomes in the direction of poor brain health. These effects were largely homogeneous across cardiovascular health and AD polygenic risk groups, with some effects shown to be stronger at poor cardiovascular health and/or higher AD risk., Conclusions: Total and hospital-treated infections were associated with poorer white matter microstructure (higher ISOVF or OD or lower ICVF), with some heterogeneity across cardiovascular health and AD risk. Longitudinal studies with multiple repeats on neuroimaging markers in comparable samples are needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)
Published: 2024
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26. Hospital-treated prevalent infections, the plasma proteome and incident dementia among UK older adults.

Author: Beydoun MA, Beydoun HA, Noren Hooten N, Meirelles O, Li Z, El-Hajj ZW, Weiss J, Maino Vieytes CA, Launer LJ, Evans MK, and Zonderman AB
Abstract: The plasma proteome can mediate the association of hospital-treated infections with dementia incidence. We screened up to 37,269 UK Biobank participants aged 50-74 years for the presence of a prevalent hospital-treated infection, subsequently tested as a predictor for ≤1,463 plasma proteins and dementia incidence. Four-way decomposition models decomposed infection-dementia total effect into pure mediation, pure interaction, neither or both through the plasma proteome. Hospital-treated infections increased dementia two-fold. The strongest mediation effect was through the growth differentiation factor 15 (GDF15) protein. Top 17 proteomic mediators explained collectively 5% of the total effect, while pathway analysis of all mediators (k = 221 plasma proteins) revealed top pathways including the immune system, signal transduction, metabolism, disease and metabolism of proteins, with the GDF15 cluster reflecting most strongly the "transmembrane receptor protein tyrosine kinase signaling pathway". The association of hospital-treated infections with dementia was partially mediated through GDF15 and other plasma proteomic markers., Competing Interests: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of AT Augusta Military Medical Center, the Defense Health Agency, Department of Defense, or US Government. Reference to any commercial products within this publication does not create or imply any endorsement by AT Augusta Military Medical Center, the Defense Health Agency, Department of Defense, or US Government. The authors declare no conflict of interest., (© 2023.)
Published: 2023
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27. Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.

Author: Tin A, Fohner AE, Yang Q, Brody JA, Davies G, Yao J, Liu D, Caro I, Lindbohm JV, Duggan MR, Meirelles O, Harris SE, Gudmundsdottir V, Taylor AM, Henry A, Beiser AS, Shojaie A, Coors A, Fitzpatrick AL, Langenberg C, Satizabal CL, Sitlani CM, Wheeler E, Tucker-Drob EM, Bressler J, Coresh J, Bis JC, Candia J, Jennings LL, Pietzner M, Lathrop M, Lopez OL, Redmond P, Gerszten RE, Rich SS, Heckbert SR, Austin TR, Hughes TM, Tanaka T, Emilsson V, Vasan RS, Guo X, Zhu Y, Tzourio C, Rotter JI, Walker KA, Ferrucci L, Kivimäki M, Breteler MMB, Cox SR, Debette S, Mosley TH, Gudnason VG, Launer LJ, Psaty BM, Seshadri S, and Fornage M
Subjects: Middle Aged, Humans, Aged, Cognition, Neurons, Biomarkers, Alzheimer Disease, Cognitive Dysfunction
Abstract: Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets., (© 2023. The Author(s).)
Published: 2023
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28. SARS-CoV-2 infection establishes a stable and age-independent CD8 + T cell response against a dominant nucleocapsid epitope using restricted T cell receptors.

Author: Choy C, Chen J, Li J, Gallagher DT, Lu J, Wu D, Zou A, Hemani H, Baptiste BA, Wichmann E, Yang Q, Ciffelo J, Yin R, McKelvy J, Melvin D, Wallace T, Dunn C, Nguyen C, Chia CW, Fan J, Ruffolo J, Zukley L, Shi G, Amano T, An Y, Meirelles O, Wu WW, Chou CK, Shen RF, Willis RA, Ko MSH, Liu YT, De S, Pierce BG, Ferrucci L, Egan J, Mariuzza R, and Weng NP
Subjects: Humans, SARS-CoV-2 metabolism, Epitopes, T-Lymphocyte, Receptors, Antigen, T-Cell metabolism, Nucleocapsid metabolism, Spike Glycoprotein, Coronavirus, CD8-Positive T-Lymphocytes, COVID-19
Abstract: The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8 + T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8 + T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here, we analyzed CD8 + T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein and found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8 + T cells but significantly enhanced activation-induced proliferation compared to that of the uninfected donors. The frequencies of N-specific CD8 + T cells and their proliferative response to stimulation did not decrease over one year. We identified the N 222-230 peptide (LLLDRLNQL, referred to as LLL thereafter) as a dominant epitope that elicited the greatest proliferative response from both convalescent and uninfected donors. Single-cell sequencing of T cell receptors (TCR) from LLL-specific CD8 + T cells revealed highly restricted Vα gene usage (TRAV12-2) with limited CDR3α motifs, supported by structural characterization of the TCR-LLL-HLA-A2 complex. Lastly, transcriptome analysis of LLL-specific CD8 + T cells from donors who had expansion (expanders) or no expansion (non-expanders) after in vitro stimulation identified increased chromatin modification and innate immune functions of CD8 + T cells in non-expanders. These results suggests that SARS-CoV-2 infection induces LLL-specific CD8 + T cell responses with a restricted TCR repertoire., (© 2023. Springer Nature Limited.)
Published: 2023
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29. Cardiovascular health, infection burden, and incident dementia in the UK Biobank.

