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1. Physical activity derived from questionnaires and wrist-worn accelerometers: comparability and the role of demographic, lifestyle, and health factors among a population-based sample of older adults

Author

Koolhaas CM, van Rooij FJA, Cepeda M, Tiemeier H, Franco OH, and Schoufour JD

Subjects
Physical activity, questionnaire, accelerometer, disagreement, elderly, Infectious and parasitic diseases, RC109-216
Abstract

Chantal M Koolhaas,1 Frank JA van Rooij,1 Magda Cepeda,1 Henning Tiemeier,1–3 Oscar H Franco,1 Josje D Schoufour1 1Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands; 3Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands Background: Agreement between questionnaires and accelerometers to measure physical activity (PA) differs between studies and might be related to demographic, lifestyle, and health characteristics, including disability and depressive symptoms.Methods: We included 1,410 individuals aged 51–94 years from the population-based Rotterdam Study. Participants completed the LASA Physical Activity Questionnaire and wore a wrist-worn accelerometer on the nondominant wrist for 1 week thereafter. We compared the Spearman correlation and disagreement (level and direction) for total PA across levels of demographic, lifestyle, and health variables. The level of disagreement was defined as the absolute difference between questionnaire- and accelerometer-derived PA, whereas the direction of disagreement was defined as questionnaire PA minus accelerometer PA. We used linear regression analyses with the level and direction of disagreement as outcome, including all demographic, lifestyle, and health variables in the model.Results: We observed a Spearman correlation of 0.30 between questionnaire- and accelerometer-derived PA in the total population. The level of disagreement (ie, absolute difference) was 941.9 (standard deviation [SD] 747.0) minutes/week, and the PA reported by questionnaire was on average 529.4 (SD 1,079.5) minutes/week lower than PA obtained by the accelerometer. The level of disagreement decreased with higher educational levels. Additionally, participants with obesity, higher disability scores, and more depressive symptoms underestimated their self-reported PA more than their healthier counterparts.Conclusion: We observed large differences in PA time derived from the LASA Physical Activity Questionnaire and the wrist-worn accelerometer. Differences between the methods were related to body-mass index, level of disability, and presence of depressive symptoms. Future studies using questionnaires and/or accelerometers should account for these differences. Keywords: physical activity, questionnaire, accelerometer, disagreement, elderly

Published
2017

2. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author

Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Richmond, Rebecca C., Teumer, Alexander, Zhao, Jing Hua, Zhao, Wei, Uitterlinden, Andre G., Zillikens, M. Carola, Hansen, Torben, van der Velde, Nathalie, van Duijn, Cornelia M., Voortman, Trudy, van Rooij, FJA, Franco Duran, Oscar, Loos, Ruth J.F., den Hoed, M, Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Richmond, Rebecca C., Teumer, Alexander, Zhao, Jing Hua, Zhao, Wei, Uitterlinden, Andre G., Zillikens, M. Carola, Hansen, Torben, van der Velde, Nathalie, van Duijn, Cornelia M., Voortman, Trudy, van Rooij, FJA, Franco Duran, Oscar, Loos, Ruth J.F., and den Hoed, M

Abstract

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Published
2022

4. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Vuckovic, D, Bao, EL, Akbari, P, Lareau, CA, Mousas, A, Jiang, T, Chen, M-H, Raffield, LM, Tardaguila, M, Huffman, JE, Ritchie, SC, Megy, K, Ponstingl, H, Penkett, CJ, Albers, PK, Wigdor, EM, Sakaue, S, Moscati, A, Manansala, R, Lo, KS, Qian, H, Akiyama, M, Bartz, TM, Ben-Shlomo, Y, Beswick, A, Bork-Jensen, J, Bottinger, EP, Brody, JA, van Rooij, FJA, Chitrala, KN, Wilson, PWF, Choquet, H, Danesh, J, Di Angelantonio, E, Dimou, N, Ding, J, Elliott, P, Esko, T, Evans, MK, Felix, SB, Floyd, JS, Broer, L, Grarup, N, Guo, MH, Guo, Q, Greinacher, A, Haessler, J, Hansen, T, Howson, JMM, Huang, W, Jorgenson, E, Kacprowski, T, Kahonen, M, Kamatani, Y, Kanai, M, Karthikeyan, S, Koskeridis, F, Lange, LA, Lehtimaki, T, Linneberg, A, Liu, Y, Lyytikainen, L-P, Manichaikul, A, Matsuda, K, Mohlke, KL, Mononen, N, Murakami, Y, Nadkarni, GN, Nikus, K, Pankratz, N, Pedersen, O, Preuss, M, Psaty, BM, Raitakari, OT, Rich, SS, Rodriguez, BAT, Rosen, JD, Rotter, JI, Schubert, P, Spracklen, CN, Surendran, P, Tang, H, Tardif, J-C, Ghanbari, M, Volker, U, Volzke, H, Watkins, NA, Weiss, S, Cai, N, Kundu, K, Watt, SB, Walter, K, Zonderman, AB, Cho, K, Li, Y, Loos, RJF, Knight, JC, Georges, M, Stegle, O, Evangelou, E, Okada, Y, Roberts, DJ, Inouye, M, Johnson, AD, Auer, PL, Astle, WJ, Reiner, AP, Butterworth, AS, Ouwehand, WH, Lettre, G, Sankaran, VG, Soranzo, N, Vuckovic, D, Bao, EL, Akbari, P, Lareau, CA, Mousas, A, Jiang, T, Chen, M-H, Raffield, LM, Tardaguila, M, Huffman, JE, Ritchie, SC, Megy, K, Ponstingl, H, Penkett, CJ, Albers, PK, Wigdor, EM, Sakaue, S, Moscati, A, Manansala, R, Lo, KS, Qian, H, Akiyama, M, Bartz, TM, Ben-Shlomo, Y, Beswick, A, Bork-Jensen, J, Bottinger, EP, Brody, JA, van Rooij, FJA, Chitrala, KN, Wilson, PWF, Choquet, H, Danesh, J, Di Angelantonio, E, Dimou, N, Ding, J, Elliott, P, Esko, T, Evans, MK, Felix, SB, Floyd, JS, Broer, L, Grarup, N, Guo, MH, Guo, Q, Greinacher, A, Haessler, J, Hansen, T, Howson, JMM, Huang, W, Jorgenson, E, Kacprowski, T, Kahonen, M, Kamatani, Y, Kanai, M, Karthikeyan, S, Koskeridis, F, Lange, LA, Lehtimaki, T, Linneberg, A, Liu, Y, Lyytikainen, L-P, Manichaikul, A, Matsuda, K, Mohlke, KL, Mononen, N, Murakami, Y, Nadkarni, GN, Nikus, K, Pankratz, N, Pedersen, O, Preuss, M, Psaty, BM, Raitakari, OT, Rich, SS, Rodriguez, BAT, Rosen, JD, Rotter, JI, Schubert, P, Spracklen, CN, Surendran, P, Tang, H, Tardif, J-C, Ghanbari, M, Volker, U, Volzke, H, Watkins, NA, Weiss, S, Cai, N, Kundu, K, Watt, SB, Walter, K, Zonderman, AB, Cho, K, Li, Y, Loos, RJF, Knight, JC, Georges, M, Stegle, O, Evangelou, E, Okada, Y, Roberts, DJ, Inouye, M, Johnson, AD, Auer, PL, Astle, WJ, Reiner, AP, Butterworth, AS, Ouwehand, WH, Lettre, G, Sankaran, VG, and Soranzo, N

Abstract

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Published
2020

5. Macronutrient intake and frailty: the Rotterdam Study

Author

Verspoor, Eline, Voortman, Trudy, van Rooij, FJA, Rivadeneira, Fernando, Franco Duran, OH, Jong, Jessica, Schoufour, Josje, Verspoor, Eline, Voortman, Trudy, van Rooij, FJA, Rivadeneira, Fernando, Franco Duran, OH, Jong, Jessica, and Schoufour, Josje

Published
2020

6. Objectives, design and main findings until 2020 from the Rotterdam Study

Author

Ikram, Arfan, Brusselle, Guy, Ghanbari, Mohsen, Goedegebure, André, Ikram, Kamran, Kavousi, Maryam, Leening - Kieboom, Brenda, Klaver, Caroline, de Knegt, Rob, Luik, Annemarie, Nijsten, Tamar, Peeters, Robin, van Rooij, FJA, Stricker, Bruno, Uitterlinden, André, Vernooij, Meike, Voortman, Trudy, Ikram, Arfan, Brusselle, Guy, Ghanbari, Mohsen, Goedegebure, André, Ikram, Kamran, Kavousi, Maryam, Leening - Kieboom, Brenda, Klaver, Caroline, de Knegt, Rob, Luik, Annemarie, Nijsten, Tamar, Peeters, Robin, van Rooij, FJA, Stricker, Bruno, Uitterlinden, André, Vernooij, Meike, and Voortman, Trudy

