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1. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author: Sterenborg, R.B.T.M., Steinbrenner, I., Li, Yong, Bujnis, M.N., Naito, T., Marouli, E., Galesloot, T.E., Babajide, O., Andreasen, L., Astrup, A., Åsvold, B.O., Bandinelli, S., Beekman, M., Beilby, J.P., Bork-Jensen, J., Boutin, T., Brody, J.A., Brown, S.J., Brumpton, B., Campbell, P.J., Cappola, A.R., Ceresini, G., Chaker, L., Chasman, D.I., Concas, M.P., Coutinho de Almeida, Rodrigo, Cross, S.M., Cucca, F., Deary, I.J., Kjaergaard, A.D., Echouffo Tcheugui, J.B., Ellervik, C., Eriksson, J.G., Ferrucci, L., Freudenberg, J., Fuchsberger, C., Gieger, C., Giulianini, F., Gögele, M., Graham, S.E., Grarup, N., Gunjača, I., Hansen, T., Harding, B.N., Harris, S.E., Haunsø, S., Hayward, C., Hui, J., Ittermann, T., Jukema, J.W., Kajantie, E., Kanters, J.K., Kårhus, L.L., Kiemeney, L.A.L.M., Kühnel, B., Lahti, J., Langenberg, C., Lapauw, B., Leese, G., Li, Shuo, Liewald, D.C.M., Linneberg, A., Lominchar, J.V.T., Luan, Jian'an, Martin, N.G., Matana, A., Meima, M.E., Meitinger, T., Meulenbelt, I., Mitchell, B.D., Møllehave, L.T., Mora, S., Naitza, S., Nauck, M., Netea-Maier, R.T., Noordam, R., Nursyifa, C., Okada, Y., Onano, S., Papadopoulou, A., Palmer, C.N.A., Pattaro, C., Pedersen, O., Peters, A., Pietzner, M., Polašek, O., Pramstaller, P.P., Psaty, B.M., Punda, A., Ray, D., Redmond, P., Richards, J.B., Ridker, P.M., Russ, T.C., Ryan, K.A., Olesen, M.S., Schultheiss, U.T., Selvin, E., Siddiqui, M.K., Teumer, A., Medici, M., Sterenborg, R.B.T.M., Steinbrenner, I., Li, Yong, Bujnis, M.N., Naito, T., Marouli, E., Galesloot, T.E., Babajide, O., Andreasen, L., Astrup, A., Åsvold, B.O., Bandinelli, S., Beekman, M., Beilby, J.P., Bork-Jensen, J., Boutin, T., Brody, J.A., Brown, S.J., Brumpton, B., Campbell, P.J., Cappola, A.R., Ceresini, G., Chaker, L., Chasman, D.I., Concas, M.P., Coutinho de Almeida, Rodrigo, Cross, S.M., Cucca, F., Deary, I.J., Kjaergaard, A.D., Echouffo Tcheugui, J.B., Ellervik, C., Eriksson, J.G., Ferrucci, L., Freudenberg, J., Fuchsberger, C., Gieger, C., Giulianini, F., Gögele, M., Graham, S.E., Grarup, N., Gunjača, I., Hansen, T., Harding, B.N., Harris, S.E., Haunsø, S., Hayward, C., Hui, J., Ittermann, T., Jukema, J.W., Kajantie, E., Kanters, J.K., Kårhus, L.L., Kiemeney, L.A.L.M., Kühnel, B., Lahti, J., Langenberg, C., Lapauw, B., Leese, G., Li, Shuo, Liewald, D.C.M., Linneberg, A., Lominchar, J.V.T., Luan, Jian'an, Martin, N.G., Matana, A., Meima, M.E., Meitinger, T., Meulenbelt, I., Mitchell, B.D., Møllehave, L.T., Mora, S., Naitza, S., Nauck, M., Netea-Maier, R.T., Noordam, R., Nursyifa, C., Okada, Y., Onano, S., Papadopoulou, A., Palmer, C.N.A., Pattaro, C., Pedersen, O., Peters, A., Pietzner, M., Polašek, O., Pramstaller, P.P., Psaty, B.M., Punda, A., Ray, D., Redmond, P., Richards, J.B., Ridker, P.M., Russ, T.C., Ryan, K.A., Olesen, M.S., Schultheiss, U.T., Selvin, E., Siddiqui, M.K., Teumer, A., and Medici, M.
Abstract: Contains fulltext : 304858.pdf (Publisher’s version ) (Open Access), To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.
Published: 2024

2. Thyroid function and atrial fibrillation: Is there a mediating role for epicardial adipose tissue?

Author: Bos D, Bano A, Hofman A, VanderWeele TJ, Kavousi M, Franco OH, Vernooij MW, Peeters RP, Ikram MA, and Chaker L
Subjects: thyroid function, epicardial fat, atrial fibrillation, causal mediation analysis, Infectious and parasitic diseases, RC109-216
Abstract: Daniel Bos,1–3,* Arjola Bano,2,4,5,* Albert Hofman,1,2 Tyler J VanderWeele,1 Maryam Kavousi,2 Oscar H Franco,2 Meike W Vernooij,2,3 Robin P Peeters,2,4,5 M Arfan Ikram,1,2 Layal Chaker,1,2,4,5 1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 2Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands; 3Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands; 4Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, The Netherlands; 5Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands *These authors contributed equally to this work Background: The underlying mechanism of the association between thyroid function and atrial fibrillation (AF) is poorly understood, but epicardial adipose tissue (EAT) could be a promising mediator.Methods: In the 1995 participants (mean age 64.5 years) from the population-based Rotterdam Study, we measured thyroid function (thyroid-stimulating hormone, free thyroxine [FT4]) and performed computed tomography to quantify EAT volumes. All participants were followed for the occurrence of AF. We assessed associations of thyroid-stimulating hormone and FT4 with EAT and AF and performed causal mediation analysis to decompose the overall effect of thyroid function on AF with EAT as mediator.Results: Higher FT4 levels were associated with larger EAT volumes in persons with large waist circumferences, defined by sex-specific cutoffs (0.08 mL more EAT per 1-SD increase in FT4, 95% CI: 0.02, 0.14), but not in persons with a normal waist circumference. In persons with a large waist circumference, higher FT4 levels were associated with a higher AF risk (hazard ratio 1.50, 95% CI: 1.22, 1.83). We found no evidence of a mediating role of EAT in the association of thyroid function with AF (mediated interaction 1.6%, pure indirect effect 3.2%). The estimate of reference interaction of EAT with thyroid function on AF risk was more substantial (10.8%), but statistically nonsignificant.Conclusions: Higher FT4 levels are associated with larger EAT volumes in persons with abdominal obesity. We report no mediating role of EAT in the association of thyroid function with AF, but found evidence for a suggested interaction of FT4 with EAT volumes on AF risk. Keywords: thyroid function, epicardial fat, atrial fibrillation, causal mediation analysis
Published: 2018

3. Porphyrin - Fullerene host - Guest chemistry [1]

Author: Sun, D, Tham, FS, Reed, CA, Chaker, L, Burgess, M, and Boyd, PDW
Subjects: General Chemistry, Chemical Sciences
Published: 2000