Author: Beydoun HA, Beydoun MA, Meirelles O, Erickson LD, Gamaldo AA, Weiss J, Launer LJ, Evans MK, and Zonderman AB
Subjects: Female, Male, Humans, Aged, Biological Specimen Banks, United Kingdom epidemiology, Risk Factors, Alzheimer Disease epidemiology, Cardiovascular Diseases epidemiology
Abstract: Introduction: Among older adults, total and hospitalized infection may be associated with incidence of all-cause and Alzheimer's disease (AD) dementias, with variation by cardiovascular health (CVH)., Methods: We used Cox proportional hazards (PH) models to examine the relationships between International Classification of Diseases-10th revision (ICD-10)-specific viral and bacterial infectious agents and incident all-cause and AD dementia among 355,046 UK Biobank participants ≥50 years at baseline. Life's Essential 8 (LE8) index reflected CVH., Results: In both sexes, total infection burden (yes vs. no) was associated with all-cause dementia, with significant interactions by LE8 tertiles, whereby this relationship was significant only in the lowest LE8 tertile. Hospital-treated infection burden (yes vs no) was significantly related to all-cause and AD dementia, with no significant interaction with LE8 tertile. Age group patterns were detected., Discussion: AD and all-cause dementia were related to hospital-treated infections, while CVH modified the relationship of total infection burden with all-cause dementia. Highlights Secondary analysis on >355,000 UK Biobank participants ≥50 years at baseline. Alzheimer's disease and all-cause dementia are both related to hospital-treated infection. Cardiovascular health modifies association of infection burden with all-cause dementia., (© 2023 Alzheimer's Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
Published: 2023
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30. Pathways explaining racial/ethnic and socio-economic disparities in dementia incidence: the UK Biobank study.

Author: Beydoun MA, Beydoun HA, Fanelli-Kuczmarski MT, Weiss J, Georgescu MF, Meirelles O, Lyall DM, Evans MK, and Zonderman AB
Subjects: Humans, Health Status Disparities, Social Class, United Kingdom epidemiology, Biological Specimen Banks, Dementia epidemiology
Abstract: Background: Pathways explaining racial/ethnic disparities in dementia risk are under-evaluated., Methods: We examine those disparities and their related pathways among UK Biobank study respondents (50-74 y, N = 323,483; 3.6% non-White minorities) using a series of Cox proportional hazards and generalized structural equations models (GSEM)., Results: After ≤15 years, 5,491 all-cause dementia cases were diagnosed. Racial minority status (RACE_ETHN, Non-White vs. White) increased dementia risk by 24% (HR = 1.24, 95% CI: 1.07-1.45, P = 0.005), an association attenuated by socio-economic status (SES), (HR = 1.12, 95% CI: 0.96-1.31). Total race-dementia effect was mediated through both SES and Life's Essential 8 lifestyle sub-score (LE8 LIFESTYLE ), combining diet, smoking, physical activity, and sleep factors. SES was inversely related to dementia risk (HR = 0.69, 95% CI: 0.67, 0.72, P < 0.001). Pathways explaining excess dementia risk among racial minorities included 'RACE_ETHN(-) → SES(-) → DEMENTIA', 'RACE_ETHN(-) → SES(-) → Poor cognitive performance, COGN(+) → DEMENTIA' and 'RACE_ETHN(-) → SES(+) → LE8 LIFESTYLE (-) → DEMENTIA'., Conclusions: Pending future interventions, lifestyle factors including diet, smoking, physical activity, and sleep are crucial for reducing racial and socio-economic disparities in dementia.
Published: 2023
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31. The rocky road of 55 years of change in the relationship of cardiovascular risk factors to cognition.

Author: Meirelles O, Arnette A, Gudnason V, and Launer L
Abstract: The mixed evidence that high levels of cardiovascular risk factors (CVRF) are associated with lower cognitive test scores of may be due to confounding of age across studies. We pooled and harmonized individual-level data (30,967 persons, age range 42-96y) from five prospective cohorts to examine the trajectories of betas estimating 1-year-age associations of a cognitive outcome (Digit Symbol Substitution Test; DSST) to five CVRF: systolic and e blood pressure, total cholesterol, fasting glucose and body mass index. Linear and quadratic piecewise regression models were fit to the trajectory patterns of these betas. The trajectories showed with each 1-year age increment, higher CVRF were associated with lower DSST, but associations attenuated toward zero as age increased. In addition, the pattern across age of each CVRF-DSST trajectory ranged from linear to non-liner. Without accounting for participant age in cohort comparisons, conclusions about the potential benefit on cognitive function of modifiable CVRF control will continue to be mixed and lead to delays in developing prevention programs., Competing Interests: Disclosure: The authors have no conflicts to disclose Conflict of Interest OM, AA, VG and LJL have no relevant financial or non-financial interests to disclose. The authors declare that beyond the listed sources of funding, no other support was received during preparation of this manuscript.
Published: 2023
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32. Gut microbiome and stages of diabetes in middle-aged adults: CARDIA microbiome study.

Author: Hu YH, Meyer K, Lulla A, Lewis CE, Carnethon MR, Schreiner PJ, Sidney S, Shikany JM, Meirelles O, and Launer LJ
Abstract: Background: Animal and human studies suggest the gut microbiome is linked to diabetes but additional data are needed on the associations of the gut microbiome to specific diabetes characteristics. The aim of this study was to examine the associations of gut microbiome composition to insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], duration of diabetes, and 4 stages of diabetes [normoglycemia, pre-diabetes, and diabetes with (+) and without (-) medication for diabetes]., Methods: Data are from a sub-sample (n = 605) of Black and White participants from the 30-year follow-up exam of the prospectively followed community-based Coronary Artery Risk Development in Young Adults cohort (2015-2016; aged 48-60 years). Stool samples were collected and sequenced using the 16S ribosomal RNA method. Microbial measures included: α diversity (within-person), β diversity (between-person), and taxonomies. All analyses were adjusted for demographic, clinical, lifestyle factors, and use of relevant medications (full adjustment). Multivariate linear regression models were used to assess the association of diabetes characteristics with α diversity and genera abundance, while the association with β diversity was analyzed using permutational multivariate analysis of variance. Statistical significance was set to p-value < 0.05 for α and β diversity analyses and to q-value < 0.1 for genera abundance analyses., Results: There were 16.7% of participants with pre-diabetes, and 14.4% with diabetes (9% diabetes+) with median (interquartile range) diabetes duration of 5 (5-10) years. In the fully adjusted models, compared to those with no diabetes, longer diabetes duration and the diabetes + group had a lower α diversity. There were significant differences in β diversity across diabetes-related characteristics. A significantly reduced abundance of butyrate-producing genera was associated with higher HOMA-IR (ex., Anaerostipes and Lachnospiraceae_UCG.004), longer diabetes duration (ex., Agathobacter and Ruminococcus), and diabetes + (ex., Faecalibacterium and Romboutsia)., Conclusions: Our results suggest that an adverse alteration of gut microbiome composition is related to higher insulin resistance, longer diabetes duration, and is present in those persons with diabetes using medications. These diabetes-related characteristics were also associated with lower levels of certain butyrate-producing bacteria that produce health-promoting short-chain fatty acids. Understanding the role of gut microbiota in glucose regulation may provide new strategies to reduce the burden of diabetes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Published: 2023
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33. Race, sex, and mid-life changes in brain health: Cardia MRI substudy.