Published
2020

8. Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study

Author

Universitat Rovira i Virgili, Huang T, Wang T, Zheng Y, Ellervik C, Li X, Gao M, Fang Z, Chai JF, Ahluwalia TVS, Wang Y, Voortman T, Noordam R, Frazier-Wood A, Scholz M, Sonestedt E, Akiyama M, Dorajoo R, Zhou A, Kilpeläinen TO, Kleber ME, Crozier SR, Godfrey KM, Lemaitre R, Felix JF, Shi Y, Gupta P, Khor CC, Lehtimäki T, Wang CA, Tiesler CMT, Thiering E, Standl M, Rzehak P, Marouli E, He M, Lecoeur C, Corella D, Lai CQ, Moreno LA, Pitkänen N, Boreham CA, Zhang T, Saw SM, Ridker PM, Graff M, van Rooij FJA, Uitterlinden AG, Hofman A, van Heemst D, Rosendaal FR, de Mutsert R, Burkhardt R, Schulz CA, Ericson U, Kamatani Y, Yuan JM, Power C, Hansen T, Sørensen TIA, Tjønneland A, Overvad K, Delgado G, Cooper C, Djousse L, Rivadeneira F, Jameson K, Zhao W, Liu J, Lee NR, Raitakari O, Kähönen M, Viikari J, Grote V, Langhendries JP, Koletzko B, Escribano J, Verduci E, Dedoussis G, Yu C, Tham YC, Lim B, Lim SH, Froguel P, Balkau B, Fink NR, Vinding RK, Sevelsted A, Bisgaard H, Coltell O, Dallongeville J, Gottrand F, Pahkala K, Niinikoski H, Hyppönen E, Pedersen O, März W, Inskip H, Jaddoe VWV, Dennison E, Wong TY, Sabanayagam C, Tai ES, Mohlke KL, Mackey DA, Gruszfeld D, Deloukas P, Tucker KL, Fumeron F, Bønnelykke K, Rossing P, Estruch R, Ordovas JM, Arnett DK, Meirhaeghe A, Amouyel P, Cheng CY, Sim X, Teo YY, van Dam RM, Koh WP, Orho-Melander M, Loeffler M, Kubo M, Thiery J, Mook-Kanamori DO, Mozaffarian D, Psaty BM, Franco OH, Wu T, North KE, Davey Smith G, Chavarro JE, Chasman DI, Qi L BIRTH-GENE (BIG) Study Working Group, Universitat Rovira i Virgili, and Huang T, Wang T, Zheng Y, Ellervik C, Li X, Gao M, Fang Z, Chai JF, Ahluwalia TVS, Wang Y, Voortman T, Noordam R, Frazier-Wood A, Scholz M, Sonestedt E, Akiyama M, Dorajoo R, Zhou A, Kilpeläinen TO, Kleber ME, Crozier SR, Godfrey KM, Lemaitre R, Felix JF, Shi Y, Gupta P, Khor CC, Lehtimäki T, Wang CA, Tiesler CMT, Thiering E, Standl M, Rzehak P, Marouli E, He M, Lecoeur C, Corella D, Lai CQ, Moreno LA, Pitkänen N, Boreham CA, Zhang T, Saw SM, Ridker PM, Graff M, van Rooij FJA, Uitterlinden AG, Hofman A, van Heemst D, Rosendaal FR, de Mutsert R, Burkhardt R, Schulz CA, Ericson U, Kamatani Y, Yuan JM, Power C, Hansen T, Sørensen TIA, Tjønneland A, Overvad K, Delgado G, Cooper C, Djousse L, Rivadeneira F, Jameson K, Zhao W, Liu J, Lee NR, Raitakari O, Kähönen M, Viikari J, Grote V, Langhendries JP, Koletzko B, Escribano J, Verduci E, Dedoussis G, Yu C, Tham YC, Lim B, Lim SH, Froguel P, Balkau B, Fink NR, Vinding RK, Sevelsted A, Bisgaard H, Coltell O, Dallongeville J, Gottrand F, Pahkala K, Niinikoski H, Hyppönen E, Pedersen O, März W, Inskip H, Jaddoe VWV, Dennison E, Wong TY, Sabanayagam C, Tai ES, Mohlke KL, Mackey DA, Gruszfeld D, Deloukas P, Tucker KL, Fumeron F, Bønnelykke K, Rossing P, Estruch R, Ordovas JM, Arnett DK, Meirhaeghe A, Amouyel P, Cheng CY, Sim X, Teo YY, van Dam RM, Koh WP, Orho-Melander M, Loeffler M, Kubo M, Thiery J, Mook-Kanamori DO, Mozaffarian D, Psaty BM, Franco OH, Wu T, North KE, Davey Smith G, Chavarro JE, Chasman DI, Qi L BIRTH-GENE (BIG) Study Working Group

Abstract

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose

Published
2019

11. Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

Author

Huckins, LM, Hatzikotoulas, K, Southam, L, Thornton, LM, Steinberg, J, Aguilera-McKay, F, Treasure, J, Schmidt, U, Gunasinghe, C, Romero, A, Curtis, C, Rhodes, D, Moens, J, Kalsi, G, Dempster, D, Leung, R, Keohane, A, Burghardt, R, Ehrlich, S, Hebebrand, J, Hinney, A, Ludolph, A, Walton, E, Deloukas, P, Hofman, Bert, Palotie, A, Palta, P, van Rooij, FJA, Stirrups, K, Adan, R, Boni, C, Cone, R, Dedoussis, G, Van Furth, E, Gonidakis, F, Gorwood, P, Hudson, J, Kaprio, J, Kas, M, Keski-Rahonen, A, Kiezebrink, K, Knudsen, GP, Slof-Op 't Landt, MCT, Maj, M, Monteleone, A M, Monteleone, P, Raevuori, AH, Reichborn-Kjennerud, T, Tozzi, F, Tsitsika, A, van Elburg, A, Collier, DA, Sullivan, PF, Breen, G, Bulik, CM, Zeggini, E, Huckins, LM, Hatzikotoulas, K, Southam, L, Thornton, LM, Steinberg, J, Aguilera-McKay, F, Treasure, J, Schmidt, U, Gunasinghe, C, Romero, A, Curtis, C, Rhodes, D, Moens, J, Kalsi, G, Dempster, D, Leung, R, Keohane, A, Burghardt, R, Ehrlich, S, Hebebrand, J, Hinney, A, Ludolph, A, Walton, E, Deloukas, P, Hofman, Bert, Palotie, A, Palta, P, van Rooij, FJA, Stirrups, K, Adan, R, Boni, C, Cone, R, Dedoussis, G, Van Furth, E, Gonidakis, F, Gorwood, P, Hudson, J, Kaprio, J, Kas, M, Keski-Rahonen, A, Kiezebrink, K, Knudsen, GP, Slof-Op 't Landt, MCT, Maj, M, Monteleone, A M, Monteleone, P, Raevuori, AH, Reichborn-Kjennerud, T, Tozzi, F, Tsitsika, A, van Elburg, A, Collier, DA, Sullivan, PF, Breen, G, Bulik, CM, and Zeggini, E

Published
2018

13. Genome-wide association meta-analysis of fish and EPA plus DHA consumption in 17 US and European cohorts

Author

Mozaffarian, D, Dashti, HS, Wojczynski, MK, Chu, AY, Nettleton, JA, Mannisto, S, Kristiansson, K, Reedik, M, Lahti, J, Houston, DK, Cornelis, MC, van Rooij, FJA, Dimitriou, M, Kanoni, S, Mikkila, V, Steffen, LM, Otto, MCD, Qi, L, Psaty, B, Djousse, L, Rotter, JI, Harald, K, Perola, M, Rissanen, H, Jula, A, Krista, F, Mihailov, E, Feitosa, MF, Ngwa, JS, Xue, LT, Jacques, PF, Perala, MM, Palotie, A, Liu, YM, Nalls, NA, Ferrucci, L, Hernandez, D, Manichaikul, A, Tsai, MY, Jong, Jan, Hofman, Bert, Uitterlinden, André, Rallidis, L, Ridker, PM, Rose, LM, Buring, JE, Lehtimaki, T, Kahonen, M, Viikari, J, Lemaitre, R, Salomaa, V, Knekt, P, Metspalu, A, Borecki, IB, Cupples, LA, Eriksson, JG, Kritchevsky, SB, Bandinelli, S, Siscovick, D, Franco Duran, OH, Deloukas, P, Dedoussis, G, Chasman, DI, Raitakari, O, Tanaka, T, Mozaffarian, D, Dashti, HS, Wojczynski, MK, Chu, AY, Nettleton, JA, Mannisto, S, Kristiansson, K, Reedik, M, Lahti, J, Houston, DK, Cornelis, MC, van Rooij, FJA, Dimitriou, M, Kanoni, S, Mikkila, V, Steffen, LM, Otto, MCD, Qi, L, Psaty, B, Djousse, L, Rotter, JI, Harald, K, Perola, M, Rissanen, H, Jula, A, Krista, F, Mihailov, E, Feitosa, MF, Ngwa, JS, Xue, LT, Jacques, PF, Perala, MM, Palotie, A, Liu, YM, Nalls, NA, Ferrucci, L, Hernandez, D, Manichaikul, A, Tsai, MY, Jong, Jan, Hofman, Bert, Uitterlinden, André, Rallidis, L, Ridker, PM, Rose, LM, Buring, JE, Lehtimaki, T, Kahonen, M, Viikari, J, Lemaitre, R, Salomaa, V, Knekt, P, Metspalu, A, Borecki, IB, Cupples, LA, Eriksson, JG, Kritchevsky, SB, Bandinelli, S, Siscovick, D, Franco Duran, OH, Deloukas, P, Dedoussis, G, Chasman, DI, Raitakari, O, and Tanaka, T

Published
2017

14. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Author

Joshi, PK, Pirastu, N, Kentistou, KA, Fischer, K, Hofer, E, Schraut, KE, Clark, DW, Nutile, T, Barnes, CLK, Timmers, P, Shen, X, Gandin, I, McDaid, AF, Hansen, TF, Gordon, SD, Giulianini, F, Boutin, TS, Abdellaoui, A, Zhao, W, Medina-Gomez, C, Bartz, TM, Trompet, S, Lange, LA, Raffield, L, van der Spek, Ashley, Galesloot, TE, Proitsi, P, Yanek, LR, Bielak, LF, Payton, A, Murgia, F, Concas, MP, Biino, G, Tajuddin, S M, Seppala, I, Amin, Najaf, Boerwinkle, E, Borglum, AD, Campbell, A (Archie), Demerath, EW, Demuth, I, Faul, JD, Ford, I, Gialluisi, A, Gogele, M, Graff, M, Hingorani, A, Hottenga, JJ, Hougaard, DM, Hurme, MA, Ikram, Arfan, Jylha, M, Kuh, D, Ligthart, L, Lill, CM, Lindenberger, U, Lumley, T, Magi, R, Marques-Vidal, P, Medland, SE, Milani, L, Nagy, R, Ollier, WER, Peyser, PA, Pramstaller, PP, Ridker, PM, Rivadeneira, F, Ruggiero, D, Saba, Y, Schmidt, R, Schmidt, H, Slagboom, PE (Eline), Smith, BH, Smith, JA, Sotoodehnia, N, Steinhagen-Thiessen, E, van Rooij, FJA, Verbeek, AL, Vermeulen, SH, Vollenweider, P, Wang, YP, Werge, T, Whitfield, JB, Zonderman, AB, Lehtimaki, T, Evans, MK, Pirastu, M, Fuchsberger, C, Bertram, L, Pendleton, N, Kardia, SLR, Ciullo, M, Becker, DM, Wong, A, Psaty, BM, Duijn, Cornelia, Wilson, JG, Jukema, JW, Kiemeney, L, Uitterlinden, André, Franceschini, N, North, KE, Weir, DR, Metspalu, A, Boomsma, DI, Hayward, C, Chasman, D, Martin, NG, Sattar, N, Campbell, H, Esko, T, Kutalik, Z, Wilson, JF, Joshi, PK, Pirastu, N, Kentistou, KA, Fischer, K, Hofer, E, Schraut, KE, Clark, DW, Nutile, T, Barnes, CLK, Timmers, P, Shen, X, Gandin, I, McDaid, AF, Hansen, TF, Gordon, SD, Giulianini, F, Boutin, TS, Abdellaoui, A, Zhao, W, Medina-Gomez, C, Bartz, TM, Trompet, S, Lange, LA, Raffield, L, van der Spek, Ashley, Galesloot, TE, Proitsi, P, Yanek, LR, Bielak, LF, Payton, A, Murgia, F, Concas, MP, Biino, G, Tajuddin, S M, Seppala, I, Amin, Najaf, Boerwinkle, E, Borglum, AD, Campbell, A (Archie), Demerath, EW, Demuth, I, Faul, JD, Ford, I, Gialluisi, A, Gogele, M, Graff, M, Hingorani, A, Hottenga, JJ, Hougaard, DM, Hurme, MA, Ikram, Arfan, Jylha, M, Kuh, D, Ligthart, L, Lill, CM, Lindenberger, U, Lumley, T, Magi, R, Marques-Vidal, P, Medland, SE, Milani, L, Nagy, R, Ollier, WER, Peyser, PA, Pramstaller, PP, Ridker, PM, Rivadeneira, F, Ruggiero, D, Saba, Y, Schmidt, R, Schmidt, H, Slagboom, PE (Eline), Smith, BH, Smith, JA, Sotoodehnia, N, Steinhagen-Thiessen, E, van Rooij, FJA, Verbeek, AL, Vermeulen, SH, Vollenweider, P, Wang, YP, Werge, T, Whitfield, JB, Zonderman, AB, Lehtimaki, T, Evans, MK, Pirastu, M, Fuchsberger, C, Bertram, L, Pendleton, N, Kardia, SLR, Ciullo, M, Becker, DM, Wong, A, Psaty, BM, Duijn, Cornelia, Wilson, JG, Jukema, JW, Kiemeney, L, Uitterlinden, André, Franceschini, N, North, KE, Weir, DR, Metspalu, A, Boomsma, DI, Hayward, C, Chasman, D, Martin, NG, Sattar, N, Campbell, H, Esko, T, Kutalik, Z, and Wilson, JF