4. Selective supramolecular porphyrin/fullerene interactions

Author: Boyd, PDW, Hodgson, MC, Rickard, CEF, Oliver, AG, Chaker, L, Brothers, PJ, Bolskar, RD, Tham, FS, and Reed, CA
Subjects: General Chemistry, Chemical Sciences
Abstract: Naturally assembling cocrystallates of C60 and C70 fullerenes with tetraphenylporphyrins (H2TPP · C60 · 3 toluene, 1; H2T(3,5-dibutyl)PP · C60, 2; H2T(3,5-dimethyl)PP · 1.5C60 · 2 toluene, 3; H2T(piv)PP · C60, 4; H2T(3,5-dimethyl)PP · C70 · 4 toluene, 5; ZnTPP · C70, 6; NiT(4-methyl)PP · 2C70 · 2 toluene, 7) show unusually short porphyrin/fullerene contacts (2.7-3.0 Å) compared with typical π-π interactions (3.0-3.5 Å). In the C60 structures, an electron-rich, 6:6 ring juncture, C-C bond lies over the center of the porphyrin ring. In the C70 structures, the ellipsoidal fullerene makes porphyrin contact at its equator rather than its poles; a carbon atom from three fused six-membered rings lies closest to the center of the porphyrin. These structures provide an explanation for the manner in which tetraphenylporphyrin-appended silica stationary phases effect the chromatographic separation of fullerenes. The interaction of the curved π surface of a fullerene with the planar π surface of a porphyrin, without the need for matching convex with concave surfaces, represents a new recognition element in supramolecular chemistry. NMR measurements show that this interaction persists in toluene solution, suggesting a simple way to assemble van der Waals complexes of donor-acceptor chromophores.
Published: 1999

5. The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Author: Xu, Y.F., Derakhshan, A., Hysaj, O., Wildisen, L., Ittermann, T., Pingitore, A., Abolhassani, N., Medici, M., Kiemeney, L.A., Riksen, N.P., Dullaart, R.P.F., Trompet, S., Dörr, M., Brown, S.J., Schmidt, Börge, Führer-Sakel, D., Vanderpump, M.P.J., Muendlein, A., Drexel, H., Fink, H.A., Ikram, M.K., Kavousi, M., Rhee, C.M., Bensenor, I.M., Azizi, F., Hankey, G.J., Iacoviello, M., Imaizumi, M., Ceresini, G., Ferrucci, L., Sgarbi, J.A., Bauer, D.C., Wareham, N., Boelaert, K., Bakker, S.J.L., Jukema, J.W., Vaes, B., Iervasi, G., Yeap, B.B., Westendorp, R.G.J., Korevaar, T.I.M., Völzke, H., Razvi, S., Gussekloo, J., Walsh, J.P., Cappola, A.R., Rodondi, N., Peeters, R.P., Chaker, L., Xu, Y.F., Derakhshan, A., Hysaj, O., Wildisen, L., Ittermann, T., Pingitore, A., Abolhassani, N., Medici, M., Kiemeney, L.A., Riksen, N.P., Dullaart, R.P.F., Trompet, S., Dörr, M., Brown, S.J., Schmidt, Börge, Führer-Sakel, D., Vanderpump, M.P.J., Muendlein, A., Drexel, H., Fink, H.A., Ikram, M.K., Kavousi, M., Rhee, C.M., Bensenor, I.M., Azizi, F., Hankey, G.J., Iacoviello, M., Imaizumi, M., Ceresini, G., Ferrucci, L., Sgarbi, J.A., Bauer, D.C., Wareham, N., Boelaert, K., Bakker, S.J.L., Jukema, J.W., Vaes, B., Iervasi, G., Yeap, B.B., Westendorp, R.G.J., Korevaar, T.I.M., Völzke, H., Razvi, S., Gussekloo, J., Walsh, J.P., Cappola, A.R., Rodondi, N., Peeters, R.P., and Chaker, L.
Abstract: Contains fulltext : 297328.pdf (Publisher’s version ) (Closed access), BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT(4)) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT(4) based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT(4), and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT(4), thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 co
Published: 2023

6. Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms

Author: Amin, N, Jovanova, O, Adams, H H H, Dehghan, A, Kavousi, M, Vernooij, M W, Peeters, R P, de Vrij, F M S, van der Lee, S J, van Rooij, J G J, van Leeuwen, E M, Chaker, L, Demirkan, A, Hofman, A, Brouwer, R W W, Kraaij, R, Willems van Dijk, K, Hankemeier, T, van Ijcken, W F J, Uitterlinden, A G, Niessen, W J, Franco, O H, Kushner, S A, Ikram, M A, Tiemeier, H, and van Duijn, C M
Published: 2017
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7. Association between serum IgG levels and time to first antibiotic prescription in COPD patients

Author: Vanoverschelde, A, primary, Khan, S R, additional, Dalm, V A, additional, Chaker, L, additional, Brusselle, G, additional, Stricker, B H, additional, and Lahousse, L, additional
Published: 2022
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8. The association of maternal thyroid function with placental hemodynamics

Author: Barjaktarovic, M., Korevaar, T.I.M., Chaker, L., Jaddoe, V.W.V., de Rijke, Y.B., Visser, T.J., Steegers, E.A.P., and Peeters, R.P.
Published: 2017
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9. Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies

Author: Syrogiannouli, L., Wildisen, L., Meuwese, C., Bauer, D.C., Cappola, A.R., Gussekloo, J., Elzen, W.P.J. den, Trompet, S., Westendorp, R.G.J., Jukema, J.W., Ferrucci, L., Ceresini, G., Asvold, B.O., Chaker, L., Peeters, R.P., Imaizumi, M., Ohishi, W., Vaes, B., Volzke, H., Sgarbi, J.A., Walsh, J.P., Dullaart, R.P.F., Bakker, S.J.L., Iacoviello, M., Rodondi, N., Giovane, C. del, Thyroid Studies Collaboration, Epidemiology, Internal Medicine, Laboratory for Endocrinology, APH - Personalized Medicine, APH - Aging & Later Life, Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)
Subjects: baseline imbalance, cohorts, continuous outcome, individual participant data, non-randomized studies, Prevention, Clinical Sciences, 360 Soziale Probleme, Sozialdienste, 610 Medicine & health, Psychiatry and Mental health, SDG 3 - Good Health and Well-being, 360 Social problems & social services, Public Health and Health Services, Psychology, 610 Medizin und Gesundheit
Abstract: BackgroundIn non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).MethodsFor the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.ResultsTen of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.ConclusionANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.
Published: 2022
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10. Thyroid Status and Brain Circulation: The Rotterdam Study.

Author: Fani, L., Roa Dueñas, O., Bos, D., Vernooij, M.W., Klaver, C.C.W., Ikram, M.K., Peeters, R.P., Ikram, M.Arfan, Chaker, L., Fani, L., Roa Dueñas, O., Bos, D., Vernooij, M.W., Klaver, C.C.W., Ikram, M.K., Peeters, R.P., Ikram, M.Arfan, and Chaker, L.
Abstract: Item does not contain fulltext, CONTEXT: Whether thyroid dysfunction is related to altered brain circulation in the general population remains unknown. OBJECTIVE: We determined the association of thyroid hormones with different markers of brain circulation within community-dwelling elderly people. METHODS: This was a population-based study of 3 subcohorts of the Rotterdam Study, starting in 1989, 2000, and 2006. A total of 5142 participants (mean age, 63.8 years; 55.4% women), underwent venipuncture to measure serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Between 2005 and 2015, all participants underwent phase-contrast brain magnetic resonance imaging to assess global brain perfusion (mL of blood flow/100 mL of brain/minute). Arteriolar retinal calibers were assessed using digitized images of stereoscopic fundus color transparencies in 3105 participants as markers of microcirculation. We investigated associations of TSH, FT4 with brain circulation measures using (non)linear regression models. RESULTS: FT4 (in pmol/L) levels had an inverse U-shaped association with global brain perfusion, such that high and low levels of FT4 were associated with lower global brain perfusion than middle levels of FT4. The difference in global brain perfusion between high FT4 levels (25 pmol/L) and middle FT4 levels (FT4 = 15 pmol/L; P nonlinearity = .002) was up to -2.44 mL (95% CI -4.31; -0.56). Higher and lower levels of FT4, compared with middle FT4 levels, were associated with arteriolar retinal vessels (mean difference up to -2.46 µm, 95% CI -4.98; 0.05 for lower FT4). CONCLUSION: These results suggest that thyroid dysfunction could lead to brain diseases such as stroke or dementia through suboptimal brain circulation that is potentially modifiable.
Published: 2022

11. Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia:a systematic review and individual-participant data meta-analysis