Author: Moonen JEF, Nasrallah IM, Detre JA, Dolui S, Erus G, Davatzikos C, Meirelles O, Bryan RN, and Launer LJ
Subjects: Humans, Female, Male, Middle Aged, Brain diagnostic imaging, Magnetic Resonance Imaging methods, Apolipoprotein E4, Quality of Life, Cardia, White Matter diagnostic imaging
Abstract: Objective: To examine longitudinal race and sex differences in mid-life brain health and to evaluate whether cardiovascular health (CVH) or apolipoprotein E (APOE) ε4 explain differences., Methods: The study included 478 Black and White participants (mean age: 50 years). Total (TBV), gray (GMV), white (WMV), and white matter hyperintensity (WMH) volumes and GM-cerebral blood flow (CBF) were acquired with 3T-magnetic resonance imaging at baseline and 5-year follow-up. Analyses were based on general linear models., Results: There were race x sex interactions for GMV (P-interaction = .004) and CBF (P-interaction = .01) such that men showed more decline than women, and this was most evident in Blacks. Blacks compared to Whites had a significantly greater increase in WMH (P = .002). All sex-race differences in change were marginally attenuated by CVH and APOE ε4., Conclusion: Race-sex differences in brain health emerge by mid-life. Identifying new environmental factors beyond CVH is needed to develop early interventions to maintain brain health., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
Published: 2022
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34. Association of Cerebral Blood Flow With Longitudinal Changes in Cerebral Microstructural Integrity in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Author: Bouhrara M, Triebswetter C, Kiely M, Bilgel M, Dolui S, Erus G, Meirelles O, Bryan NR, Detre JA, and Launer LJ
Subjects: Adolescent, Adult, Cerebrovascular Circulation physiology, Female, Humans, Longitudinal Studies, Middle Aged, Prospective Studies, Young Adult, Coronary Vessels, Diffusion Tensor Imaging methods
Abstract: Importance: Decreased cerebral tissue integrity and cerebral blood flow (CBF) are features of neurodegenerative diseases. Brain tissue maintenance is an energy-demanding process, making it particularly sensitive to hypoperfusion. However, little is known about the association between blood flow and brain microstructural integrity, including in normative aging., Objective: To assess associations between CBF and changes in cerebral tissue integrity in white matter and gray matter brain regions., Design, Setting, and Participants: In this longitudinal cohort study, magnetic resonance imaging was performed on 732 healthy adults from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective longitudinal study (baseline age of 18-30 years) that examined participants up to 8 times during 30 years (1985-1986 to 2015-2016). Cerebral blood flow was measured at baseline (year 25 of the CARDIA study), and changes in diffusion tensor indices of fractional anisotropy (FA) and mean diffusivity (MD), measures of microstructural tissue integrity, were measured at both baseline and after approximately 5 years of follow-up (year 30). Analyses were conducted from November 5, 2020, to January 29, 2022., Main Outcomes and Measures: Automated algorithms and linear mixed-effects statistical models were used to evaluate the associations between CBF at baseline and changes in FA or MD., Results: After exclusion of participants with missing or low-quality data, 654 at baseline (342 women; mean [SD] age, 50.3 [3.5] years) and 433 at follow-up (230 women; mean [SD] age, 55.1 [3.5] years) were scanned for CBF or FA and MD imaging. In the baseline cohort, 247 participants were Black (37.8%) and 394 were White (60.2%); in the follow-up cohort, 156 were Black (36.0%) and 277 were White (64.0%). Cross-sectionally, FA and MD were associated with CBF in most regions evaluated, with lower CBF values associated with lower FA or higher MD values, including the frontal white matter lobes (for CBF and MD: mean [SE] β = -1.4 [0.5] × 10-6; for CBF and FA: mean [SE] β = 2.9 [1.0] × 10-4) and the parietal white matter lobes (for CBF and MD: mean [SE] β = -2.4 [0.6] × 10-6; for CBF and FA: mean [SE] β = 4.4 [1.1] × 10-4). Lower CBF values at baseline were also significantly associated with steeper regional decreases in FA or increases in MD in most brain regions investigated, including the frontal (for CBF and MD: mean [SE] β = -1.1 [0.6] × 10-6; for CBF and FA: mean [SE] β = 2.9 [1.0] × 10-4) and parietal lobes (for CBF and MD: mean [SE] β = -1.5 [0.7] × 10-6; for CBF and FA: mean [SE] β = 4.4 [1.1] × 10-4)., Conclusions and Relevance: Results of this longitudinal cohort study of the association between CBF and diffusion tensor imaging metrics suggest that blood flow may be significantly associated with brain tissue microstructure. This work may lay the foundation for investigations to clarify the nature of early brain damage in neurodegeneration. Such studies may lead to new neuroimaging biomarkers of brain microstructure and function for disease progression.
Published: 2022
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35. Association of the Gut Microbiota With Cognitive Function in Midlife.