Published
2017

17. Meta-GWAS Accuracy and Power (MetaGAP) calculator shows that hiding heritability is partially due to imperfect genetic correlations across studies

Author

Vlaming, Ronald, Okbay, Aysu, Rietveld, Niels, Johannesson, M, Magnusson, PKE, Uitterlinden, André, van Rooij, FJA, Hofman, Bert, Groenen, Patrick, Thurik, Roy, Koellinger, PD, Vlaming, Ronald, Okbay, Aysu, Rietveld, Niels, Johannesson, M, Magnusson, PKE, Uitterlinden, André, van Rooij, FJA, Hofman, Bert, Groenen, Patrick, Thurik, Roy, and Koellinger, PD

Abstract

Large-scale genome-wide association results are typically obtained from a fixed-effects meta-analysis of GWAS summary statistics from multiple studies spanning different regions and/or time periods. This approach averages the estimated effects of genetic variants across studies. In case genetic effects are heterogeneous across studies, the statistical power of a GWAS and the predictive accuracy of polygenic scores are attenuated, contributing to the so-called ‘missing heritability’. Here, we describe the online Meta-GWAS Accuracy and Power (MetaGAP) calculator (available at www.devlaming.eu) which quantifies this attenuation based on a novel multi-study framework. By means of simulation studies, we show that under a wide range of genetic architectures, the statistical power and predictive accuracy provided by this calculator are accurate. We compare the predictions from the MetaGAP calculator with actual results obtained in the GWAS literature. Specifically, we use genomic-relatedness-matrix restricted maximum likelihood to estimate the SNP heritability and cross-study genetic correlation of height, BMI, years of education, and self-rated health in three large samples. These estimates are used as input parameters for the MetaGAP calculator. Results from the calculator suggest that cross-study heterogeneity has led to attenuation of statistical power and predictive accuracy in recent large-scale GWAS efforts on these traits (e.g., for years of education, we estimate a relative loss of 51–62% in the number of genome-wide significant loci and a relative loss in polygenic score R2 of 36–38%). Hence, cross-study heterogeneity contributes to the missing heritability.

Published
2017

18. Physical Activity Types and Coronary Heart Disease Risk in Middle-Aged and Elderly Persons

Author

Koolhaas, Chantal, Dhana, K, Golubic, R, Schoufour, Josje, Hofman, Bert, van Rooij, FJA, Franco Duran, OH, and Epidemiology

Abstract

Physical activity is associated with decreased risk of coronary heart disease (CHD). The specific physical activity types that provide beneficial effects in an older population remain unclear. We assessed the association of total physical activity, walking, cycling, domestic work, sports, and gardening with CHD by using Cox proportional hazard models among 5,901 participants aged > 55 (median age, 67) years from the prospective population-based Rotterdam Study, enrolled between 1997 and 2001. Activities were categorized into tertiles, and the lowest tertiles were used as reference. In the multivariable model, we adjusted for age, sex, smoking, alcohol consumption, education, diet, and other physical activity types. During 15 years of follow-up (median, 10.3 (interquartile range, 8.0-11.8) years), 642 participants (10.9%) experienced a CHD event. In the multivariable model, the respective hazard ratios for the medium and high categories compared with the low category were 0.79 (95% confidence interval CI): 0.66, 0.96) and 0.71 (95% CI: 0.58, 0.87) for total physical activity, 0.76 (95% CI: 0.63, 0.92) and 0.70 (95% CI: 0.57, 0.88) for cycling, and 0.81 (95% CI: 0.66, 0.98) and 0.71 (95% CI: 0.56, 0.90) for domestic work. Walking, sports, and gardening were not associated with CHD. In conclusion, in this long-term follow-up study of older adults, domestic work and cycling were associated with reduced CHD risk. Physical activity should be promoted in this population with the aim to prevent CHD.

Published
2016

19. Interactions of Dietary Whole-Grain Intake With Fasting Glucose– and Insulin-Related Genetic Loci in Individuals of European Descent

Author

Göran Hallmans, Josée Dupuis, Amanda J. Bennett, Ruth J. F. Loos, George Dedoussis, Emily Sonestedt, Rozenn N. Lemaitre, Toshiko Tanaka, Christopher J. Groves, André G. Uitterlinden, Stavroula Kanoni, Nita G. Forouhi, Zheng Ye, Jerome I. Rotter, Jose C. Florez, Ingegerd Johansson, Jose M. Ordovas, Julius S. Ngwa, David S. Siscovick, A. Smith, Luigi Ferrucci, Claudia Langenberg, Ingrid B. Borecki, Jennifer A. Nettleton, Stefania Bandinelli, James S. Pankow, Per Sjögren, M. C. Zillikens, Ulf Risérus, Kenneth J. Mukamal, Stephen B. Kritchevsky, Marju Orho-Melander, Georgia Saylor, van Rooij Fja., Nicholas J. Wareham, C M van Duijn, James B. Meigs, Jack L. Follis, Sijbrands Ejg., Witteman Jcm., Frida Renström, Luc Djoussé, Inga Prokopenko, Laufey Steingrimsdottir, Tamara B. Harris, Olov Rolandsson, L. J. Launer, Mike A. Nalls, Erik Ingelsson, Denise K. Houston, Dariush Mozaffarian, Mary K. Wojczynski, Kenneth Rice, Jennifer S. Anderson, Yongmei Liu, Nicola M. McKeown, Mary F. Feitosa, Melissa E. Garcia, Paul W. Franks, Albert Hofman, Frank B. Hu, Hivert M-F., Constantina Papoutsakis, and L A Cupples

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Type 2 diabetes, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Pancreatic hormone, 030304 developmental biology, 2. Zero hunger, Advanced and Specialized Nursing, 0303 health sciences, business.industry, Insulin, medicine.disease, Endocrinology, L-Glucose, chemistry, business, TCF7L2, Body mass index
Abstract

OBJECTIVE Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS Via meta-analysis of data from 14 cohorts comprising ∼48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value RESULTS Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: −0.009 mmol/l glucose [−0.013 to −0.005], P < 0.0001 and −0.011 pmol/l [ln] insulin [−0.015 to −0.007], P = 0.0003). No interactions met our multiple testing–adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. CONCLUSIONS Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