Author: Toloza, F. J. (Freddy J K), Derakhshan, A. (Arash), Männistö, T. (Tuija), Bliddal, S. (Sofie), Popova, P. V. (Polina V), Carty, D. M. (David M), Chen, L. (Liangmiao), Taylor, P. (Peter), Mosso, L. (Lorena), Oken, E. (Emily), Suvanto, E. (Eila), Itoh, S. (Sachiko), Kishi, R. (Reiko), Bassols, J. (Judit), Auvinen, J. (Juha), López-Bermejo, A. (Abel), Brown, S. J. (Suzanne J), Boucai, L. (Laura), Hisada, A. (Aya), Yoshinag, J. (Jun), Shilova, E. (Ekaterina), Grineva, E. N. (Elena N), Vrijkotte, T. G. (Tanja G M), Sunyer, J. (Jordi), Jiménez-Zabala, A. (Ana), Riaño-Galan, I. (Isolina), Lopez-Espinosa, M.-J. (Maria-Jose), Prokop, L. J. (Larry J), Singh Ospina, N. (Naykky), Brito, J. P. (Juan P), Rodriguez-Gutierrez, R. (Rene), Alexander, E. K. (Erik K), Chaker, L. (Layal), Pearce, E. N. (Elizabeth N), Peeters, R. P. (Robin P), Feldt-Rasmussen, U. (Ulla), Guxens, M. (Mònica), Chatzi, L. (Leda), Delles, C. (Christian), Roeters van Lennep, J. E. (Jeanine E), Pop, V. J. (Victor J M), Lu, X. (Xuemian), Walsh, J. P. (John P), Nelson, S. M. (Scott M), Korevaar, T. I. (Tim I M), Maraka, S. (Spyridoula), Toloza, F. J. (Freddy J K), Derakhshan, A. (Arash), Männistö, T. (Tuija), Bliddal, S. (Sofie), Popova, P. V. (Polina V), Carty, D. M. (David M), Chen, L. (Liangmiao), Taylor, P. (Peter), Mosso, L. (Lorena), Oken, E. (Emily), Suvanto, E. (Eila), Itoh, S. (Sachiko), Kishi, R. (Reiko), Bassols, J. (Judit), Auvinen, J. (Juha), López-Bermejo, A. (Abel), Brown, S. J. (Suzanne J), Boucai, L. (Laura), Hisada, A. (Aya), Yoshinag, J. (Jun), Shilova, E. (Ekaterina), Grineva, E. N. (Elena N), Vrijkotte, T. G. (Tanja G M), Sunyer, J. (Jordi), Jiménez-Zabala, A. (Ana), Riaño-Galan, I. (Isolina), Lopez-Espinosa, M.-J. (Maria-Jose), Prokop, L. J. (Larry J), Singh Ospina, N. (Naykky), Brito, J. P. (Juan P), Rodriguez-Gutierrez, R. (Rene), Alexander, E. K. (Erik K), Chaker, L. (Layal), Pearce, E. N. (Elizabeth N), Peeters, R. P. (Robin P), Feldt-Rasmussen, U. (Ulla), Guxens, M. (Mònica), Chatzi, L. (Leda), Delles, C. (Christian), Roeters van Lennep, J. E. (Jeanine E), Pop, V. J. (Victor J M), Lu, X. (Xuemian), Walsh, J. P. (John P), Nelson, S. M. (Scott M), Korevaar, T. I. (Tim I M), and Maraka, S. (Spyridoula)
Abstract: Background: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. Methods: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. Findings: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of thes
Published: 2022

12. Disentangling the association between kidney function and atrial fibrillation: a bidirectional Mendelian randomization study

Author: Geurts, S, primary, Van Der Burgh, A C, additional, Ikram, M A, additional, Kors, J A, additional, Stricker, B H C, additional, Deckers, J W, additional, Hoorn, E J, additional, Chaker, L, additional, and Kavousi, M, additional
Published: 2021
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13. Higher thyroid stimulating hormone leads to cardiovascular disease and an unfavorable lipid profile: EVidence from multi-cohort Mendelian randomization and metabolomic profiling

Author: Van Vliet, N.A., primary, Bos, M.M., additional, Thesing, C.S., additional, Chaker, L., additional, Pietzner, M., additional, Houtman, E., additional, Neville, M.J., additional, Li-Gao, R., additional, Trompet, S., additional, Mustafa, R., additional, Ahmadizar, F., additional, Beekman, M., additional, Bot, M., additional, Budde, K., additional, Christodoulides, C., additional, Dehghan, A., additional, Delles, C., additional, Elliott, P., additional, Evangelou, M., additional, Gao, H., additional, Ghanbari, M., additional, Van Herwaarden, A.E., additional, Ikram, M.A., additional, Jaeger, M., additional, Jukema, J.W., additional, Karaman, I., additional, Karpe, F., additional, Kloppenburg, M., additional, Meessen, J.M.T.A., additional, Meulenbelt, I., additional, Milaneschi, Y., additional, Mooijaart, S.P., additional, Mook-Kanamori, D.O., additional, Netea, M.G., additional, Netea-Maier, R.T., additional, Peeters, R.P., additional, Penninx, B.W.J.H., additional, Sattar, N., additional, Slagboom, P.E., additional, Suchiman, H.E.D., additional, Völzke, H., additional, Van Dijk, K. Willems, additional, and Noordam, R., additional
Published: 2021
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14. Psychological causes of non-compliance with electronically monitored occlusion therapy for amblyopia

Author: Loudon, S.E., Passchier, J., Chaker, L., de Vos, S., Fronius, M., Harrad, R.A., Looman, C.W.N., Simonsz, B., and Simonsz, H.J.
Subjects: Amblyopia -- Care and treatment, Amblyopia -- Psychological aspects, Amblyopia -- Research, Patient compliance -- Psychological aspects, Patient compliance -- Research, Therapeutics, Ophthalmological -- Usage, Therapeutics, Ophthalmological -- Research, Health
Published: 2009

15. Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk: A Mendelian Randomization Study

Author: Kuś, A., Marouli, E., Greco, M.F. Del, Chaker, L., Bednarczuk, T., Peeters, R.P., Teumer, A., Medici, M., Deloukas, P., Kuś, A., Marouli, E., Greco, M.F. Del, Chaker, L., Bednarczuk, T., Peeters, R.P., Teumer, A., Medici, M., and Deloukas, P.
Abstract: Item does not contain fulltext, Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 × 10(-4)). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (β = 0.026 SD, p = 1.9 × 10(-3)), pulse pressure (β = -0.477 mmHg, p = 7.5 × 10(-10)), and T2D risk (odds ratio = 0.95, p = 2.5 × 10(-3)). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 × 10(-4)). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.
Published: 2021

16. Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling

Author: Vliet, N.A. van, Bos, M.M., Thesing, C.S., Chaker, L., Pietzner, M., Houtman, E., Neville, M.J., Li-Gao, R., Trompet, S., Mustafa, R., Ahmadizar, F., Beekman, M., Bot, M., Budde, K., Christodoulides, C., Dehghan, A., Delles, C., Elliott, P., Evangelou, M., Gao, H., Ghanbari, M., Herwaarden, A.E. van, Ikram, M.Arfan, Jaeger, M., Jukema, J.W., Karaman, I., Karpe, F., Kloppenburg, M., Meessen, J., Meulenbelt, I., Milaneschi, Y., Mooijaart, S.P., Mook-Kanamori, D.O., Netea, M.G., Netea, R.T., Peeters, R.P., Penninx, B., Sattar, N., Slagboom, P.Eline, Suchiman, H. Eka D., Völzke, H., Dijk, K.W van, Noordam, R., Heemst, D. van, Vliet, N.A. van, Bos, M.M., Thesing, C.S., Chaker, L., Pietzner, M., Houtman, E., Neville, M.J., Li-Gao, R., Trompet, S., Mustafa, R., Ahmadizar, F., Beekman, M., Bot, M., Budde, K., Christodoulides, C., Dehghan, A., Delles, C., Elliott, P., Evangelou, M., Gao, H., Ghanbari, M., Herwaarden, A.E. van, Ikram, M.Arfan, Jaeger, M., Jukema, J.W., Karaman, I., Karpe, F., Kloppenburg, M., Meessen, J., Meulenbelt, I., Milaneschi, Y., Mooijaart, S.P., Mook-Kanamori, D.O., Netea, M.G., Netea, R.T., Peeters, R.P., Penninx, B., Sattar, N., Slagboom, P.Eline, Suchiman, H. Eka D., Völzke, H., Dijk, K.W van, Noordam, R., and Heemst, D. van
Abstract: Contains fulltext : 245686.pdf (Publisher’s version ) (Open Access), BACKGROUND: Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. METHODS: Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. RESULTS: Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.5
Published: 2021