Author: Meyer K, Lulla A, Debroy K, Shikany JM, Yaffe K, Meirelles O, and Launer LJ
Subjects: Age Factors, Alabama, California, Chicago, Cohort Studies, Cross-Sectional Studies, Female, Humans, Longitudinal Studies, Male, Middle Aged, Minnesota, Prospective Studies, Race Factors, Risk Factors, Socioeconomic Factors, Black or African American statistics & numerical data, Aging pathology, Cognition physiology, Gastrointestinal Microbiome physiology, White People statistics & numerical data
Abstract: Importance: Animal experiments and small clinical studies support a role for the gut microbiota in cognitive functioning. Few studies have investigated gut microbiota and cognition in large community samples., Objective: To examine associations of gut microbial composition with measures of cognition in an established population-based study of middle-aged adults., Design, Setting, and Participants: This cross-sectional study analyzed data from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) cohort in 4 US metropolitan centers between 2015 and 2016. Data were analyzed in 2019 and 2020., Exposures: Stool DNA were sequenced, and the following gut microbial measures were gathered: (1) β-diversity (between-person) derived with multivariate principal coordinates analysis; (2) α-diversity (within-person), defined as richness (genera count) and the Shannon index (integrative measure of genera richness and evenness); and (3) taxonomy (107 genera, after filtering)., Main Outcomes and Measures: Cognitive status was assessed using 6 clinic-administered cognitive tests: Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop, category fluency, and letter fluency. A global score measure derived using principal components analysis was also assessed; the first principal component explained 56% of variability., Results: Microbiome data were available on 597 CARDIA participants; mean (SD) age was 55.2 (3.5) years, 268 participants (44.7%) were men, and 270 (45.2%) were Black. In multivariable-adjusted principal coordinates analysis, permutational multivariate analysis of variance tests for β-diversity were statistically significant for all cognition measures (principal component analysis, P = .001; MoCA, P = .001; DSST, P = .001; RAVLT, P = .001; Stroop, P = .007; category fluency, P = .001) with the exception of letter fluency (P = .07). After adjusting for sociodemographic variables (age, race, sex, education), health behaviors (physical activity, diet, smoking, medication use), and clinical covariates (body mass index, diabetes, hypertension), Barnesiella was positively associated with the first principal component (β, 0.16; 95% CI, 0.08-0.24), DSST (β, 1.18; 95% CI, 0.35-2.00), and category fluency (β, 0.59; 95% CI, 0.31-0.87); Lachnospiraceae FCS020 group was positively associated with DSST (β, 2.67; 95% CI, 1.10-4.23), and Sutterella was negatively associated with MoCA (β, -0.27; 95% CI, -0.44 to -0.11)., Conclusions and Relevance: In this cross-sectional study, microbial community composition, based on β-diversity, was associated with all cognitive measures in multivariable-adjusted analysis. These data contribute to a growing body of literature suggesting that the gut microbiota may be associated with cognitive aging, but must be replicated in larger samples and further researched to identify relevant pathways.
Published: 2022
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36. Contributions of Cerebral Blood Flow to Associations Between Blood Pressure Levels and Cognition: The Age, Gene/Environment Susceptibility-Reykjavik Study.

Author: Moonen JE, Sabayan B, Sigurdsson S, van Buchem MA, Gudnason V, Meirelles O, and Launer LJ
Subjects: Age Factors, Aged, Aged, 80 and over, Brain diagnostic imaging, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Humans, Iceland, Magnetic Resonance Imaging, Male, Blood Pressure physiology, Brain physiopathology, Cerebrovascular Circulation physiology, Cognition physiology
Abstract: [Figure: see text].
Published: 2021
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37. Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

Author: Wolters FJ, Chibnik LB, Waziry R, Anderson R, Berr C, Beiser A, Bis JC, Blacker D, Bos D, Brayne C, Dartigues JF, Darweesh SKL, Davis-Plourde KL, de Wolf F, Debette S, Dufouil C, Fornage M, Goudsmit J, Grasset L, Gudnason V, Hadjichrysanthou C, Helmer C, Ikram MA, Ikram MK, Joas E, Kern S, Kuller LH, Launer L, Lopez OL, Matthews FE, McRae-McKee K, Meirelles O, Mosley TH Jr, Pase MP, Psaty BM, Satizabal CL, Seshadri S, Skoog I, Stephan BCM, Wetterberg H, Wong MM, Zettergren A, and Hofman A
Subjects: Age Distribution, Aged, Aged, 80 and over, Cohort Studies, Europe epidemiology, Female, Humans, Incidence, Male, Sex Distribution, United States epidemiology, Dementia epidemiology
Abstract: Objective: To determine changes in the incidence of dementia between 1988 and 2015., Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex., Results: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%])., Conclusion: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
Published: 2020
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38. Carotid Intima-Media Thickness and Markers of Brain Health in a Biracial Middle-Aged Cohort: CARDIA Brain MRI Sub-study.

Author: Cermakova P, Ding J, Meirelles O, Reis J, Religa D, Schreiner PJ, Jacobs DR, Bryan RN, and Launer LJ
Subjects: Black or African American statistics & numerical data, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Organ Size, United States, White Matter diagnostic imaging, White People statistics & numerical data, Brain diagnostic imaging, Carotid Intima-Media Thickness, Cerebrovascular Circulation, Magnetic Resonance Imaging
Abstract: Background: We investigated whether carotid intima-media thickness is associated with measures of cerebral blood flow (CBF), white matter hyperintensities, and brain volume in a biracial cohort of middle-aged individuals., Methods: We performed a cross-sectional cohort study based on data from a multicenter, population-based study Coronary Artery Risk Development in Young Adults. Using linear and logistic regression, we estimated the association of the composite intima-media thickness measured in three segments of carotid arteries (common carotid artery, carotid artery bulb, and internal carotid artery) with volume (cm3) and CBF (mL/100 g/min) in the total brain and gray matter as well as volume of white matter hyperintensities (cm3)., Results: In the analysis, 461 participants (54% women, 34% African Americans) were included. Greater intima-media thickness was associated with lower CBF in gray matter (β=-1.36; p = .04) and total brain (β=-1.26; p = .04), adjusting for age, sex, race, education, and total brain volume. The associations became statistically nonsignificant after further controlling for cardiovascular risk factors. Intima-media thickness was not associated with volumes of total brain, gray matter, and white matter hyperintensities., Conclusions: This study suggests that lower CBF in middle age is associated with markers of atherosclerosis in the carotid arteries. This association may reflect early long-term exposure to traditional cardiovascular risk factors. Early intervention on atherosclerotic risk factors may modulate the trajectory of CBF as people age and develop brain pathology., (Published by Oxford University Press on behalf of The Gerontological Society of America 2019.)
Published: 2020
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39. Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies.