Published
2010

20. Genome-wide association study identifies 74 loci associated with educational attainment

Author

Okbay, Aysu, Beauchamp, JP, Fontana, MA, Lee, JJ, Pers, TH, Rietveld, Niels, Turley, P, Chen, GB, Emilsson, V, Meddens, SFW, Oskarsson, S, Pickrell, JK, Thom, K, Timshel, P, Vlaming, Ronald, Abdellaoui, A, Ahluwalia, TS, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Johan, Concas, MP, Derringer, J, Furlotte, NA, Galesloot, TE, Girotto, G, Gupta, R, Hall, LM, Harris, SE, Hofer, E, Horikoshi, M, Huffman, JE, Kaasik, K, Kalafati, IP, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sven, de Leeuw, C, Lind, PA, Lindgren, KO, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, MB, van der Most, PJ, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, WJ, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, KE, Shi, JX, Smith, AV, Poot, Raymond, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N (Niek), Vuckovic, D, Wellmann, J, Westra, HJ, Yang, JY, Zhao, W, Zhu, ZH, Alizadeh, BZ, Amin, Najaf, Bakshi, A, Baumeister, SE, Biino, G, Bonnelykke, K, Boyle, PA, Campbell, H, Cappuccio, FP, Davies, G, De Neve, JE, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, DM, Faul, JD, Feitosa, MF, Forstner, AJ, Gandin, I, Gunnarsson, B, Halldorsson, BV, Harris, TB, Heath, AC, Hocking, LJ, Holliday, EG, Homuth, G, Horan, MA, Hottenga, JJ, De Jager, PL, Joshi, PK, Jugessur, A, Kaakinen, MA, Kahonen, M, Kanoni, S, Keltigangas-Jarvinen, L, Kiemeney, LALM, Kolcic, I, Koskinen, S, Kraja, AT, Kroh, M, Kutalik, Z, Latvala, A, Launer, LJ, Lebreton, MP, Levinson, DF, Lichtenstein, P, Lichtner, P, Liewald, DCM, Loukola, A, Madden, PA, Magi, R, Maki-Opas, T, Marioni, RE, Marques-Vidal, P, Meddens, GA, McMahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, GW, Myhre, R, Nelson, CP, Nyholt, DR, Ollier, WER, Palotie, A, Paternoster, L, Pedersen, NL, Petrovic, KE, Porteous, DJ, Raikkonen, K, Ring, SM, Robino, A, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, AR, Sarin, AP, Schmidt, Heléna, Scott, RJ, Smith, BH, Smith, JA, Staessen, JA, Steinhagen-Thiessen, E, Strauch, K, Terracciano, A, Tobin, MD, Ulivi, S, Vaccargiu, S, Quaye, L, van Rooij, FJA, Venturini, C, Vinkhuyzen, AAE, Volker, U, Volzke, H, Vonk, JM, Vozzi, D, Waage, J, Ware, EB, Willemsen, G, Attia, JR, Bennett, DA, Berger, K, Bertram, L, Bisgaard, H, Boomsma, DI, Borecki, IB, Bultmann, U, Chabris, CF, Cucca, F, Cusi, D, Deary, IJ, Dedoussis, GV, Duijn, Cornelia, Eriksson, JG, Franke, B, Franke, L, Gasparini, P, Gejman, PV, Gieger, C, Grabe, HJ, Gratten, J, Groenen, Patrick, Gudnason, V, van der Harst, P, Hayward, C, Hinds, DA, Hoffmann, W, Hyppnen, E, Iacono, WG, Jacobsson, B, Jarvelin, MR, Jockel, KH, Kaprio, J, Kardia, SLR, Lehtimaki, T, Lehrer, SF, Magnusson, PKE, Martin, NG, McGue, M, Metspalu, A, Pendleton, N, Penninx, BWJH, Perola, M, Pirastu, N, Pirastu, M, Polasek, O, Posthuma, Daniëlle, Power, C, Province, MA, Samani, NJ, Schlessinger, D, Schmidt, R, Sorensen, TIA, Spector, TD, Stefansson, K, Thorsteinsdottir, U, Thurik, Roy, Timpson, NJ, Tiemeier, Henning, Tung, JY, Uitterlinden, André, Vitart, V, Vollenweider, P, Weir, DR, Wilson, JF, Wright, AF, Conley, DC, Krueger, RF, Smith, GD, Hofman, Bert, Laibson, DI, Medland, SE, Meyer, MN, Yang, Jiaqi, Johannesson, M, Visscher, PM, Esko, T, Koellinger, PD, Cesarini, D, Benjamin, DJ, Okbay, Aysu, Beauchamp, JP, Fontana, MA, Lee, JJ, Pers, TH, Rietveld, Niels, Turley, P, Chen, GB, Emilsson, V, Meddens, SFW, Oskarsson, S, Pickrell, JK, Thom, K, Timshel, P, Vlaming, Ronald, Abdellaoui, A, Ahluwalia, TS, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Johan, Concas, MP, Derringer, J, Furlotte, NA, Galesloot, TE, Girotto, G, Gupta, R, Hall, LM, Harris, SE, Hofer, E, Horikoshi, M, Huffman, JE, Kaasik, K, Kalafati, IP, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sven, de Leeuw, C, Lind, PA, Lindgren, KO, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, MB, van der Most, PJ, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, WJ, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, KE, Shi, JX, Smith, AV, Poot, Raymond, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N (Niek), Vuckovic, D, Wellmann, J, Westra, HJ, Yang, JY, Zhao, W, Zhu, ZH, Alizadeh, BZ, Amin, Najaf, Bakshi, A, Baumeister, SE, Biino, G, Bonnelykke, K, Boyle, PA, Campbell, H, Cappuccio, FP, Davies, G, De Neve, JE, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, DM, Faul, JD, Feitosa, MF, Forstner, AJ, Gandin, I, Gunnarsson, B, Halldorsson, BV, Harris, TB, Heath, AC, Hocking, LJ, Holliday, EG, Homuth, G, Horan, MA, Hottenga, JJ, De Jager, PL, Joshi, PK, Jugessur, A, Kaakinen, MA, Kahonen, M, Kanoni, S, Keltigangas-Jarvinen, L, Kiemeney, LALM, Kolcic, I, Koskinen, S, Kraja, AT, Kroh, M, Kutalik, Z, Latvala, A, Launer, LJ, Lebreton, MP, Levinson, DF, Lichtenstein, P, Lichtner, P, Liewald, DCM, Loukola, A, Madden, PA, Magi, R, Maki-Opas, T, Marioni, RE, Marques-Vidal, P, Meddens, GA, McMahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, GW, Myhre, R, Nelson, CP, Nyholt, DR, Ollier, WER, Palotie, A, Paternoster, L, Pedersen, NL, Petrovic, KE, Porteous, DJ, Raikkonen, K, Ring, SM, Robino, A, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, AR, Sarin, AP, Schmidt, Heléna, Scott, RJ, Smith, BH, Smith, JA, Staessen, JA, Steinhagen-Thiessen, E, Strauch, K, Terracciano, A, Tobin, MD, Ulivi, S, Vaccargiu, S, Quaye, L, van Rooij, FJA, Venturini, C, Vinkhuyzen, AAE, Volker, U, Volzke, H, Vonk, JM, Vozzi, D, Waage, J, Ware, EB, Willemsen, G, Attia, JR, Bennett, DA, Berger, K, Bertram, L, Bisgaard, H, Boomsma, DI, Borecki, IB, Bultmann, U, Chabris, CF, Cucca, F, Cusi, D, Deary, IJ, Dedoussis, GV, Duijn, Cornelia, Eriksson, JG, Franke, B, Franke, L, Gasparini, P, Gejman, PV, Gieger, C, Grabe, HJ, Gratten, J, Groenen, Patrick, Gudnason, V, van der Harst, P, Hayward, C, Hinds, DA, Hoffmann, W, Hyppnen, E, Iacono, WG, Jacobsson, B, Jarvelin, MR, Jockel, KH, Kaprio, J, Kardia, SLR, Lehtimaki, T, Lehrer, SF, Magnusson, PKE, Martin, NG, McGue, M, Metspalu, A, Pendleton, N, Penninx, BWJH, Perola, M, Pirastu, N, Pirastu, M, Polasek, O, Posthuma, Daniëlle, Power, C, Province, MA, Samani, NJ, Schlessinger, D, Schmidt, R, Sorensen, TIA, Spector, TD, Stefansson, K, Thorsteinsdottir, U, Thurik, Roy, Timpson, NJ, Tiemeier, Henning, Tung, JY, Uitterlinden, André, Vitart, V, Vollenweider, P, Weir, DR, Wilson, JF, Wright, AF, Conley, DC, Krueger, RF, Smith, GD, Hofman, Bert, Laibson, DI, Medland, SE, Meyer, MN, Yang, Jiaqi, Johannesson, M, Visscher, PM, Esko, T, Koellinger, PD, Cesarini, D, and Benjamin, DJ

Abstract

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals(1). Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample(1,2) of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Published
2016

21. Gene x dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry

Author

Nettleton, JA, Follis, JL, Ngwa, JS, Smith, CE, Ahmad, Shahzad, Tanaka, T, Wojczynski, MK, Voortman, Trudy, Lemaitre, RN, Kristiansson, K, Nuotio, ML, Houston, DK, Perala, MM, Qi, QB, Sonestedt, E, Manichaikul, A, Kanoni, S, Ganna, A, Mikkila, V, North, KE, Siscovick, DS, Harald, K, McKeown, NM, Johansson, I, Rissanen, H, Liu, YM, Lahti, J, Hu, FB, Bandinelli, S, Rukh, G, Rich, S, Booij, L, Dmitriou, M, Ax, E, Raitakari, O, Mukamal, K, Mannisto, S, Hallmans, G, Jula, A, Ericson, U, Jacobs, DR, van Rooij, FJA, Deloukas, P, Sjogren, P, Kahonen, M, Djousse, L, Perola, M, Barroso, I, Hofman, Bert, Stirrups, K, Viikari, J, Uitterlinden, André, Kalafati, IP, Franco Duran, OH, Mozaffarian, D, Salomaa, V, Borecki, IB, Knekt, P, Kritchevsky, SB, Eriksson, JG, Dedoussis, GV, Qi, L, Ferrucci, L, Orho-Melander, M, Zillikens, M.C., Ingelsson, E, Lehtimaki, T, Renstrom, F, Cupples, LA, Loos, RJF, Franks, PW, Nettleton, JA, Follis, JL, Ngwa, JS, Smith, CE, Ahmad, Shahzad, Tanaka, T, Wojczynski, MK, Voortman, Trudy, Lemaitre, RN, Kristiansson, K, Nuotio, ML, Houston, DK, Perala, MM, Qi, QB, Sonestedt, E, Manichaikul, A, Kanoni, S, Ganna, A, Mikkila, V, North, KE, Siscovick, DS, Harald, K, McKeown, NM, Johansson, I, Rissanen, H, Liu, YM, Lahti, J, Hu, FB, Bandinelli, S, Rukh, G, Rich, S, Booij, L, Dmitriou, M, Ax, E, Raitakari, O, Mukamal, K, Mannisto, S, Hallmans, G, Jula, A, Ericson, U, Jacobs, DR, van Rooij, FJA, Deloukas, P, Sjogren, P, Kahonen, M, Djousse, L, Perola, M, Barroso, I, Hofman, Bert, Stirrups, K, Viikari, J, Uitterlinden, André, Kalafati, IP, Franco Duran, OH, Mozaffarian, D, Salomaa, V, Borecki, IB, Knekt, P, Kritchevsky, SB, Eriksson, JG, Dedoussis, GV, Qi, L, Ferrucci, L, Orho-Melander, M, Zillikens, M.C., Ingelsson, E, Lehtimaki, T, Renstrom, F, Cupples, LA, Loos, RJF, and Franks, PW

Abstract

Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

Published
2015

23. Meat Consumption and Its Association With C-Reactive Protein and Incident Type 2 Diabetes The Rotterdam Study

Author

van Woudenbergh, GJ, Kuijsten, A, Tigcheler, B, Sijbrands, E.J.G., van Rooij, FJA, Hofman, Bert, Witteman, JCM, Feskens, EJM, Internal Medicine, and Epidemiology

Subjects
SDG 3 - Good Health and Well-being, food and beverages
Abstract

OBJECTIVE-To investigate whether intake of different types of meat is associated with circulating C-reactive protein (CRP) and risk of type 2 diabetes in a prospective cohort study. RESEARCH DESIGN AND METHODS-Our analysis included 4,366 Dutch participants who did not have diabetes at baseline. During a median follow-up period of 12.4 years, 456 diabetes cases were confirmed. Intake of red meat, processed meat, and poultry was derived from a food frequency questionnaire, and their association with serum high-sensitivity CRP was examined cross-sectionally using linear regression models. Their association with risk of type 2 diabetes was examined using multivariate Cox propor RESULTS-An increment of 50 g of processed meat was associated with increased CRP concentration (beta(processed meat) = 0.12; P = 0.01), whereas intake of red meat and poultry was not. When comparing the highest to the lowest category of meat intake with respect to diabetes incidence, the adjusted relative risks were as follows: for red meat (1.42 [95% CI 1.06-1.91]), for processed meat (1.87 [1.26-2.78]), and for poultry (0.95 [0.74-1.22]). Additional analysis showed that the associations were n CONCLUSIONS-Intake of processed meat is associated with higher risk of type 2 diabetes. It appears unlikely that CRP mediates this association.

Published
2012

24. De genetica van ondernemerschap

Author

van der Loos, MJHM (Matthijs), Groenen, Patrick, Hofman, Bert, Koellinger, PD, Rivadeneira, Fernando, van Rooij, FJA, Thurik, Roy, Uitterlinden, André, Erasmus School of Economics, Econometrics, Epidemiology, Applied Economics, and Internal Medicine

Published
2011

26. Coronary Calcium Score Improves Classification of Coronary Heart Disease Risk in the Elderly The Rotterdam Study

Author

Smale, Suzette, Proenca, RV, Koller, MT (Michael), Kavousi, Maryam, van Rooij, FJA, Hunink, Myriam, Steyerberg, Ewout, Hofman, Bert, Oudkerk, M, Witteman, JCM, Epidemiology, Public Health, and Radiology & Nuclear Medicine

Subjects
nutritional and metabolic diseases, cardiovascular diseases
Abstract

Objectives The purpose of this study was to examine the effect of coronary artery calcium (CAC) on the classification of 10-year hard coronary heart disease (CHD) risk and to empirically derive cut-off values of the calcium score for a general population of elderly patients. Background Although CAC scoring has been found to improve CHD risk prediction, there are limited data on its impact in clinical practice. Methods The study comprised 2,028 asymptomatic participants (age 69.6 +/- 6.2 years) from the Rotterdam Study. During a median follow-up of 9.2 years, 135 hard coronary events occurred. Persons were classified into low (20%) 10-year coronary risk categories based on a Framingham refitted risk model. In a second step, the model was extended by CAC, and reclassification percentages were calculated. Cutoff values of CAC for persons in the intermediate-risk category were empirically derived based on 10-year hard CHD risk. Results Reclassification by means of CAC scoring was most substantial in persons initially classified as intermediate risk. In this group, 52% of men and women were reclassified, all into more accurate risk categories. CAC values above 615 or below 50 Agatston units were found appropriate to reclassify persons into high or low risk, respectively. Conclusions In a general population of elderly patients at intermediate CHD risk, CAC scoring is a powerful method to reclassify persons into more appropriate risk categories. Empirically derived CAC cutoff values at which persons at intermediate risk reclassified to either high or low risk were 615 and 50 Agatston units, respectively. (J Am Coll Cardiol 2010;56:1407-14) (C) 2010 by the American College of Cardiology Foundation

Published
2010

27. Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.