17. Thyroid Function and Mood Disorders: A Mendelian Randomization Study

Author: Kuś, A., Kjaergaard, A.D., Marouli, E., Greco, M.F. Del, Sterenborg, R.B.T.M., Chaker, L., Peeters, R.P., Bednarczuk, T., Åsvold, B.O., Burgess, S., Deloukas, P., Teumer, A., Ellervik, C., Medici, M., Kuś, A., Kjaergaard, A.D., Marouli, E., Greco, M.F. Del, Sterenborg, R.B.T.M., Chaker, L., Peeters, R.P., Bednarczuk, T., Åsvold, B.O., Burgess, S., Deloukas, P., Teumer, A., Ellervik, C., and Medici, M.
Abstract: Item does not contain fulltext, Background: Observational studies suggest that even minor variations in thyroid function are associated with the risk of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). However, it is unknown whether these associations are causal or not. We used a Mendelian randomization (MR) approach to investigate causal effects of minor variations in thyrotropin (TSH) and free thyroxine (fT4) levels on MDD and BD risk. Materials and Methods: We performed two-sample MR analyses using data from the largest publicly available genome-wide association studies on normal-range TSH (n = 54,288) and fT4 (n = 49,269) levels, MDD (170,756 cases, 329,443 controls) and BD (20,352 cases, 31,358 controls). Secondary MR analyses investigated the effects of TSH and fT4 levels on specific MDD and BD subtypes. Reverse MR was also performed to assess the effects of MDD and BD on TSH and fT4 levels. Results: There were no associations between genetically predicted TSH and fT4 levels and MDD risk, nor MDD subtypes and minor depressive symptoms. A one standard deviation increase in fT4 levels was nominally associated with an 11% decrease in the overall BD risk (odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.80-0.98, p = 0.022) and a 13% decrease in the BD type 1 risk (OR = 0.87, CI = 0.75-1.00, p = 0.047). In the reverse direction, genetic predisposition to MDD and BD was not associated with TSH nor fT4 levels. Conclusions: Variations in normal-range TSH and fT4 levels have no effects on the risk of MDD and its subtypes, and neither on minor depressive symptoms. This indicates that depressive symptoms should not be attributed to minor variations in thyroid function. Borderline associations with BD and BD type 1 risks suggest that further clinical studies should investigate the effect of thyroid hormone treatment in BD.
Published: 2021

18. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author: Gorski, M. (Mathias), Jung, B. (Bettina), Li, Y. (Yong), Matias-Garcia, P.R. (Pamela R.), Wuttke, M. (Matthias), Coassin, S. (Stefan), Thio, C.H.L. (Chris H.L.), Kleber, M.E. (Marcus E.), Winkler, T.W. (Thomas W.), Wanner, V. (Veronika), Chai, J.-F. (Jin-Fang), Chu, A.Y. (Audrey Y), Cocca, M. (Massimiliano), Feitosa, M.F. (Mary Furlan), Ghasemi, S. (Sahar), Hoppmann, A. (Anselm), Horn, K. (Katrin), Li, M. (Man), Nutile, T. (Teresa), Scholz, M. (Markus), Sieber, K.B. (Karsten B.), Teumer, A. (Alexander), Tin, A. (Adrienne), Wang, J. (Judy), Tayo, B. (Bamidele), Ahluwalia, T.S. (Tarunveer Singh), Almgren, P. (Peter), Bakker, S.J.L. (Stephan), Banas, B. (Bernhard), Bansal, N. (Nisha), Biggs, M.L. (M.), Boerwinkle, E.A. (Eric), Bottinger, E.P. (Erwin), Brenner, H. (Hermann), Carroll, R.J. (Robert J.), Chalmers, J. (John), Chee, M.-L. (Miao-Li), Chee, M.-L. (Miao-Ling), Cheng, C.-Y. (Ching-Yu), Coresh, J. (Josef), de Borst, M.H. (Martin H.), Degenhardt, F. (Frauke), Eckardt, K.-U. (Kai-Uwe), Endlich, K. (Karlhans), Franke, A. (Andre), Freitag-Wolf, S. (Sandra), Gampawar, P. (Piyush), Gansevoort, R.T. (Ron), Ghanbari, M. (Mohsen), Gieger, C. (Christian), Hamet, P. (Pavel), Ho, K. (Kevin), Hofer, E. (Edith), Holleczek, B. (B.), Xian Foo, V.H. (Valencia Hui), Hutri-Kähönen, N. (Nina), Hwang, S.-J. (Shih-Jen), Ikram, M.A. (Arfan), Josyula, N.S. (Navya Shilpa), Kähönen, M. (Mika), Khor, C.C., Koenig, W. (Wolfgang), Kramer, H. (Holly), Krämer, B.K. (Bernhard), Kuhnel, B. (Brigitte), Lange, L.A. (Leslie A.), Lehtimäki, T. (Terho), Lieb, W. (Wolfgang), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (H. Marike), Franke, L. (Lude), van der Harst, P. (Pim), Matullo, G., Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M. (Morris), Wolffenbuttel, B.H.R. (Bruce), Wijmenga, C. (Cisca), Abecasis, G.R. (Gonçalo), Baras, A. (Aris), Cantor, M. (Michael), Coppola, G. (Giovanni), Economides, A. (Aris), Lotta, L.A. (Luca A.), Overton, J.D. (John D.), Reid, J.G. (Jeffrey G.), Shuldiner, A. (Alan), Beechert, C. (Christina), Forsythe, C. (Caitlin), Fuller, E.D. (Erin D.), Gu, Z. (Zhenhua), Lattari, M. (Michael), Lopez, A. (Alexander), Schleicher, T.D. (Thomas D.), Padilla, M.S. (Maria Sotiropoulos), Toledo, K. (Karina), Widom, L. (Louis), Wolf, S.E. (Sarah E.), Pradhan, M. (Manasi), Manoochehri, K. (Kia), Ulloa, R.H. (Ricardo H.), Bai, X. (Xiaodong), Balasubramanian, S. (Suganthi), Barnard, L. (Leland), Blumenfeld, A. (Andrew), Eom, G. (Gisu), Habegger, L. (Lukas), Hawes, A. (Alicia), Khalid, S. (Shareef), Maxwell, E.K. (Evan K.), Salerno, W. (William), Staples, J.C. (Jeffrey C.), Jones, M.B. (Marcus B.), Mitnaul, L.J. (Lyndon), Loos, R.J.F. (Ruth J.F.), Lukas, M.A. (Mary Ann), Lyytikäinen, L.-P. (Leo-Pekka), Meisinger, C. (Christa), Meitinger, T. (Thomas), Melander, O. (Olle), Milaneschi, Y. (Yuri), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Mychaleckyj, J.C. (Josyf), Nadkarni, G. (Girish), Nauck, M. (Matthias), Nikus, K. (Kjell), Ning, B. (Boting), Nolte, I.M. (Ilja), O'Donoghue, M.L. (Michelle L.), Orho-Melander, M. (Marju), Pendergrass, S.A. (Sarah), Penninx, B.W.J.H. (Brenda), Preuss, M. (Michael), Psaty, B.M. (Bruce M.), Raffield, L.M. (Laura M.), Raitakari, O. (Olli), Rettig, R. (Rainer), Rheinberger, M. (Myriam), Rice, K.M. (Kenneth M.), Rosenkranz, A.R. (Alexander R.), Rossing, K., Rotter, J.I. (Jerome I.), Sabanayagam, C. (Charumathi), Schmidt, H. (Helena), Schmidt, R. (Reinhold), Schöttker, B. (Ben), Schulz, C.A. (Christina Alexandra), Sedaghat, S. (Sanaz), Shaffer, C.M. (Christian M.), Strauch, K. (Konstantin), Szymczak, S. (Silke), Taylor, K.D. (Kent D.), Tremblay, J. (Johanne), Chaker, L. (Layal), Most, P.J. (Peter) van der, Verweij, N. (Niek), Völker, U. (Uwe), Waldenberger, M. (Melanie), Wallentin, L.C. (Lars), Waterworth, D.M. (Dawn M.), White, H.D. (Harvey), Wilson, J.G. (James G.), Wong, T.-Y. (Tien-Yin), Woodward, M. (Mark), Yang, Q. (Qiong), Yasuda, M. (Masayuki), Yerges-Armstrong, L.M. (Laura), Zhang, Y. (Yan), Wanner, C. (Christoph), Böger, C.A. (Carsten), Köttgen, A. (Anna), Kronenberg, F. (Florian), Penninx, B.W.J.H., Heid, I.M. (Iris), Gorski, M. (Mathias), Jung, B. (Bettina), Li, Y. (Yong), Matias-Garcia, P.R. (Pamela R.), Wuttke, M. (Matthias), Coassin, S. (Stefan), Thio, C.H.L. (Chris H.L.), Kleber, M.E. (Marcus E.), Winkler, T.W. (Thomas W.), Wanner, V. (Veronika), Chai, J.-F. (Jin-Fang), Chu, A.Y. (Audrey Y), Cocca, M. (Massimiliano), Feitosa, M.F. (Mary Furlan), Ghasemi, S. (Sahar), Hoppmann, A. (Anselm), Horn, K. (Katrin), Li, M. (Man), Nutile, T. (Teresa), Scholz, M. (Markus), Sieber, K.B. (Karsten B.), Teumer, A. (Alexander), Tin, A. (Adrienne), Wang, J. (Judy), Tayo, B. (Bamidele), Ahluwalia, T.S. (Tarunveer Singh), Almgren, P. (Peter), Bakker, S.J.L. (Stephan), Banas, B. (Bernhard), Bansal, N. (Nisha), Biggs, M.L. (M.), Boerwinkle, E.A. (Eric), Bottinger, E.P. (Erwin), Brenner, H. (Hermann), Carroll, R.J. (Robert J.), Chalmers, J. (John), Chee, M.-L. (Miao-Li), Chee, M.-L. (Miao-Ling), Cheng, C.-Y. (Ching-Yu), Coresh, J. (Josef), de Borst, M.H. (Martin H.), Degenhardt, F. (Frauke), Eckardt, K.-U. (Kai-Uwe), Endlich, K. (Karlhans), Franke, A. (Andre), Freitag-Wolf, S. (Sandra), Gampawar, P. (Piyush), Gansevoort, R.T. (Ron), Ghanbari, M. (Mohsen), Gieger, C. (Christian), Hamet, P. (Pavel), Ho, K. (Kevin), Hofer, E. (Edith), Holleczek, B. (B.), Xian Foo, V.H. (Valencia Hui), Hutri-Kähönen, N. (Nina), Hwang, S.-J. (Shih-Jen), Ikram, M.A. (Arfan), Josyula, N.S. (Navya Shilpa), Kähönen, M. (Mika), Khor, C.C., Koenig, W. (Wolfgang), Kramer, H. (Holly), Krämer, B.K. (Bernhard), Kuhnel, B. (Brigitte), Lange, L.A. (Leslie A.), Lehtimäki, T. (Terho), Lieb, W. (Wolfgang), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (H. Marike), Franke, L. (Lude), van der Harst, P. (Pim), Matullo, G., Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M. (Morris), Wolffenbuttel, B.H.R. (Bruce), Wijmenga, C. (Cisca), Abecasis, G.R. (Gonçalo), Baras, A. (Aris), Cantor, M. (Michael), Coppola, G. (Giovanni), Economides, A. (Aris), Lotta, L.A. (Luca A.), Overton, J.D. (John D.), Reid, J.G. (Jeffrey G.), Shuldiner, A. (Alan), Beechert, C. (Christina), Forsythe, C. (Caitlin), Fuller, E.D. (Erin D.), Gu, Z. (Zhenhua), Lattari, M. (Michael), Lopez, A. (Alexander), Schleicher, T.D. (Thomas D.), Padilla, M.S. (Maria Sotiropoulos), Toledo, K. (Karina), Widom, L. (Louis), Wolf, S.E. (Sarah E.), Pradhan, M. (Manasi), Manoochehri, K. (Kia), Ulloa, R.H. (Ricardo H.), Bai, X. (Xiaodong), Balasubramanian, S. (Suganthi), Barnard, L. (Leland), Blumenfeld, A. (Andrew), Eom, G. (Gisu), Habegger, L. (Lukas), Hawes, A. (Alicia), Khalid, S. (Shareef), Maxwell, E.K. (Evan K.), Salerno, W. (William), Staples, J.C. (Jeffrey C.), Jones, M.B. (Marcus B.), Mitnaul, L.J. (Lyndon), Loos, R.J.F. (Ruth J.F.), Lukas, M.A. (Mary Ann), Lyytikäinen, L.-P. (Leo-Pekka), Meisinger, C. (Christa), Meitinger, T. (Thomas), Melander, O. (Olle), Milaneschi, Y. (Yuri), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Mychaleckyj, J.C. (Josyf), Nadkarni, G. (Girish), Nauck, M. (Matthias), Nikus, K. (Kjell), Ning, B. (Boting), Nolte, I.M. (Ilja), O'Donoghue, M.L. (Michelle L.), Orho-Melander, M. (Marju), Pendergrass, S.A. (Sarah), Penninx, B.W.J.H. (Brenda), Preuss, M. (Michael), Psaty, B.M. (Bruce M.), Raffield, L.M. (Laura M.), Raitakari, O. (Olli), Rettig, R. (Rainer), Rheinberger, M. (Myriam), Rice, K.M. (Kenneth M.), Rosenkranz, A.R. (Alexander R.), Rossing, K., Rotter, J.I. (Jerome I.), Sabanayagam, C. (Charumathi), Schmidt, H. (Helena), Schmidt, R. (Reinhold), Schöttker, B. (Ben), Schulz, C.A. (Christina Alexandra), Sedaghat, S. (Sanaz), Shaffer, C.M. (Christian M.), Strauch, K. (Konstantin), Szymczak, S. (Silke), Taylor, K.D. (Kent D.), Tremblay, J. (Johanne), Chaker, L. (Layal), Most, P.J. (Peter) van der, Verweij, N. (Niek), Völker, U. (Uwe), Waldenberger, M. (Melanie), Wallentin, L.C. (Lars), Waterworth, D.M. (Dawn M.), White, H.D. (Harvey), Wilson, J.G. (James G.), Wong, T.-Y. (Tien-Yin), Woodward, M. (Mark), Yang, Q. (Qiong), Yasuda, M. (Masayuki), Yerges-Armstrong, L.M. (Laura), Zhang, Y. (Yan), Wanner, C. (Christoph), Böger, C.A. (Carsten), Köttgen, A. (Anna), Kronenberg, F. (Florian), Penninx, B.W.J.H., and Heid, I.M. (Iris)
Abstract: Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline (“CKDi25”; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized varia
Published: 2021
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19. Meta-analyses identify DNA methylation associated with kidney function and damage