Author: Ding J, Davis-Plourde KL, Sedaghat S, Tully PJ, Wang W, Phillips C, Pase MP, Himali JJ, Gwen Windham B, Griswold M, Gottesman R, Mosley TH, White L, Guðnason V, Debette S, Beiser AS, Seshadri S, Ikram MA, Meirelles O, Tzourio C, and Launer LJ
Subjects: Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Incidence, Male, Middle Aged, Observational Studies as Topic, Prospective Studies, Risk, Alzheimer Disease epidemiology, Antihypertensive Agents therapeutic use, Dementia epidemiology
Abstract: Background: Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia., Methods: We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses., Results: Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease., Interpretation: Over a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia., Funding: The Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
Published: 2020
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40. Assessment of multiphasic contrast-enhanced MR textures in differentiating small renal mass subtypes.

Author: Hoang UN, Mojdeh Mirmomen S, Meirelles O, Yao J, Merino M, Metwalli A, Marston Linehan W, and Malayeri AA
Subjects: Aged, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Retrospective Studies, Sensitivity and Specificity, Contrast Media, Image Enhancement methods, Kidney Neoplasms diagnostic imaging, Magnetic Resonance Imaging methods
Abstract: Purpose: This study seeks to evaluate the use of quantitative texture parameters extracted from multiphasic contrast-enhanced magnetic resonance (MR) imaging in differentiating between benign and malignant masses (oncocytoma vs. clear cell and papillary RCC) and between common subtypes of renal cell carcinoma (clear cell vs. papillary RCC) in small renal masses (< 4 cm)., Method: One-hundred and forty-two renal lesions (90 clear cell and 22 papillary RCCs; 30 oncocytomas) were identified in a cohort of 41 patients (18 men, 23 women: mean age, 52.8 ± 14.4 years) who underwent preoperative multiphasic contrast-enhanced MR with four phases (unenhanced, arterial, venous, and delayed) between 2015 and 2016. In this study, texture features were extracted from entire cross-sectional tumoral region in three consecutive slices containing the largest cross-sectional area from each of the four phases. The change in imaging feature between precontrast imaging and each postcontrast phase was calculated. Data dimension reduction and feature selection were performed by conducting (1) pairwise Wilcoxon rank test followed by modified false discovery rate adjustment, and (2) Lasso regression. Multivariate modeling incorporating the selected features was performed using random forest classification method., Results: Histogram imaging features were informative variables in differentiating between benign and malignant masses, while textures imaging features were of added value in differentiating between subtypes of RCCs. Papillary RCCs were distinguished from clear cell RCCs (sensitivity 65.5%, specificity 88%, and accuracy 77.9%), oncocytomas from clear cell RCCs (sensitivity 67.3%, specificity 88.9%, and accuracy 79.3%), and oncocytomas from papillary and clear cell RCCs (sensitivity 64.7%, specificity 85.9%, and accuracy 77.9%)., Conclusions: A combination of histogram and texture imaging features on multiphasic MR can help differentiate histologic cell types in common small renal masses (< 4 cm).
Published: 2018
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41. The AGES-Reykjavik Study suggests that change in kidney measures is associated with subclinical brain pathology in older community-dwelling persons.

Author: Sedaghat S, Ding J, Eiriksdottir G, van Buchem MA, Sigurdsson S, Ikram MA, Meirelles O, Gudnason V, Levey AS, and Launer LJ
Subjects: Aged, Albuminuria urine, Cerebral Small Vessel Diseases diagnosis, Creatinine urine, Disease Progression, Female, Follow-Up Studies, Glomerular Filtration Rate physiology, Humans, Incidence, Independent Living, Magnetic Resonance Imaging, Male, Prospective Studies, Renal Insufficiency, Chronic urine, Risk Factors, Serum Albumin, White Matter diagnostic imaging, Albuminuria physiopathology, Cerebral Small Vessel Diseases epidemiology, Kidney physiopathology, Renal Insufficiency, Chronic physiopathology, White Matter pathology
Abstract: Decreased glomerular filtration rate (GFR) and albuminuria may be accompanied by brain pathology. Here we investigated whether changes in these kidney measures are linked to development of new MRI-detected infarcts and microbleeds, and progression of white matter hyperintensity volume. The study included 2671 participants from the population-based AGES-Reykjavik Study (mean age 75, 58.7% women). GFR was estimated from serum creatinine, and albuminuria was assessed by urinary albumin-to-creatinine ratio. Brain MRI was acquired at baseline (2002-2006) and 5 years later (2007-2011). New MRI-detected infarcts and microbleeds were counted on the follow-up scans. White matter hyperintensity progression was estimated as percent change in white matter hyperintensity volumes between the two exams. Participants with a large eGFR decline (over 3 ml/min/1.73m 2 per year) had more incident subcortical infarcts (odds ratio 1.53; 95% confidence interval 1.05, 2.22), and more marked progression of white matter hyperintensity volume (difference: 8%; 95% confidence interval: 4%, 12%), compared to participants without a large decline. Participants with incident albuminuria (over 30 mg/g) had 21% more white matter hyperintensity volume progression (95% confidence interval: 14%, 29%) and 1.86 higher odds of developing new deep microbleeds (95% confidence interval 1.16, 2.98), compared to participants without incident albuminuria. The findings were independent of cardiovascular risk factors. Changes in kidney measures were not associated with occurrence of cortical infarcts. Thus, larger changes in eGFR and albuminuria are associated with increased risk for developing manifestations of cerebral small vessel disease. Individuals with larger changes in these kidney measures should be considered as a high risk population for accelerated brain pathology., (Copyright © 2018 International Society of Nephrology. All rights reserved.)
Published: 2018
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42. N-Terminal pro-Brain Natriuretic Peptide and Associations With Brain Magnetic Resonance Imaging (MRI) Features in Middle Age: The CARDIA Brain MRI Study.