Author

Chen, P, Takeuchi, F, Lee, J-Y, Li, H, Wu, J-Y, Liang, J, Long, J, Tabara, Y, Goodarzi, MO, Pereira, MA, Kim, YJ, Go, MJ, Stram, DO, Vithana, E, Khor, C-C, Liu, J, Liao, J, Ye, X, Wang, Y, Lu, L, Young, TL, Lee, J, Thai, AC, Cheng, C-Y, van Dam, RM, Friedlander, Y, Heng, C-K, Koh, W-P, Chen, C-H, Chang, L-C, Pan, W-H, Qi, Q, Isono, M, Zheng, W, Cai, Q, Gao, Y, Yamamoto, K, Ohnaka, K, Takayanagi, R, Kita, Y, Ueshima, H, Hsiung, CA, Cui, J, Sheu, WH-H, Rotter, JI, Chen, Y-DI, Hsu, C, Okada, Y, Kubo, M, Takahashi, A, Tanaka, T, van Rooij, FJA, Ganesh, SK, Huang, J, Huang, T, Yuan, J, Hwang, J-Y, CHARGE Hematology Working Group, Gross, MD, Assimes, TL, Miki, T, Shu, X-O, Qi, L, Chen, Y-T, Lin, X, Aung, T, Wong, T-Y, Teo, Y-Y, Kim, B-J, Kato, N, Tai, E-S, Chen, P, Takeuchi, F, Lee, J-Y, Li, H, Wu, J-Y, Liang, J, Long, J, Tabara, Y, Goodarzi, MO, Pereira, MA, Kim, YJ, Go, MJ, Stram, DO, Vithana, E, Khor, C-C, Liu, J, Liao, J, Ye, X, Wang, Y, Lu, L, Young, TL, Lee, J, Thai, AC, Cheng, C-Y, van Dam, RM, Friedlander, Y, Heng, C-K, Koh, W-P, Chen, C-H, Chang, L-C, Pan, W-H, Qi, Q, Isono, M, Zheng, W, Cai, Q, Gao, Y, Yamamoto, K, Ohnaka, K, Takayanagi, R, Kita, Y, Ueshima, H, Hsiung, CA, Cui, J, Sheu, WH-H, Rotter, JI, Chen, Y-DI, Hsu, C, Okada, Y, Kubo, M, Takahashi, A, Tanaka, T, van Rooij, FJA, Ganesh, SK, Huang, J, Huang, T, Yuan, J, Hwang, J-Y, CHARGE Hematology Working Group, Gross, MD, Assimes, TL, Miki, T, Shu, X-O, Qi, L, Chen, Y-T, Lin, X, Aung, T, Wong, T-Y, Teo, Y-Y, Kim, B-J, Kato, N, and Tai, E-S

Abstract

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10(-23)], HBS1L/MYB [8.5 × 10(-15)], MYO9B [9.0 × 10(-12)], and CYBA [1.1 × 10(-8)] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.

Published
2014

28. Prevalence, Incidence, and Lifetime Risk for the Development of COPD in the Elderly The Rotterdam Study

Author

van Durme, YMTA, Verhamme, Katia, Stijnen, T (Theo), van Rooij, FJA, Van Pottelberge, GR, Hofman, Bert, Joos, GF, Stricker, Bruno, Brusselle, Guy, Epidemiology, and Medical Informatics

Subjects
respiratory tract diseases
Abstract

Background: COPD is a major cause of chronic morbidity and mortality throughout the world. Although the prevalence of COPD is already well documented, there are only few studies regarding the incidence of COPD. Methods: In a prospective population-based cohort study among subjects aged >= 55 years, COPD was diagnosed with an algorithm based on the validation of hospital discharge letters, files from the general practitioner, and spirometry reports. Results: In this study cohort of 7,983 participants, 648 cases were identified with incident COPD after a median follow-up time of 11 years (interquartile range, 7.8 years). This resulted in an overall incidence rate (IR) of 9.2/1,000 person-years (PY) [95% confidence interval (CI), 8.5 to 10.0]. The IR of COPD was higher among men (14.4/1,000 PY; 95% CI, 13.0 to 16.0) than among women (6.2/1,000 PY; 95% CI, 5.5 to 7.0), and higher in smokers than in never-smokers (12.8/1,000 PY; 95% CI, 11.7 to 13.9 and 3.9/1,000 PY; 95% CI, 3.2 to 4.7, respectively). Remarkable was the high incidence in the youngest female age category of 55 to 59 years (7.4/1,000 PY; 95% CI, 4.1 to 12.6). For a 55-year-old man and woman still free of COPD at cohort entry, the risk for the development of COPD over the coming 40 years was 24% and 16%, respectively. Conclusion. The overall incidence of COPD in an elderly population is 9.2/1,000 PY, with a remarkably, high incidence in the youngest women, suggesting a further shift toward the female sex in the gender distribution of COPD. During their further lives, one of four men and one of six women free of COPD at the age of 55 years will have COPD develop.

Published
2009

29. Eating Fish and Risk of Type 2 Diabetes A population-based, prospective follow-up study

Author

van Woudenbergh, GJ, van Ballegooijen, AJ, Kuijsten, A, Sijbrands, E.J.G., van Rooij, FJA, Geleijnse, JM (Marianne), Hofman, Bert, Witteman, JCM, Feskens, EJM, Internal Medicine, and Epidemiology

Subjects
SDG 3 - Good Health and Well-being
Abstract

OBJECTIVE - To investigate the relation between total fish, type of fish (lean and fatty), and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake and risk of type 2 diabetes in a population-based cohort. RESEARCH DESIGN AND METHODS - The analysis included 4,472 Dutch participants aged >= 55 years without diabetes at baseline. Dietary intake was assessed with a semiquantitative food frequency questionnaire. Hazard ratios (relative risk [RR]) with 95% CIs were used to examine risk associations adjusted for age, sex, lifestyle, and nutritional factors. RESULTS - After 15 years of follow-up, 463 participants developed type 2 diabetes. Median fish intake, mainly lean fish (81%), was 10 g/day. Total fish intake was associated positively with risk of type 2 diabetes; the RR was 1.32 (95% Cl 1.02-1.70) in the highest total fish group (>= 28 g/day) compared with that for non-fish eaters (P-trend = 0.04). Correspondingly, lean fish intake tended to be associated positively with type 2 diabetes (RR highest group [>= 23 g/day] 1.30 [95% CI 1.01-1..68]; P-trend = 0.06), but fatty fish was not. No association was observed between EPA and DHA intake and type 2 diabetes (RR highest group [>= 149.4 mg/day] 1.22 [0.97-1.53]). With additional adjustment for intake of selenium, cholesterol, and vitamin D, this RR decreased to 1.05 (0.80-1.38; P-trend = 0.77). CONCLUSIONS - The findings do not support a beneficial effect of total fish, type of fish, or EPA and DHA intake on the risk of type 2 diabetes. Alternatively, other dietary components, such as selenium, and unmeasured contaminants present in fish might explain our results.

Published
2009

30. Matrix metalloproteinase 3 haplotypes and dementia and Alzheimer's disease - The Rotterdam Study

Author

Reitz, C, van Rooij, FJA, de Maat, Moniek, Heijer, Tom, Hofman, Bert, Witteman, JCM, Breteler, Monique, Epidemiology, Hematology, and Neurology

Abstract

Evidence by post-mortem and animal studies suggests that matrix metalloprotemases (MMPs) may play an important role in the pathophysiology of Alzheimer's disease (AD) through degradation of amyloid beta. We investigated in 5999 elderly whether MMP3-haplotypes are associated with cognitive performance over time, dementia and AD. We also explored the association of MMP-3 haplotypes with changes in hippocampal volume and severity of periventricular and subcortical white matter lesions (WML). There was no association between any individual polymorphism or MMP-3 haplotypes and performance in MMSE over time, dementia or AD, and there was no association between MMP-3 genotypes or haplotypes with hippocampal volume or severity of periventricular or subcortical WML. These associations did not differ between strata of APOE epsilon 4 genotype. Our observations do not suggest that variation in the MMP3 gene is causally involved in dementia or AD. (C) 2007 Elsevier Inc. All rights reserved.

Published
2008

31. Effect of oral acyclovir after penetrating keratoplasty for herpetic keratitis: a placebo-controlled multicenter trial

Author

van Rooij, FJA, Rijneveld, WJ, Remeijer, L (Lies), Völker-Dieben, HJM, Eggink, CA, Geerards, AJ, Mulder, PGH (Paul), Doornenbal, P, Beekhuis, WH (Houdijn), Epidemiology, Virology, and Ophthalmology

Subjects
genetic structures, Neurosensory disorders [UMCN 3.3]
Abstract

Item does not contain fulltext OBJECTIVE: To determine the prophylactic effect of oral acyclovir on the recurrence rate of herpetic eye disease after penetrating keratoplasty. DESIGN: A randomized, double-masked, placebo-controlled multicenter trial. PARTICIPANTS: Sixty-eight consecutive patients (68 eyes) with corneal opacities due to herpetic eye disease who underwent penetrating keratoplasty. INTERVENTION: Oral acyclovir 400 mg twice daily or placebo tablets for 6 months. MAIN OUTCOME MEASURES: The recurrence rate of herpetic eye disease-related events and rejection episodes, proven by viral cell culture or polymerase chain reaction. RESULTS: During the 2-year follow-up period, there were 3 culture-proven herpetic eye disease recurrences in the acyclovir group and 9 in the placebo group. Lifetime survival analysis of the probability of remaining free from recurrence revealed a significantly reduced risk of recurrent herpetic disease in the acyclovir-treated group. CONCLUSION: This study suggests that oral acyclovir effectively prevents herpes-related recurrences after penetrating keratoplasty in herpetic eye disease.