Author: Schlosser, P. (Pascal), Tin, A. (Adrienne), Matias-Garcia, P. R. (Pamela R.), Thio, C. H. (Chris H. L.), Joehanes, R. (Roby), Liu, H. (Hongbo), Weihs, A. (Antoine), Yu, Z. (Zhi), Hoppmann, A. (Anselm), Grundner-Culemann, F. (Franziska), Min, J. L. (Josine L.), Adeyemo, A. A. (Adebowale A.), Agyemang, C. (Charles), Arnlov, J. (Johan), Aziz, N. A. (Nasir A.), Baccarelli, A. (Andrea), Bochud, M. (Murielle), Brenner, H. (Hermann), Breteler, M. M. (Monique M. B.), Carmeli, C. (Cristian), Chaker, L. (Layal), Chambers, J. C. (John C.), Cole, S. A. (Shelley A.), Coresh, J. (Josef), Corre, T. (Tanguy), Correa, A. (Adolfo), Cox, S. R. (Simon R.), de Klein, N. (Niek), Delgado, G. E. (Graciela E.), Domingo-Relloso, A. (Arce), Eckardt, K.-U. (Kai-Uwe), Ekici, A. B. (Arif B.), Endlich, K. (Karlhans), Evans, K. L. (Kathryn L.), Floyd, J. S. (James S.), Fornage, M. (Myriam), Franke, L. (Lude), Fraszczyk, E. (Eliza), Gao, X. (Xu), Gao, X. (Xin), Ghanbari, M. (Mohsen), Ghasemi, S. (Sahar), Gieger, C. (Christian), Greenland, P. (Philip), Grove, M. L. (Megan L.), Harris, S. E. (Sarah E.), Hemani, G. (Gibran), Henneman, P. (Peter), Herder, C. (Christian), Horvath, S. (Steve), Hou, L. (Lifang), Hurme, M. A. (Mikko A.), Hwang, S.-J. (Shih-Jen), Järvelin, M.-R. (Marjo-Riitta), Kardia, S. L. (Sharon L. R.), Kasela, S. (Silva), Kleber, M. E. (Marcus E.), Koenig, W. (Wolfgang), Kooner, J. S. (Jaspal S.), Kramer, H. (Holly), Kronenberg, F. (Florian), Kuhnel, B. (Brigitte), Lehtimaki, T. (Terho), Lind, L. (Lars), Liu, D. (Dan), Liu, Y. (Yongmei), Lloyd-Jones, D. M. (Donald M.), Lohman, K. (Kurt), Lorkowski, S. (Stefan), Lu, A. T. (Ake T.), Marioni, R. E. (Riccardo E.), Marz, W. (Winfried), McCartney, D. L. (Daniel L.), Meeks, K. A. (Karlijn A. C.), Milani, L. (Lili), Mishra, P. P. (Pashupati P.), Nauck, M. (Matthias), Navas-Acien, A. (Ana), Nowak, C. (Christoph), Peters, A. (Annette), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ratliff, S. M. (Scott M.), Reiner, A. P. (Alex P.), Rosas, S. E. (Sylvia E.), Schottker, B. (Ben), Schwartz, J. (Joel), Sedaghat, S. (Sanaz), Smith, J. A. (Jennifer A.), Sotoodehnia, N. (Nona), Stocker, H. R. (Hannah R.), Stringhini, S. (Silvia), Sundstrom, J. (Johan), Swenson, B. R. (Brenton R.), Tellez-Plaza, M. (Maria), van Meurs, J. B. (Joyce B. J.), van Vliet-Ostaptchouk, J. V. (Jana V.), Venema, A. (Andrea), Verweij, N. (Niek), Walker, R. M. (Rosie M.), Wielscher, M. (Matthias), Winkelmann, J. (Juliane), Wolffenbuttel, B. H. (Bruce H. R.), Zhao, W. (Wei), Zheng, Y. (Yinan), Loh, M. (Marie), Snieder, H. (Harold), Levy, D. (Daniel), Waldenberger, M. (Melanie), Susztak, K. (Katalin), Kottgen, A. (Anna), Teumer, A. (Alexander), Schlosser, P. (Pascal), Tin, A. (Adrienne), Matias-Garcia, P. R. (Pamela R.), Thio, C. H. (Chris H. L.), Joehanes, R. (Roby), Liu, H. (Hongbo), Weihs, A. (Antoine), Yu, Z. (Zhi), Hoppmann, A. (Anselm), Grundner-Culemann, F. (Franziska), Min, J. L. (Josine L.), Adeyemo, A. A. (Adebowale A.), Agyemang, C. (Charles), Arnlov, J. (Johan), Aziz, N. A. (Nasir A.), Baccarelli, A. (Andrea), Bochud, M. (Murielle), Brenner, H. (Hermann), Breteler, M. M. (Monique M. B.), Carmeli, C. (Cristian), Chaker, L. (Layal), Chambers, J. C. (John C.), Cole, S. A. (Shelley A.), Coresh, J. (Josef), Corre, T. (Tanguy), Correa, A. (Adolfo), Cox, S. R. (Simon R.), de Klein, N. (Niek), Delgado, G. E. (Graciela E.), Domingo-Relloso, A. (Arce), Eckardt, K.-U. (Kai-Uwe), Ekici, A. B. (Arif B.), Endlich, K. (Karlhans), Evans, K. L. (Kathryn L.), Floyd, J. S. (James S.), Fornage, M. (Myriam), Franke, L. (Lude), Fraszczyk, E. (Eliza), Gao, X. (Xu), Gao, X. (Xin), Ghanbari, M. (Mohsen), Ghasemi, S. (Sahar), Gieger, C. (Christian), Greenland, P. (Philip), Grove, M. L. (Megan L.), Harris, S. E. (Sarah E.), Hemani, G. (Gibran), Henneman, P. (Peter), Herder, C. (Christian), Horvath, S. (Steve), Hou, L. (Lifang), Hurme, M. A. (Mikko A.), Hwang, S.-J. (Shih-Jen), Järvelin, M.-R. (Marjo-Riitta), Kardia, S. L. (Sharon L. R.), Kasela, S. (Silva), Kleber, M. E. (Marcus E.), Koenig, W. (Wolfgang), Kooner, J. S. (Jaspal S.), Kramer, H. (Holly), Kronenberg, F. (Florian), Kuhnel, B. (Brigitte), Lehtimaki, T. (Terho), Lind, L. (Lars), Liu, D. (Dan), Liu, Y. (Yongmei), Lloyd-Jones, D. M. (Donald M.), Lohman, K. (Kurt), Lorkowski, S. (Stefan), Lu, A. T. (Ake T.), Marioni, R. E. (Riccardo E.), Marz, W. (Winfried), McCartney, D. L. (Daniel L.), Meeks, K. A. (Karlijn A. C.), Milani, L. (Lili), Mishra, P. P. (Pashupati P.), Nauck, M. (Matthias), Navas-Acien, A. (Ana), Nowak, C. (Christoph), Peters, A. (Annette), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ratliff, S. M. (Scott M.), Reiner, A. P. (Alex P.), Rosas, S. E. (Sylvia E.), Schottker, B. (Ben), Schwartz, J. (Joel), Sedaghat, S. (Sanaz), Smith, J. A. (Jennifer A.), Sotoodehnia, N. (Nona), Stocker, H. R. (Hannah R.), Stringhini, S. (Silvia), Sundstrom, J. (Johan), Swenson, B. R. (Brenton R.), Tellez-Plaza, M. (Maria), van Meurs, J. B. (Joyce B. J.), van Vliet-Ostaptchouk, J. V. (Jana V.), Venema, A. (Andrea), Verweij, N. (Niek), Walker, R. M. (Rosie M.), Wielscher, M. (Matthias), Winkelmann, J. (Juliane), Wolffenbuttel, B. H. (Bruce H. R.), Zhao, W. (Wei), Zheng, Y. (Yinan), Loh, M. (Marie), Snieder, H. (Harold), Levy, D. (Daniel), Waldenberger, M. (Melanie), Susztak, K. (Katalin), Kottgen, A. (Anna), and Teumer, A. (Alexander)
Abstract: Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
Published: 2021