Author: Ferguson IT, Elbejjani M, Sabayan B, Jacobs DR Jr, Meirelles O, Sanchez OA, Tracy R, Bryan N, and Launer LJ
Abstract: Objective: As part of research on the heart-brain axis, we investigated the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with brain structure and function in a community-based cohort of middle-aged adults from the Brain Magnetic Resonance Imaging sub-study of the Coronary Artery Risk Development in Young Adults (CARDIA) Study., Approach and Results: In a cohort of 634 community-dwelling adults with a mean (range) age of 50.4 (46-52) years, we examined the cross-sectional association of NT-proBNP to total, gray (GM) and white matter (WM) volumes, abnormal WM load and WM integrity, and to cognitive function tests [the Digit Symbol Substitution Test (DSST), the Stroop test, and the Rey Auditory-Verbal Learning Test]. These associations were examined using linear regression models adjusted for demographic and cardiovascular risk factors and cardiac output. Higher NT-proBNP concentration was significantly associated with smaller GM volume (β = -3.44; 95% CI = -5.32, -0.53; p = 0.003), even after additionally adjusting for cardiac output (β = -2.93; 95% CI = -5.32, -0.53; p = 0.017). Higher NT-proBNP levels were also associated with lower DSST scores. NT-proBNP was not related to WM volume, WM integrity, or abnormal WM load., Conclusion: In this middle-aged cohort, subclinical levels of NT-proBNP were related to brain function and specifically to GM and not WM measures, extending similar findings in older cohorts. Further research is warranted into biomarkers of cardiac dysfunction as a target for early markers of a brain at risk.
Published: 2018
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43. White matter microstructure, white matter lesions, and hypertension: An examination of early surrogate markers of vascular-related brain change in midlife.

Author: Haight T, Nick Bryan R, Erus G, Hsieh MK, Davatzikos C, Nasrallah I, D'Esposito M, Jacobs DR Jr, Lewis C, Schreiner P, Sidney S, Meirelles O, and Launer LJ
Subjects: Adult, Diffusion Tensor Imaging, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Brain diagnostic imaging, Cerebrovascular Disorders diagnostic imaging, White Matter diagnostic imaging
Abstract: Objective: We examined imaging surrogates of white matter microstructural abnormalities which may precede white matter lesions (WML) and represent a relevant marker of cerebrovascular injury in adults in midlife., Methods: In 698 community-dwelling adults (mean age 50 years ±3.5 SD) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study, WML were identified on structural MR and fractional anisotropy (FA), representing WM microstructural integrity, was derived using Diffusion Tensor Imaging. FA and WML maps were overlaid on a parcellated T1-template, based on an expert-delineated brain atlas, which included 42 WM tract ROIs. Analyses occurred in stages: 1) WML were quantified for the different tracts (i.e., frequency, volume, volume relative to tract size); 2) the interdependence of FA in normal appearing WM (NAWM) and WML was examined across tracts; 3) associations of NAWM FA and hypertension status were assessed controlling for WML volume. In the latter analysis, both overall hypertension (i.e. hypertension vs. normotension and prehypertension vs. normotension) and hypertension categorized by antihypertensive treatment status (yes/no) and blood pressure control (e.g., diastolic <90 mmHg, systolic <140 mmHg), were assessed., Results: WML were widely distributed across different WM tracts, however, WML volume was small. Mean NAWM FA was lower in participants with vs. participants without WML in given tracts. Hypertension was significantly associated with lower mean NAWM FA globally across tracts, both before and after adjustment for WML volume. Moreover, the magnitude of this association differed by treatment status and the level of control of the hypertension., Conclusions: In middle-aged adults, NAWM FA could represent a relevant marker of cerebrovascular injury when WML are minimally present.
Published: 2018
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44. Associations of plasma clusterin and Alzheimer's disease-related MRI markers in adults at mid-life: The CARDIA Brain MRI sub-study.

Author: Haight T, Bryan RN, Meirelles O, Tracy R, Fornage M, Richard M, Nasrallah I, Yaffe K, Jacobs DR Jr, Lewis C, Schreiner P, Sidney S, Davatzikos C, and Launer LJ
Subjects: Alzheimer Disease diagnostic imaging, Alzheimer Disease genetics, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Alzheimer Disease blood, Biomarkers blood, Clusterin blood, Magnetic Resonance Imaging methods
Abstract: Background: Clinical and epidemiological studies of older persons have implicated clusterin in Alzheimer's disease (AD) pathogenesis. In the context of identifying early biomarkers of risk, we examined associations of plasma clusterin and characteristics of AD in middle-aged individuals from the community., Materials and Methods: Subjects were 639 cognitively normal individuals (mean age 50 ± 3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Clusterin was quantified using ELISA (mean 255± 31 ng/ml). Associations were assessed between clusterin and volumes of brain regions known to atrophy in early AD, including entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and volumes of structures affected in later AD were examined for comparison., Results: In multivariable models, higher clusterin had a negative non-linear association with ECV (combined left and right hemispheres), and this association was influenced by the highest clusterin levels. Compared to mean clusterin, 1 and 2 standard deviation (SD) level increases in clusterin were associated with -2.1% (95% CI: -3.3,-0.9) and -7.3% (95% CI: -11.3,-3.3) lower ECV, respectively. Similar relationships were observed between clusterin and HV, although the relationship was stronger for left-side HV than the right-side. However, the association was not significant after adjusting for covariates. Negative non-linear associations between clusterin and MTLV were strongest for the left side: compared to mean clusterin, 1 and 2 SD level increases in clusterin were associated with -0.9% (95% CI: -1.9, 0.1) and -3.7% (95% CI: -7.1, -0.3) lower MTLV. There were no significant associations between clusterin and brain structures affected in later AD., Conclusions: In middle-aged adults unselected for AD, plasma clusterin was associated with lower volume of the entorhinal cortex, an area that atrophies early in AD. Clusterin could be informative as part of a multi-component preclinical marker for AD.
Published: 2018
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45. Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium.

Author: Chibnik LB, Wolters FJ, Bäckman K, Beiser A, Berr C, Bis JC, Boerwinkle E, Bos D, Brayne C, Dartigues JF, Darweesh SKL, Debette S, Davis-Plourde KL, Dufouil C, Fornage M, Grasset L, Gudnason V, Hadjichrysanthou C, Helmer C, Ikram MA, Ikram MK, Kern S, Kuller LH, Launer L, Lopez OL, Matthews F, Meirelles O, Mosley T, Ower A, Psaty BM, Satizabal CL, Seshadri S, Skoog I, Stephan BCM, Tzourio C, Waziry R, Wong MM, Zettergren A, and Hofman A
Subjects: Aged, Aged, 80 and over, Alzheimer Disease diagnosis, Alzheimer Disease genetics, Cohort Studies, Dementia diagnosis, Dementia genetics, Female, Humans, Incidence, Male, Population Surveillance, Proportional Hazards Models, Prospective Studies, Alzheimer Disease epidemiology, Dementia epidemiology, Gene-Environment Interaction
Abstract: Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
Published: 2017
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46. Metabolites Associated With Lean Mass and Adiposity in Older Black Men.