Published
2003

32. The Molecular Genetic Architecture of Self-Employment

Author

van der Loos, MJHM, Rietveld, CA, Eklund, N, Koellinger, PD, Rivadeneira, F, Abecasis, GR, Ankra-Badu, GA, Baumeister, SE, Benjamin, DJ, Biffar, R, Blankenberg, S, Boomsma, DI, Cesarini, D, Cucca, F, de Geus, EJC, Dedoussis, G, Deloukas, P, Dimitriou, M, Eiriksdottir, G, Eriksson, J, Gieger, C, Gudnason, V, Höhne, B, Holle, R, Hottenga, JJ, Isaacs, A, Järvelin, MR, Johannesson, M, Kaakinen, M, Kähönen, M, Kanoni, S, Laaksonen, MA, Lahti, J, Launer, LJ, Lehtimäki, T, Loitfelder, M, Magnusson, PKE, Naitza, S, Oostra, BA, Perola, M, Petrovic, K, Quaye, L, Raitakari, O, Ripatti, S, Scheet, P, Schlessinger, D, Schmidt, CO, Schmidt, H, Schmidt, R, Senft, A, Smith, AV, Spector, TD, Surakka, I, Svento, R, Terracciano, A, Tikkanen, E, van Duijn, CM, Viikari, J, Völzke, H, Wichmann, HE, Wild, PS, Willems, SM, Willemsen, G, van Rooij, FJA, Groenen, PJF, Uitterlinden, AG, Hofman, A, Thurik, AR, van der Loos, MJHM, Rietveld, CA, Eklund, N, Koellinger, PD, Rivadeneira, F, Abecasis, GR, Ankra-Badu, GA, Baumeister, SE, Benjamin, DJ, Biffar, R, Blankenberg, S, Boomsma, DI, Cesarini, D, Cucca, F, de Geus, EJC, Dedoussis, G, Deloukas, P, Dimitriou, M, Eiriksdottir, G, Eriksson, J, Gieger, C, Gudnason, V, Höhne, B, Holle, R, Hottenga, JJ, Isaacs, A, Järvelin, MR, Johannesson, M, Kaakinen, M, Kähönen, M, Kanoni, S, Laaksonen, MA, Lahti, J, Launer, LJ, Lehtimäki, T, Loitfelder, M, Magnusson, PKE, Naitza, S, Oostra, BA, Perola, M, Petrovic, K, Quaye, L, Raitakari, O, Ripatti, S, Scheet, P, Schlessinger, D, Schmidt, CO, Schmidt, H, Schmidt, R, Senft, A, Smith, AV, Spector, TD, Surakka, I, Svento, R, Terracciano, A, Tikkanen, E, van Duijn, CM, Viikari, J, Völzke, H, Wichmann, HE, Wild, PS, Willems, SM, Willemsen, G, van Rooij, FJA, Groenen, PJF, Uitterlinden, AG, Hofman, A, and Thurik, AR

Abstract

Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σg2/σP2 = 25%, h2 = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10-5 were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases. © 2013 van der Loos et al.

Published
2013

33. Serum Uric Acid and Chronic Kidney Disease: The Role of Hypertension

Author

Sedaghat, S, Hoorn, Ewout, van Rooij, FJA, Hofman, Bert, Franco Duran, OH, Witteman, JCM, Dehghan, Abbas, Sedaghat, S, Hoorn, Ewout, van Rooij, FJA, Hofman, Bert, Franco Duran, OH, Witteman, JCM, and Dehghan, Abbas

Abstract

Background: There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association. Methods: We included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR <60 ml/min/1.73 m(2). All associations were corrected for socio-demographic and cardiovascular factors. Results: Each unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m(2) faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98-1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15-1.22). In the stratified analyses, we observed tha Conclusions: Our findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.

Published
2013

34. The Molecular Genetic Architecture of Self-Employment

Author

van der Loos, MJHM (Matthijs), Rietveld, Niels, Eklund, N, Koellinger, PD, Rivadeneira, Fernando, Abecasis, GR, Ankra-Badu, GA, Baumeister, SE, Benjamin, DJ, Biffar, R, Blankenberg, S, Boomsma, DI, Cesarini, D, Cucca, F, de Geus, EJC, Dedoussis, G, Deloukas, P, Dimitriou, M, Eiriksdottir, G, Eriksson, J, Gieger, C, Gudnason, V, Hoehne, B, Holle, R, Hottenga, JJ (Jouke Jan), Isaacs, Aaron, Jarvelin, MR, Johannesson, M, Kaakinen, M, Kahonen, M, Kanoni, S, Laaksonen, MA, Lahti, J, Launer, LJ (Lenore), Lehtimaki, T, Loitfelder, M, Magnusson, PKE, Naitza, S, Oostra, Ben, Perola, M, Petrovic, K, Quaye, L, Raitakari, O, Ripatti, S, Scheet, P, Schlessinger, D, Schmidt, CO, Schmidt, H, Schmidt, R, Senft, A, Smith, AV, Spector, TD, Surakka, I, Svento, R, Terracciano, A, Tikkanen, E, van Duijn, CM, Viikari, J, Voelzke, Henry, Wichmann, H-E, Wild, PS, Willems, SM, Willemsen, G, van Rooij, FJA, Groenen, Patrick, Uitterlinden, André, Hofman, Bert, Thurik, Roy, van der Loos, MJHM (Matthijs), Rietveld, Niels, Eklund, N, Koellinger, PD, Rivadeneira, Fernando, Abecasis, GR, Ankra-Badu, GA, Baumeister, SE, Benjamin, DJ, Biffar, R, Blankenberg, S, Boomsma, DI, Cesarini, D, Cucca, F, de Geus, EJC, Dedoussis, G, Deloukas, P, Dimitriou, M, Eiriksdottir, G, Eriksson, J, Gieger, C, Gudnason, V, Hoehne, B, Holle, R, Hottenga, JJ (Jouke Jan), Isaacs, Aaron, Jarvelin, MR, Johannesson, M, Kaakinen, M, Kahonen, M, Kanoni, S, Laaksonen, MA, Lahti, J, Launer, LJ (Lenore), Lehtimaki, T, Loitfelder, M, Magnusson, PKE, Naitza, S, Oostra, Ben, Perola, M, Petrovic, K, Quaye, L, Raitakari, O, Ripatti, S, Scheet, P, Schlessinger, D, Schmidt, CO, Schmidt, H, Schmidt, R, Senft, A, Smith, AV, Spector, TD, Surakka, I, Svento, R, Terracciano, A, Tikkanen, E, van Duijn, CM, Viikari, J, Voelzke, Henry, Wichmann, H-E, Wild, PS, Willems, SM, Willemsen, G, van Rooij, FJA, Groenen, Patrick, Uitterlinden, André, Hofman, Bert, and Thurik, Roy

Published
2013

35. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

Author

Amin, Najaf, Byrne, E, Johnson, J, Chenevix-Trench, G, Walter, Stefan, Nolte, IM (Ilja), Vink, JM, Rawal, R, Mangino, M, Teumer, A, Keers, JC, Verwoert, G, Baumeister, S, Biffar, R, Petersmann, A, Dahmen, N, Doering, A, Isaacs, Aaron, Broer, Linda, Wray, NR, Montgomery, GW, Levy, D, Psaty, BM, Gudnason, V, Chakravarti, A, Sulem, P, Gudbjartsson, DF, Kiemeney, LA, Thorsteinsdottir, U, Stefansson, K, van Rooij, FJA, Aulchenko, YS, Hottenga, JJ (Jouke Jan), Rivadeneira, FR, Hofman, Bert, Uitterlinden, André, Hammond, CJ, Shin, SY, Ikram, A, Witteman, JCM, Janssens, Cecile, Snieder, H, Tiemeier, Henning, Wolfenbuttel, BHR, Oostra, Ben, Heath, AC, Wichmann, E, Spector, TD, Grabe, HJ, Boomsma, DI, Martin, NG, Duijn, Cornelia, Amin, Najaf, Byrne, E, Johnson, J, Chenevix-Trench, G, Walter, Stefan, Nolte, IM (Ilja), Vink, JM, Rawal, R, Mangino, M, Teumer, A, Keers, JC, Verwoert, G, Baumeister, S, Biffar, R, Petersmann, A, Dahmen, N, Doering, A, Isaacs, Aaron, Broer, Linda, Wray, NR, Montgomery, GW, Levy, D, Psaty, BM, Gudnason, V, Chakravarti, A, Sulem, P, Gudbjartsson, DF, Kiemeney, LA, Thorsteinsdottir, U, Stefansson, K, van Rooij, FJA, Aulchenko, YS, Hottenga, JJ (Jouke Jan), Rivadeneira, FR, Hofman, Bert, Uitterlinden, André, Hammond, CJ, Shin, SY, Ikram, A, Witteman, JCM, Janssens, Cecile, Snieder, H, Tiemeier, Henning, Wolfenbuttel, BHR, Oostra, Ben, Heath, AC, Wichmann, E, Spector, TD, Grabe, HJ, Boomsma, DI, Martin, NG, and Duijn, Cornelia

Abstract

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N = 18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values = 1.6 x 10(-11) and 2.7 x 10(-11)), which were also in strong linkage disequilibrium (r(2) = 0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value = 3.9 x 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value = 7.1 x 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value = 2.2 x 10(-05)) and Parkinson's disease pathways (P-value = 3.6 x 10(-05)). Molecular Psychiatry (2012) 17, 1116-1129; doi: 10.1038/mp.2011.101; published online 30 August 2011

Published
2012

36. Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis

Author

Franceschini, N, van Rooij, FJA, Prins, BP, Feitosa, MF, Karakas, M, Eckfeldt, JH, Folsom, AR, Kopp, J, Vaez, A, Andrews, JS, Baumert, J, Boraska, V, Broer, Linda, Hayward, C, Ngwa, JS, Okada, Y, Polasek, O, Westra, HJ, Wang, YA, Del Greco, F, Glazer, NL, Kapur, K, Id, P, Lopez, LM, Schillert, A, Smith, AV, Winkler, CA, Zgaga, L, Bandinelli, S, Bergmann, S, Boban, M, Bochud, M, Chen, YD, Davies, G, Dehghan, Abbas, Ding, JZ (Jing Zhong), Doering, A, Durda, JP, Ferrucci, L, Franco Duran, OH, Franke, L, Gunjaca, G, Hofman, Bert, Hsu, FC, Kolcic, I, Kraja, A, Kubo, M, Lackner, KJ, Launer, L, Loehr, LR, Li, G (Guo), Meisinger, C, Nakamura, Y, Schwienbacher, C, Starr, JM, Takahashi, A, Torlak, V, Uitterlinden, André, Vitart, V, Waldenberger, M, Wild, PS, Kirin, M, Zeller, T, Zemunik, T, Zhang, QY, Ziegler, A, Blankenberg, S, Boerwinkle, E, Borecki, IB, Campbell, H, Deary, IJ, Frayling, TM, Gieger, C, Harris, TB, Hicks, AA, Koenig, W, O'Donnell, CJ, Fox, CS, Pramstaller, PP, Psaty, BM, Reiner, AP, Rotter, JI, Rudan, I, Snieder, H, Tanaka, T, Duijn, Cornelia, Vollenweider, P, Waeber, G, Wilson, JF, Witteman, JCM, Wolffenbuttel, BHR, Wright, AF, Wu, QY, Liu, YM, Jenny, NS, North, KE, Felix, Janine, Alizadeh, BZ, Cupples, LA, Perry, JRB, Morris, AP, Franceschini, N, van Rooij, FJA, Prins, BP, Feitosa, MF, Karakas, M, Eckfeldt, JH, Folsom, AR, Kopp, J, Vaez, A, Andrews, JS, Baumert, J, Boraska, V, Broer, Linda, Hayward, C, Ngwa, JS, Okada, Y, Polasek, O, Westra, HJ, Wang, YA, Del Greco, F, Glazer, NL, Kapur, K, Id, P, Lopez, LM, Schillert, A, Smith, AV, Winkler, CA, Zgaga, L, Bandinelli, S, Bergmann, S, Boban, M, Bochud, M, Chen, YD, Davies, G, Dehghan, Abbas, Ding, JZ (Jing Zhong), Doering, A, Durda, JP, Ferrucci, L, Franco Duran, OH, Franke, L, Gunjaca, G, Hofman, Bert, Hsu, FC, Kolcic, I, Kraja, A, Kubo, M, Lackner, KJ, Launer, L, Loehr, LR, Li, G (Guo), Meisinger, C, Nakamura, Y, Schwienbacher, C, Starr, JM, Takahashi, A, Torlak, V, Uitterlinden, André, Vitart, V, Waldenberger, M, Wild, PS, Kirin, M, Zeller, T, Zemunik, T, Zhang, QY, Ziegler, A, Blankenberg, S, Boerwinkle, E, Borecki, IB, Campbell, H, Deary, IJ, Frayling, TM, Gieger, C, Harris, TB, Hicks, AA, Koenig, W, O'Donnell, CJ, Fox, CS, Pramstaller, PP, Psaty, BM, Reiner, AP, Rotter, JI, Rudan, I, Snieder, H, Tanaka, T, Duijn, Cornelia, Vollenweider, P, Waeber, G, Wilson, JF, Witteman, JCM, Wolffenbuttel, BHR, Wright, AF, Wu, QY, Liu, YM, Jenny, NS, North, KE, Felix, Janine, Alizadeh, BZ, Cupples, LA, Perry, JRB, and Morris, AP