20. Erratum: Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms

Author: Amin, N, Jovanova, O, Adams, H H H, Dehghan, A, Kavousi, M, Vernooij, M W, Peeters, R P, de Vrij, F M S, van der Lee, S J, van Rooij, J G J, van Leeuwen, E M, Chaker, L, Demirkan, A, Hofman, A, Brouwer, R W W, Kraaij, R, Willems van Dijk, K, Hankemeier, T, van Ijcken, W F J, Uitterlinden, A G, Niessen, W J, Franco, O H, Kushner, S A, Ikram, M A, Tiemeier, H, and van Duijn, C M
Published: 2017
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21. Synthesis of 2H-benzo[2,3-g]pyridazino-[4,5-d,e]quinolin-3-one derivatives

Author: Chaker, L., Pautet, F., and Fillion, H.
Published: 1997
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22. The Genetic Basis of Thyroid Function: Novel Findings and New Approaches

Author: Kus, A., Chaker, L., Teumer, A., Peeters, R.P., Medici, M., Kus, A., Chaker, L., Teumer, A., Peeters, R.P., and Medici, M.
Abstract: Contains fulltext : 220563.pdf (publisher's version ) (Closed access), CONTEXT: Genetic factors are major determinants of thyroid function. Over the last two decades, multiple genetic variants have been associated with variations in normal range thyroid function tests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number of known variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels. EVIDENCE ACQUISITION: This review summarizes the results of genetic association studies on normal range thyroid function and explores how these genetic variants can be used in future studies to improve our understanding of thyroid hormone regulation and disease. EVIDENCE SYNTHESIS: Serum TSH and FT4 levels are determined by multiple genetic variants on virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional follow-up studies on top of GWAS hits has the potential to discover new key players in thyroid hormone regulation, as exemplified by the identification of the thyroid hormone transporter SLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these genetic variants to investigate causal associations between thyroid function and various outcomes in Mendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroid dysfunction, and to predict the individual HPT axis setpoint. CONCLUSIONS: Recent genetic studies have greatly improved our understanding of the genetic basis of thyroid function, and have revealed novel pathways involved in its regulation. In addition, these findings have paved the way for various lines of research that can improve our understanding of thyroid hormone regulation and thyroid diseases, as well as the potential use of these markers in future clinical practice.
Published: 2020

23. Thyroid Function Affects the Risk of Stroke via Atrial Fibrillation: A Mendelian Randomization Study

Author: Marouli, E., Kus, A., Greco, M.F. Del, Chaker, L., Peeters, Robin, Teumer, A., Deloukas, P., Medici, M., Marouli, E., Kus, A., Greco, M.F. Del, Chaker, L., Peeters, Robin, Teumer, A., Deloukas, P., and Medici, M.
Abstract: Contains fulltext : 220576.pdf (publisher's version ) (Closed access), CONTEXT: Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not. OBJECTIVE: To test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto's thyroiditis and Graves' disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used. MAIN OUTCOME MEASURES: Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels. RESULTS: A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto's thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index. CONCLUSION: These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto's thyroiditis as risk factors for stroke and CAD, respectively.
Published: 2020

24. Thyroid Function Affects the Risk of Stroke via Atrial Fibrillation: A Mendelian Randomization Study

Author: Marouli, E. (Eirini), Kus̈, A. (Aleksander), Del Greco M, F. (Fabiola), Chaker, L. (Layal), Peeters, R.P. (Robin), Teumer, A. (Alexander), Deloukas, P. (Panos), Medici, M. (Marco), Marouli, E. (Eirini), Kus̈, A. (Aleksander), Del Greco M, F. (Fabiola), Chaker, L. (Layal), Peeters, R.P. (Robin), Teumer, A. (Alexander), Deloukas, P. (Panos), and Medici, M. (Marco)
Abstract: CONTEXT: Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not. OBJECTIVE: To test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto's thyroiditis and Graves' disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used. MAIN OUTCOME MEASURES: Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels. RESULTS: A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto's thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index. CONCLUSION: These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto's thyroiditis as risk factors for stroke and CAD, respectively.
Published: 2020
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25. The genetic basis of thyroid function: Novel findings and new approaches

Author: Kus̈, A. (Aleksander), Chaker, L. (Layal), Teumer, A. (Alexander), Peeters, R.P. (Robin), Medici, M. (Marco), Kus̈, A. (Aleksander), Chaker, L. (Layal), Teumer, A. (Alexander), Peeters, R.P. (Robin), and Medici, M. (Marco)
Abstract: Context: Genetic factors are major determinants of thyroid function. Over the last two decades,multiple genetic variants have been associated with variations in normal range thyroid functiontests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number ofknown variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels.Evidence Acquisition: This review summarizes the results of genetic association studies onnormal range thyroid function and explores how these genetic variants can be used in futurestudies to improve our understanding of thyroid hormone regulation and disease.Evidence Synthesis: Serum TSH and FT4 levels are determined by multiple genetic variantson virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional followup studies on top of GWAS hits has the potential to discover new key players in thyroidhormone regulation, as exemplified by the identification of the thyroid hormone transporterSLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these geneticvariants to investigate causal associations between thyroid function and various outcomes inMendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroiddysfunction, and to predict the individual HPT axis setpoint.Conclusions: Recent genetic studies have greatly
Published: 2020
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26. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Author: Zhou, W. (Wei), Brumpton, B. (Ben), Kabil, O. (Omer), Gudmundsson, J. (Julius), Thorleifsson, G. (Gudmar), Weinstock, J. (Josh), Zawistowski, M. (Matthew), Nielsen, J.B. (Jonas B.), Chaker, L. (Layal), Medici, M. (Marco), Teumer, A. (Alexander), Naitza, S. (Silvia), Sanna, S. (Serena), Schultheiss, U.T. (Ulla T.), Cappola, A.R. (Anne), Karjalainen, J. (Juha), Kurki, M. (Mitja), Oneka, M. (Morgan), Taylor, P.N. (Peter N.), Fritsche, L.G. (Lars), Graham, S.E. (Sarah E.), Wolford, B.N. (Brooke N.), Overton, W. (William), Rasheed, H. (Humaira), Haug, E.B. (Eirin B.), Gabrielsen, M.E. (Maiken Elvestad), Skogholt, A.H. (Anne Heidi), Surakka, I. (Ida), Davey Smith, G. (George), Pandit, A. (Anita), Roychowdhury, T. (Tanmoy), Hornsby, W.E. (Whitney E.), Jonasson, J.G. (Jon G.), Senter, L. (Leigha), Liyanarachchi, S. (Sandya), Ringel, M.D. (Matthew D.), Xu, L. (Li), Kiemeney, L.A. (Lambertus A.), He, H. (Hao), Netea-Maier, R.T. (Romana), Mayordomo, J.I. (José), Plantinga, T.S. (Theo S.), Hrafnkelsson, J. (Jon), Hjartarson, H. (Hannes), Sturgis, E.M. (Erich M.), Palotie, A. (Aarno), Daly, M.J. (Mark), Citterio, C.E. (Cintia E.), Arvan, P. (Peter), Brummett, C.M. (Chad M.), Boehnke, M. (Michael), La Chapelle, A. (Albert) de, Stefansson, K. (Kari), Hveem, K. (Kristian), Willer, C.J. (Cristen), Asvold, B.O. (Bjorn O.), Zhou, W. (Wei), Brumpton, B. (Ben), Kabil, O. (Omer), Gudmundsson, J. (Julius), Thorleifsson, G. (Gudmar), Weinstock, J. (Josh), Zawistowski, M. (Matthew), Nielsen, J.B. (Jonas B.), Chaker, L. (Layal), Medici, M. (Marco), Teumer, A. (Alexander), Naitza, S. (Silvia), Sanna, S. (Serena), Schultheiss, U.T. (Ulla T.), Cappola, A.R. (Anne), Karjalainen, J. (Juha), Kurki, M. (Mitja), Oneka, M. (Morgan), Taylor, P.N. (Peter N.), Fritsche, L.G. (Lars), Graham, S.E. (Sarah E.), Wolford, B.N. (Brooke N.), Overton, W. (William), Rasheed, H. (Humaira), Haug, E.B. (Eirin B.), Gabrielsen, M.E. (Maiken Elvestad), Skogholt, A.H. (Anne Heidi), Surakka, I. (Ida), Davey Smith, G. (George), Pandit, A. (Anita), Roychowdhury, T. (Tanmoy), Hornsby, W.E. (Whitney E.), Jonasson, J.G. (Jon G.), Senter, L. (Leigha), Liyanarachchi, S. (Sandya), Ringel, M.D. (Matthew D.), Xu, L. (Li), Kiemeney, L.A. (Lambertus A.), He, H. (Hao), Netea-Maier, R.T. (Romana), Mayordomo, J.I. (José), Plantinga, T.S. (Theo S.), Hrafnkelsson, J. (Jon), Hjartarson, H. (Hannes), Sturgis, E.M. (Erich M.), Palotie, A. (Aarno), Daly, M.J. (Mark), Citterio, C.E. (Cintia E.), Arvan, P. (Peter), Brummett, C.M. (Chad M.), Boehnke, M. (Michael), La Chapelle, A. (Albert) de, Stefansson, K. (Kari), Hveem, K. (Kristian), Willer, C.J. (Cristen), and Asvold, B.O. (Bjorn O.)
Abstract: Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
Published: 2020
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27. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth A Systematic Review and Meta-analysis