Author: Murphy RA, Moore SC, Playdon M, Meirelles O, Newman AB, Milijkovic I, Kritchevsky SB, Schwartz A, Goodpaster BH, Sampson J, Cawthon P, Simonsick EM, Gerszten RE, Clish CB, and Harris TB
Subjects: Absorptiometry, Photon, Aged, Body Fat Distribution, Body Mass Index, Body Weight, Female, Humans, Longitudinal Studies, Male, Medicare, Prospective Studies, United States, Adiposity, Black or African American, Body Constitution, Metabolomics methods
Abstract: To identify biomarkers of body mass index, body fat, trunk fat, and appendicular lean mass, nontargeted metabolomics was performed in plasma from 319 black men in the Health, Aging and Body Composition study (median age 72 years, median body mass index 26.8 kg/m2). Body mass index was calculated from measured height and weight; percent fat, percent trunk fat, and appendicular lean mass were measured with dual-energy x-ray absorptiometry. Pearson partial correlations between body composition measures and metabolites were adjusted for age, study site, and smoking. Out of 350 metabolites, body mass index, percent fat, percent trunk fat, and appendicular lean mass were significantly correlated with 92, 48, 96, and 43 metabolites at p less than .0014. Metabolites most strongly correlated with body composition included carnitine, a marker of fatty acid oxidation (positively correlated), triacylglycerols (positively correlated), and amino acids including branched-chain amino acids (positively correlated except for acetylglycine and serine). Gaussian Graphical Models of metabolites found that 25 lipid metabolites clustered into a single network. Groups of five amino acids, three plasmalogens, and two carnitines were also observed. Findings confirm prior reports of associations between amino acids, lean mass, and fat mass in addition to associations not previously reported. Future studies should consider whether these metabolites are relevant for metabolic disease processes., (Published by Oxford University Press on behalf of The Gerontological Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
Published: 2017
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47. Proximal Femur Volumetric Bone Mineral Density and Mortality: 13 Years of Follow-Up of the AGES-Reykjavik Study.

Author: Marques EA, Elbejjani M, Gudnason V, Sigurdsson G, Lang T, Sigurdsson S, Aspelund T, Meirelles O, Siggeirsdottir K, Launer L, Eiriksdottir G, and Harris TB
Subjects: Aged, Bone Resorption mortality, Bone Resorption pathology, Bone Resorption physiopathology, Cancellous Bone pathology, Cancellous Bone physiopathology, Cortical Bone pathology, Cortical Bone physiopathology, Demography, Female, Follow-Up Studies, Humans, Male, Organ Size, Risk Factors, Bone Density physiology, Femur pathology, Femur physiopathology, Mortality
Abstract: Bone mineral density (BMD) has been linked to mortality, but little is known about the independent contribution of each endosteal bone compartment and also the rate of bone loss to risk of mortality. We examined the relationships between (1) baseline trabecular and cortical volumetric BMD (vBMD) at the proximal femur, and (2) the rate of trabecular and cortical bone loss and all-cause mortality in older adults from the AGES-Reykjavik study. The analysis of trabecular and cortical vBMD and mortality was based on the baseline cohort of 4654 participants (aged ≥66 years) with a median follow-up of 9.4 years; the association between rate of bone loss and mortality was based on 2653 participants with bone loss data (median follow-up of 5.6 years). Analyses employed multivariable Cox-proportional models to estimate hazard ratios (HRs) with time-varying fracture status; trabecular and cortical variables were included together in all models. Adjusted for important confounders, Cox models showed that participants in the lowest quartile of trabecular vBMD had an increased risk of mortality compared to participants in other quartiles (HR = 1.12; 95% confidence interval (CI), 1.01 to 1.25); baseline cortical vBMD was not related to mortality (HR = 1.08; 95% CI, 0.97 to 1.20). After adjustment for time-dependent fracture status, results were attenuated and not statistically significant. A faster loss (quartile 1 versus quartiles 2-4) in both trabecular and cortical bone was associated with higher mortality risk (HR = 1.37 and 1.33, respectively); these associations were independent of major potential confounders including time-dependent incident fractures (HR = 1.32 and 1.34, respectively). Overall, data suggest that faster bone losses over time in both the trabecular and cortical bone compartments are associated with mortality risk and that measurements of change in bone health may be more informative than single-point measurements in explaining mortality differences in older adults. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)
Published: 2017
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48. Space and location of cerebral microbleeds, cognitive decline, and dementia in the community.

Author: Ding J, Sigurðsson S, Jónsson PV, Eiriksdottir G, Meirelles O, Kjartansson O, Lopez OL, van Buchem MA, Gudnason V, and Launer LJ
Subjects: Aged, Aged, 80 and over, Brain diagnostic imaging, Executive Function, Female, Follow-Up Studies, Humans, Iceland, Incidence, Linear Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Memory, Multivariate Analysis, Neuropsychological Tests, Prevalence, Sensitivity and Specificity, Cerebral Hemorrhage diagnostic imaging, Cerebral Hemorrhage epidemiology, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction epidemiology, Dementia diagnostic imaging, Dementia epidemiology
Abstract: Objective: To assess the association of the number and anatomic location of cerebral microbleeds (CMBs), visible indicators of microvascular damage on MRI, with incident cognitive disease in the general population of older people., Methods: In the longitudinal population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, 2,602 participants 66 to 93 years of age and free of prevalent dementia underwent brain MRI and cognitive testing of verbal memory, processing speed, and executive function at baseline and a mean of 5.2 years later. Adjudicated incident dementia cases were diagnosed according to international guidelines., Results: In the multiple linear regression models adjusted for demographic, genetic, cardiovascular risk, and other cerebrovascular MRI markers, the presence of CMBs located in deep or mixed (deep and lobar) areas was associated with a greater decline in all 3 cognitive domains. Mixed CMBs were the strongest correlate for decline in memory and speed. Compared to those with no CMBs, participants with ≥3 CMBs had a steeper decline in a composite measure of global cognitive function, memory, and speed. Among those with ≥3 deep or mixed CMBs, associations were strongest for memory; the association with speed was strongest in those having ≥3 strictly lobar CMBs. People with ≥3 CMBs, regardless of their locations, had a higher incidence of all-cause dementia and vascular dementia., Conclusions: Mixed or a higher load of CMBs, with some specificity for location, is associated with accelerated cognitive decline in older people. These findings suggest a role for hypertensive vasculopathy and the combined effect of hypertensive and cerebral amyloid angiopathy in the pathogenesis of cognitive deterioration., (© 2017 American Academy of Neurology.)
Published: 2017
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49. Association of Serum Klotho with Loss of Bone Mineral Density and Fracture Risk in Older Adults.