Abstract

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 x 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMDS-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

Published
2012

37. Methods of data collection and definitions of cardiac outcomes in the Rotterdam Study

Author

Leening, Maarten, Kavousi, Maryam, Heeringa, Jan, van Rooij, FJA, van Heemst, J, Deckers, Jaap, Mattace Raso, F.U.S., Ziere, Bert, Hofman, Bert, Stricker, Bruno, Witteman, JCM, Leening, Maarten, Kavousi, Maryam, Heeringa, Jan, van Rooij, FJA, van Heemst, J, Deckers, Jaap, Mattace Raso, F.U.S., Ziere, Bert, Hofman, Bert, Stricker, Bruno, and Witteman, JCM

Abstract

The prevalence of cardiovascular diseases is rising. Therefore, adequate risk prediction and identification of its determinants is increasingly important. The Rotterdam Study is a prospective population-based cohort study ongoing since 1990 in the city of Rotterdam, The Netherlands. One of the main targets of the Rotterdam Study is to identify the determinants and prognosis of cardiovascular diseases. Case finding in epidemiological studies is strongly depending on various sources of follow-up and clear outcome definitions. The sources used for collection of data in the Rotterdam Study are diverse and the definitions of outcomes in the Rotterdam Study have changed due to the introduction of novel diagnostics and therapeutic interventions. This article gives the methods for data collection and the up-to-date definitions of the cardiac outcomes based on international guidelines, including the recently adopted cardiovascular disease mortality definitions. In all, detailed description of cardiac outcome definitions enhances the possibility to make comparisons with other studies in the field of cardiovascular research and may increase the strength of collaborations.

Published
2012

38. Candidate gene studies and the quest for the entrepreneurial gene

Author

van der Loos, MJHM (Matthijs), Koellinger, PD, Groenen, Patrick, Rietveld, Niels, Rivadeneira, Fernando, van Rooij, FJA, Uitterlinden, André, Hofman, Bert, Thurik, Roy, van der Loos, MJHM (Matthijs), Koellinger, PD, Groenen, Patrick, Rietveld, Niels, Rivadeneira, Fernando, van Rooij, FJA, Uitterlinden, André, Hofman, Bert, and Thurik, Roy

Abstract

Candidate gene studies of human behavior are gaining interest in economics and entrepreneurship research. Performing and interpreting these studies is not straightforward because the selection of candidates influences the interpretation of the results. As an example, Nicolaou et al. (Small Bus Econ 36:151¿155, 2011) report a significant association between a common genetic variant in the DRD3 gene and the tendency to be an entrepreneur. We fail to replicate this finding using a much larger, independent dataset. In addition, we discuss the candidate gene approach and give suggestions to avoid the publication of false positives.

Published
2011

40. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels

Author

Meyer, TE, Verwoert, GC, Hwang, SJ, Glazer, NL, Smith, AV, van Rooij, FJA, Ehret, GB, Boerwinkle, E, Felix, JF, Leak, TS, Harris, TB, Yang, Q, Dehghan, A, Aspelund, T, Katz, R, Homuth, G, Kocher, T, Rettig, R, Ried, JS, Gieger, C, Prucha, H, Pfeufer, A, Meitinger, T, Coresh, J, Hofman, A, Sarnak, MJ, Chen, YDI, Uitterlinden, AG, Chakravarti, A, Psaty, BM, van Duijn, CM, Linda-Kao, WH, Witteman, JCM, Gudnason, V, Siscovick, DS, Fox, CS, Köttgen, A, Meyer, TE, Verwoert, GC, Hwang, SJ, Glazer, NL, Smith, AV, van Rooij, FJA, Ehret, GB, Boerwinkle, E, Felix, JF, Leak, TS, Harris, TB, Yang, Q, Dehghan, A, Aspelund, T, Katz, R, Homuth, G, Kocher, T, Rettig, R, Ried, JS, Gieger, C, Prucha, H, Pfeufer, A, Meitinger, T, Coresh, J, Hofman, A, Sarnak, MJ, Chen, YDI, Uitterlinden, AG, Chakravarti, A, Psaty, BM, van Duijn, CM, Linda-Kao, WH, Witteman, JCM, Gudnason, V, Siscovick, DS, Fox, CS, and Köttgen, A

Abstract

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ~2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10-8) or suggestive associations (p<4×10-7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10-7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

Published
2010

44. Genome-wide associations for birth weight and correlations with adult disease

Author

Horikoshi, M, Beaumont, RN, Day, FR, Warrington, NM, Kooijman, MN, Fernandez-Tajes, J, Feenstra, B, Van Zuydam, NR, Gaulton, KJ, Grarup, N, Bradfield, JP, Strachan, DP, Li-Gao, R, Ahluwalia, TS, Kreiner, E, Rueedi, R, Lyytikäinen, L-P, Cousminer, DL, Wu, Y, Thiering, E, Wang, CA, Have, CT, Hottenga, J-J, Vilor-Tejedor, N, Joshi, PK, Boh, ETH, Ntalla, I, Pitkänen, N, Mahajan, A, Van Leeuwen, EM, Joro, R, Lagou, V, Nodzenski, M, Diver, LA, Zondervan, KT, Bustamante, M, Marques-Vidal, P, Mercader, JM, Bennett, AJ, Rahmioglu, N, Nyholt, DR, Ma, RCW, Tam, CHT, Tam, WH, CHARGE Consortium Hematology Working Group, Ganesh, SK, Van Rooij, FJA, Jones, SE, Loh, P-R, Ruth, KS, Tuke, MA, Tyrrell, J, Wood, AR, Yaghootkar, H, Scholtens, DM, Paternoster, L, Prokopenko, I, Kovacs, P, Atalay, M, Willems, SM, Panoutsopoulou, K, Wang, X, Carstensen, L, Geller, F, Schraut, KE, Murcia, M, Van Beijsterveldt, CEM, Willemsen, G, Appel, EVR, Fonvig, CE, Trier, C, Tiesler, CMT, Standl, M, Kutalik, Z, Bonàs-Guarch, S, Hougaard, DM, Sánchez, F, Torrents, D, Waage, J, Hollegaard, MV, De Haan, HG, Rosendaal, FR, Medina-Gomez, C, Ring, SM, Hemani, G, McMahon, G, Robertson, NR, Groves, CJ, Langenberg, C, Luan, J, Scott, RA, Zhao, JH, Mentch, FD, MacKenzie, SM, Reynolds, RM, Early Growth Genetics (EGG) Consortium, Lowe, WL, Tönjes, A, Stumvoll, M, Lindi, V, Lakka, TA, Van Duijn, CM, Kiess, W, Körner, A, Sørensen, TIA, Niinikoski, H, Pahkala, K, Raitakari, OT, Zeggini, E, Dedoussis, GV, Teo, Y-Y, Saw, S-M, Melbye, M, Campbell, H, Wilson, JF, Vrijheid, M, De Geus, EJCN, Boomsma, DI, Kadarmideen, HN, Holm, J-C, Hansen, T, Sebert, S, Hattersley, AT, Beilin, LJ, Newnham, JP, Pennell, CE, Heinrich, J, Adair, LS, Borja, JB, Mohlke, KL, Eriksson, JG, Widén, E, Kähönen, M, Viikari, JS, Lehtimäki, T, Vollenweider, P, Bønnelykke, K, Bisgaard, H, Mook-Kanamori, DO, Hofman, A, Rivadeneira, F, Uitterlinden, AG, Pisinger, C, Pedersen, O, Power, C, Hyppönen, E, Wareham, NJ, Hakonarson, H, Davies, E, Walker, BR, Jaddoe, VWV, Järvelin, M-R, Grant, SFA, Vaag, AA, Lawlor, DA, Frayling, TM, Smith, GD, Morris, AP, Ong, KK, Felix, JF, Timpson, NJ, Perry, JRB, Evans, DM, McCarthy, MI, and Freathy, RM

Subjects
quantitative trait, hypertension, intrauterine growth, genome-wide association studies, metabolic disorders, 3. Good health
Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$ < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$ = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$ = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$ = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

45. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.

Author

Huffman JE, Nicholas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen MH, Emmert DB, Ghanbari M, Haessler J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg A, Mangino M, Marioni RE, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BAT, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer P, Cho MH, Christofidou P, Davies G, de Geus E, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gögele M, Greinacher A, Gao H, Howard T, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Paüls-Vergés F, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JC, van Rooij FJA, Wang H, Zhao W, Becker LC, Beswick A, Brown MR, Cade BE, Campbell H, Cho K, Crapo JD, Curran JE, de Maat MPM, Doyle M, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris SE, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orrù V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott DJ, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson PWF, Ben-Shlomo Y, Blangero J, Boomsma D, Cox SR, Dehghan A, Eriksson JG, Fiorillo E, Fornage M, Hansen T, Hayward C, Ikram MA, Jukema JW, Kardia SLR, Lange LA, März W, Mathias RA, Mitchell BD, Mook-Kanamori DO, Morange PE, Pedersen O, Pramstaller PP, Redline S, Reiner A, Ridker PM, Silverman EK, Spector TD, Völker U, Wareham NJ, Wilson JF, Yao J, Trégouët DA, Johnson AD, Wolberg AS, de Vries PS, Sabater-Lleal M, Morrison AC, and Smith NL

Subjects
Humans, Liver metabolism, Polymorphism, Single Nucleotide, Whole Genome Sequencing, Female, Male, Gene Frequency, Fibrinogen genetics, Fibrinogen metabolism, Genome-Wide Association Study
Abstract

Abstract: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

Published
2024
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46. Plasma Extracellular MicroRNAs Associated With Cardiovascular Disease Risk Factors in Middle-Aged and Older Adults.

Author

Karlin H, Sooda M, Larson M, Rong J, Huan T, Mens MMJ, van Rooij FJA, Ikram MA, Courchesne P, Freedman JE, Joehanes R, Mueller GP, Kavousi M, Ghanbari M, and Levy D

Subjects
Humans, Male, Female, Middle Aged, Aged, Prospective Studies, Cross-Sectional Studies, Risk Assessment, Circulating MicroRNA blood, Circulating MicroRNA genetics, Risk Factors, Biomarkers blood, Age Factors, Cardiovascular Diseases genetics, Cardiovascular Diseases blood, Cardiovascular Diseases mortality, MicroRNAs blood, MicroRNAs genetics, Heart Disease Risk Factors
Abstract

Background: Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level., Methods and Results: Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants. Linear regression analyses were conducted to test the cross-sectional associations of each miRNA with 8 CVD risk factors. Prospective analyses of the associations of miRNAs with new-onset obesity, hypertension, type 2 diabetes, CVD, and all-cause mortality were conducted using proportional hazards regression. Replication was carried out in 1999 RS (Rotterdam Study) participants. Pathway enrichment analyses were conducted and target genes were predicted for miRNAs associated with ≥5 risk factors in the FHS. In the FHS, 6 miRNAs (miR-193b-3p, miR-122-5p, miR-365a-3p, miR-194-5p, miR-192-5p, and miR-193a-5p) were associated with ≥5 risk factors. This miRNA signature was enriched for pathways associated with CVD and several genes annotated to these pathways were predicted targets of the identified miRNAs. Furthermore, miR-193b-3p, miR-194-5p, and miR-193a-5p were each associated with ≥2 risk factors in the RS. Prospective analysis revealed 8 miRNAs associated with all-cause mortality in the FHS., Conclusions: These findings highlight associations between miRNAs and CVD risk factors that may provide valuable insights into the underlying pathogenesis of CVD.

Published
2024
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47. Association between long-term use of calcium channel blockers (CCB) and the risk of breast cancer: a retrospective longitudinal observational study protocol.

Author

Ho C, Ha NT, Youens D, Abhayaratna WP, Bulsara MK, Hughes JD, Mishra G, Pearson SA, Preen DB, Reid CM, Ruiter R, Saunders CM, Stricker BH, van Rooij FJA, Wright C, and Moorin R

Subjects
Female, Humans, Calcium Channel Blockers adverse effects, Retrospective Studies, Longitudinal Studies, Mastectomy, Australia epidemiology, Observational Studies as Topic, Meta-Analysis as Topic, Breast Neoplasms chemically induced, Breast Neoplasms drug therapy, Hypertension drug therapy
Abstract

Introduction: Calcium channel blockers (CCB), a commonly prescribed antihypertensive (AHT) medicine, may be associated with increased risk of breast cancer. The proposed study aims to examine whether long-term CCB use is associated with the development of breast cancer and to characterise the dose-response nature of any identified association, to inform future hypertension management., Methods and Analysis: The study will use data from 2 of Australia's largest cohort studies; the Australian Longitudinal Study on Women's Health, and the 45 and Up Study, combined with the Rotterdam Study. Eligible women will be those with diagnosed hypertension, no history of breast cancer and no prior CCB use at start of follow-up (2004-2009). Cumulative dose-duration exposure to CCB and other AHT medicines will be captured at the earliest date of: the outcome (a diagnosis of invasive breast cancer); a competing risk event (eg, bilateral mastectomy without a diagnosis of breast cancer, death prior to any diagnosis of breast cancer) or end of follow-up (censoring event). Fine and Gray competing risks regression will be used to assess the association between CCB use and development of breast cancer using a generalised propensity score to adjust for baseline covariates. Time-varying covariates related to interaction with health services will also be included in the model. Data will be harmonised across cohorts to achieve identical protocols and a two-step random effects individual patient-level meta-analysis will be used., Ethics and Dissemination: Ethical approval was obtained from the following Human research Ethics Committees: Curtin University (ref No. HRE2022-0335), NSW Population and Health Services Research Ethics Committee (2022/ETH01392/2022.31), ACT Research Ethics and Governance Office approval under National Mutual Acceptance for multijurisdictional data linkage research (2022.STE.00208). Results of the proposed study will be published in high-impact journals and presented at key scientific meetings., Trial Registration Number: NCT05972785., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Published
2024
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48. The Rotterdam Study. Design update and major findings between 2020 and 2024.

Author

Ikram MA, Kieboom BCT, Brouwer WP, Brusselle G, Chaker L, Ghanbari M, Goedegebure A, Ikram MK, Kavousi M, de Knegt RJ, Luik AI, van Meurs J, Pardo LM, Rivadeneira F, van Rooij FJA, Vernooij MW, Voortman T, and Terzikhan N

Subjects
Aged, Humans, Adult, Middle Aged, Cohort Studies, Netherlands epidemiology, Health Personnel
Abstract

The Rotterdam Study is a population-based cohort study, started in 1990 in the district of Ommoord in the city of Rotterdam, the Netherlands, with the aim to describe the prevalence and incidence, unravel the etiology, and identify targets for prediction, prevention or intervention of multifactorial diseases in mid-life and elderly. The study currently includes 17,931 participants (overall response rate 65%), aged 40 years and over, who are examined in-person every 3 to 5 years in a dedicated research facility, and who are followed-up continuously through automated linkage with health care providers, both regionally and nationally. Research within the Rotterdam Study is carried out along two axes. First, research lines are oriented around diseases and clinical conditions, which are reflective of medical specializations. Second, cross-cutting research lines transverse these clinical demarcations allowing for inter- and multidisciplinary research. These research lines generally reflect subdomains within epidemiology. This paper describes recent methodological updates and main findings from each of these research lines. Also, future perspective for coming years highlighted., (© 2024. Springer Nature B.V.)

Published
2024
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49. Predicting amyloid-beta pathology in the general population.

Author

Nguyen Ho PT, van Arendonk J, Steketee RME, van Rooij FJA, Roshchupkin GV, Ikram MA, Vernooij MW, and Neitzel J

Subjects
Adult, Humans, Aged, Apolipoprotein E4 genetics, Cognition, Amyloid, Amyloid beta-Peptides, Alzheimer Disease diagnosis, Alzheimer Disease genetics, Alzheimer Disease pathology
Abstract

Introduction: Reliable models to predict amyloid beta (Aβ) positivity in the general aging population are lacking but could become cost-efficient tools to identify individuals at risk of developing Alzheimer's disease., Methods: We developed Aβ prediction models in the clinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study (n = 4,119) including a broad range of easily ascertainable predictors (demographics, cognition and daily functioning, health and lifestyle factors). Importantly, we determined the generalizability of our models in the population-based Rotterdam Study (n = 500)., Results: The best performing model in the A4 Study (area under the curve [AUC] = 0.73 [0.69-0.76]), including age, apolipoprotein E (APOE) ε4 genotype, family history of dementia, and subjective and objective measures of cognition, walking duration and sleep behavior, was validated in the independent Rotterdam Study with higher accuracy (AUC = 0.85 [0.81-0.89]). Yet, the improvement relative to a model including only age and APOE ε4 was marginal., Discussion: Aβ prediction models including inexpensive and non-invasive measures were successfully applied to a general population-derived sample more representative of typical older non-demented adults., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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50. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.

Author

Wang Z, Emmerich A, Pillon NJ, Moore T, Hemerich D, Cornelis MC, Mazzaferro E, Broos S, Ahluwalia TS, Bartz TM, Bentley AR, Bielak LF, Chong M, Chu AY, Berry D, Dorajoo R, Dueker ND, Kasbohm E, Feenstra B, Feitosa MF, Gieger C, Graff M, Hall LM, Haller T, Hartwig FP, Hillis DA, Huikari V, Heard-Costa N, Holzapfel C, Jackson AU, Johansson Å, Jørgensen AM, Kaakinen MA, Karlsson R, Kerr KF, Kim B, Koolhaas CM, Kutalik Z, Lagou V, Lind PA, Lorentzon M, Lyytikäinen LP, Mangino M, Metzendorf C, Monroe KR, Pacolet A, Pérusse L, Pool R, Richmond RC, Rivera NV, Robiou-du-Pont S, Schraut KE, Schulz CA, Stringham HM, Tanaka T, Teumer A, Turman C, van der Most PJ, Vanmunster M, van Rooij FJA, van Vliet-Ostaptchouk JV, Zhang X, Zhao JH, Zhao W, Balkhiyarova Z, Balslev-Harder MN, Baumeister SE, Beilby J, Blangero J, Boomsma DI, Brage S, Braund PS, Brody JA, Bruinenberg M, Ekelund U, Liu CT, Cole JW, Collins FS, Cupples LA, Esko T, Enroth S, Faul JD, Fernandez-Rhodes L, Fohner AE, Franco OH, Galesloot TE, Gordon SD, Grarup N, Hartman CA, Heiss G, Hui J, Illig T, Jago R, James A, Joshi PK, Jung T, Kähönen M, Kilpeläinen TO, Koh WP, Kolcic I, Kraft PP, Kuusisto J, Launer LJ, Li A, Linneberg A, Luan J, Vidal PM, Medland SE, Milaneschi Y, Moscati A, Musk B, Nelson CP, Nolte IM, Pedersen NL, Peters A, Peyser PA, Power C, Raitakari OT, Reedik M, Reiner AP, Ridker PM, Rudan I, Ryan K, Sarzynski MA, Scott LJ, Scott RA, Sidney S, Siggeirsdottir K, Smith AV, Smith JA, Sonestedt E, Strøm M, Tai ES, Teo KK, Thorand B, Tönjes A, Tremblay A, Uitterlinden AG, Vangipurapu J, van Schoor N, Völker U, Willemsen G, Williams K, Wong Q, Xu H, Young KL, Yuan JM, Zillikens MC, Zonderman AB, Ameur A, Bandinelli S, Bis JC, Boehnke M, Bouchard C, Chasman DI, Smith GD, de Geus EJC, Deldicque L, Dörr M, Evans MK, Ferrucci L, Fornage M, Fox C, Garland T Jr, Gudnason V, Gyllensten U, Hansen T, Hayward C, Horta BL, Hyppönen E, Jarvelin MR, Johnson WC, Kardia SLR, Kiemeney LA, Laakso M, Langenberg C, Lehtimäki T, Marchand LL, Magnusson PKE, Martin NG, Melbye M, Metspalu A, Meyre D, North KE, Ohlsson C, Oldehinkel AJ, Orho-Melander M, Pare G, Park T, Pedersen O, Penninx BWJH, Pers TH, Polasek O, Prokopenko I, Rotimi CN, Samani NJ, Sim X, Snieder H, Sørensen TIA, Spector TD, Timpson NJ, van Dam RM, van der Velde N, van Duijn CM, Vollenweider P, Völzke H, Voortman T, Waeber G, Wareham NJ, Weir DR, Wichmann HE, Wilson JF, Hevener AL, Krook A, Zierath JR, Thomis MAI, Loos RJF, and Hoed MD

Subjects
Actinin genetics, Cross-Sectional Studies, Exercise physiology, Humans, Leisure Activities, Genome-Wide Association Study, Sedentary Behavior
Abstract

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention., (© 2022. The Author(s).)

Published
2022
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