Author: Chalhoub D, Marques E, Meirelles O, Semba RD, Ferrucci L, Satterfield S, Nevitt M, Cauley JA, and Harris T
Subjects: Absorptiometry, Photon, Aged, Biomarkers blood, Female, Geriatric Assessment, Humans, Incidence, Klotho Proteins, Longitudinal Studies, Male, Phenotype, Risk Assessment, Risk Factors, United States, Bone Density, Fractures, Bone epidemiology, Glucuronidase blood
Abstract: Objectives: Klotho deficiency has been previously linked to aging-like phenotypes such as osteoporosis, cognitive impairment, and sarcopenia. Low serum klotho was shown to be related to grip strength and disability. Nonetheless, no previous study has explored the association between serum klotho and fractures. The purpose of this report is to examine the relationship of serum klotho with bone mineral density (BMD) loss and fractures in older adults., Design: The Health, Aging, and Body Composition (Health ABC) Study is a longitudinal cohort study of 3,075 community-dwelling older adults., Setting: US clinical centers., Participants: Two thousand seven hundred and seventy six well-functioning black and white adults aged 70 to 79 years with serum klotho measurements were followed up for a median of 5 years., Measurements: Percent annualized BMD change and fracture risk were compared across klotho quartiles. A Poisson distribution was used to calculate age-adjusted fracture incidence rates, and Cox proportional hazards models for multivariable-adjusted hazard ratios., Results: The annualized percent changes in hip, femoral neck, and vertebral BMD were similar across klotho quartiles. Participants experienced 507 nonspine fractures, 203 hip fractures, and 135 vertebral fractures. The Incidence rate (IR) of nonspine fractures was 17 per 1,000 person-years. The most frequent site was hip (IR = 6 per 1,000 person-years) and the IR of vertebral fractures was 3 per 1,000 person-years. There was no association between the lowest quartile of plasma klotho and nonspine (hazard ratio (HR) = 1.19, 95% confidence interval (CI) = 0.86-1.65), hip (HR = 1.34, 95% CI = 0.79-2.27), or vertebral fractures (HR = 1.17, 95% CI = 0.65-2.11)., Conclusion: Although klotho gene is a susceptible gene for reduced BMD, klotho blood concentration does not appear to be a predictor of bone loss or fracture risk in well-functioning older adults., Competing Interests: Authors do not have conflicts of interests or disclosures to make., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)
Published: 2016
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50. Cardiac and Carotid Markers Link With Accelerated Brain Atrophy: The AGES-Reykjavik Study (Age, Gene/Environment Susceptibility-Reykjavik).

Author: Sabayan B, van Buchem MA, Sigurdsson S, Zhang Q, Meirelles O, Harris TB, Gudnason V, Arai AE, and Launer LJ
Subjects: Age Factors, Aged, Atrophy, Biomarkers blood, Carotid Artery Diseases epidemiology, Carotid Artery Diseases genetics, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Heart Diseases blood, Heart Diseases epidemiology, Heart Diseases genetics, Humans, Iceland epidemiology, Leukoencephalopathies diagnostic imaging, Leukoencephalopathies genetics, Longitudinal Studies, Male, Predictive Value of Tests, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, Brain diagnostic imaging, Carotid Artery Diseases diagnostic imaging, Carotid Intima-Media Thickness, Heart Diseases diagnosis, Leukoencephalopathies epidemiology, Magnetic Resonance Imaging, Natriuretic Peptide, Brain blood, Peptide Fragments blood
Abstract: Objective: Pathologies in the heart-brain axis might, independently or in combination, accelerate the process of brain parenchymal loss. We aimed to investigate the association of serum N-terminal brain natriuretic peptide (NT-proBNP), as a marker of cardiac dysfunction, and carotid intima media thickness (CIMT), as a marker of carotid atherosclerosis burden, with structural brain changes., Approach and Results: In the longitudinal population-based AGES-Reykjavik study (Age, Gene/Environment Susceptibility-Reykjavik), we included 2430 subjects (mean age, 74.6 years; 41.4% men) with baseline data on NT-proBNP and CITM (assessed by ultrasound imaging). Participants underwent a high-resolution brain magnetic resonance imaging at baseline and 5 years later to assess total brain (TBV), gray matter, and white matter volumes. Each unit higher log-transformed NT-proBNP was associated with 3.6 mL (95% confidence interval [CI], -6.0 to -1.1) decline in TBV and 3.5 mL (95% CI, -5.7 to -1.3) decline in gray matter volume. Likewise, each millimeter higher CIMT was associated with 10.8 mL (95% CI, -17.3 to -4.2) decline in TBV and 8.6 mL (95% CI, -14.4 to -2.8) decline in gray matter volume. There was no association between NT-proBNP and CIMT and changes in white matter volume. Compared with participants with low NT-proBNP and CIMT, participants with both high NT-proBNP and CIMT had 3.8 mL (95% CI, -6.0 to -1.6) greater decline in their TBV and 4 mL (95% CI, -6.0 to -2.0) greater decline in GMW. These associations were independent of sociodemographic and cardiovascular factors., Conclusions: Older subjects with both cardiac dysfunction and carotid atherosclerosis are at an increased risk for brain parenchymal loss. Accumulated pathologies in the heart-brain axis might accelerate brain atrophy., (© 2016 American Heart Association, Inc.)
Published: 2016
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