Author: Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth, Korevaar TIM, Derakhshan A, Taylor PN, Meima M, Chen L, Bliddal S, Carty DM, Meems M, Vaidya B, Shields B, Ghafoor F, Popova PV, Mosso L, Oken E, Suvanto E, Hisada A, Yoshinaga J, Brown SJ, Bassols J, Auvinen J, Bramer WM, López-Bermejo A, Dayan C, Boucai L, Vafeiadi M, Grineva EN, Tkachuck AS, Pop VJM, Vrijkotte TG, Guxens M, Chatzi L, Sunyer J, Jiménez-Zabala A, Riaño I, Murcia M, Lu X, Mukhtar S, Delles C, Feldt-Rasmussen U, Nelson SM, Alexander EK, Chaker L, Männistö T, Walsh JP, Pearce EN, Steegers EAP, and Peeters RP
Abstract: IMPORTANCE Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. OBJECTIVE To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. DATA SOURCES AND STUDY SELECTION Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. DATA EXTRACTION AND SYNTHESIS The primary authors provided individual participant data that were analyzed using mixed-effects models. MAIN OUTCOMES AND MEASURES The primary outcome was preterm birth (
Published: 2019

28. P3341Micro and macrovascular damage across the glycemic spectrum among women and men from general population

Author: Roos, M, primary, Aribas, E, additional, Chaker, L, additional, Klaver, C, additional, Ahmadizar, F, additional, and Kavousi, M, additional
Published: 2019
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29. P3414Differences in total life expectancy and life expectancy with and without non-communicable diseases within the reference range of thyroid function

Author: Bano, A, primary, Chaker, L, additional, Mattace-Raso, F U S, additional, Peeters, R P, additional, and Franco, O H, additional
Published: 2019
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30. Development of Risk Prediction Equations for Incident Chronic Kidney Disease

Author: Nelson, RG, Grams, ME, Ballew, SH, Sang, Y, Azizi, F, Chadban, SJ, Chaker, L, Dunning, SC, Fox, C, Hirakawa, Y, Iseki, K, Ix, J, Jafar, TH, Köttgen, A, Naimark, DMJ, Ohkubo, T, Prescott, GJ, Rebholz, CM, Sabanayagam, C, Sairenchi, T, Schöttker, B, Shibagaki, Y, Tonelli, M, Zhang, L, Gansevoort, RT, Matsushita, K, Woodward, M, Coresh, J, Shalev, V, Nelson, RG, Grams, ME, Ballew, SH, Sang, Y, Azizi, F, Chadban, SJ, Chaker, L, Dunning, SC, Fox, C, Hirakawa, Y, Iseki, K, Ix, J, Jafar, TH, Köttgen, A, Naimark, DMJ, Ohkubo, T, Prescott, GJ, Rebholz, CM, Sabanayagam, C, Sairenchi, T, Schöttker, B, Shibagaki, Y, Tonelli, M, Zhang, L, Gansevoort, RT, Matsushita, K, Woodward, M, Coresh, J, and Shalev, V
Abstract: Importance: Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions. Objective: To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR). Design, Setting, and Participants: Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5222711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2253540). Exposures: Demographic and clinical factors. Main Outcomes and Measures: Incident eGFR of less than 60 mL/min/1.73 m2. Results: Among 4441084 participants without diabetes (mean age, 54 years, 38% women), 660856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781627 participants with diabetes (mean age, 62 years, 13% women), 313646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analys
Published: 2019

31. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth:A Systematic Review and Meta-analysis

Author: Korevaar, Tim I.M., Derakhshan, Arash, Taylor, Peter N, Meima, Marcel, Chen, Liangmiao, Bliddal, Sofie, Carty, David M, Meems, Margreet, Vaidya, Bijay, Shields, Beverley, Ghafoor, Farkhanda, Popova, Polina V, Mosso, Lorena, Oken, Emily, Suvanto, Eila, Hisada, Aya, Yoshinaga, Jun, Brown, Suzanne J, Bassols, Judit, Auvinen, Juha, Bramer, Wichor M, López-Bermejo, Abel, Dayan, Colin, Boucai, Laura, Vafeiadi, Marina, Grineva, Elena N, Tkachuck, Alexandra S, Pop, Victor J M, Vrijkotte, T G, Guxens, M, Chatzi, L, Sunyer, J, Jiménez-Zabala, A, Riaño, I, Murcia, M, Lu, X, Mukhtar, S, Delles, C, Feldt-Rasmussen, U, Nelson, S M, Alexander, E K, Chaker, L, Männistö, T, Walsh, J P, Pearce, E N, Steegers, E A P, Peeters, R P, Korevaar, Tim I.M., Derakhshan, Arash, Taylor, Peter N, Meima, Marcel, Chen, Liangmiao, Bliddal, Sofie, Carty, David M, Meems, Margreet, Vaidya, Bijay, Shields, Beverley, Ghafoor, Farkhanda, Popova, Polina V, Mosso, Lorena, Oken, Emily, Suvanto, Eila, Hisada, Aya, Yoshinaga, Jun, Brown, Suzanne J, Bassols, Judit, Auvinen, Juha, Bramer, Wichor M, López-Bermejo, Abel, Dayan, Colin, Boucai, Laura, Vafeiadi, Marina, Grineva, Elena N, Tkachuck, Alexandra S, Pop, Victor J M, Vrijkotte, T G, Guxens, M, Chatzi, L, Sunyer, J, Jiménez-Zabala, A, Riaño, I, Murcia, M, Lu, X, Mukhtar, S, Delles, C, Feldt-Rasmussen, U, Nelson, S M, Alexander, E K, Chaker, L, Männistö, T, Walsh, J P, Pearce, E N, Steegers, E A P, and Peeters, R P
Abstract: Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth.Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth.Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded.Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models.Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age).Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The
Published: 2019

32. Ageing and endocrinology 3 Clinical aspects of thyroid function during ageing

Author: Chaker, L., Cappola, A.R., Mooijaart, S.P., Peeters, R.P., Epidemiology, and Internal Medicine
Published: 2018

33. Dose Dependency and a Functional Cutoff for TPO-Antibody Positivity During Pregnancy

Author: Korevaar, Tim I.M., Pop, V.J.M., Chaker, L., Goddijn, M., Rijke, Y.B. de, Bisschop, P.H., Broeren, M.A.C., Jaddoe, V.W., Medici, M., Visser, T.J., Steegers, E.A.P., Vrijkotte, T.G., Peeters, R.P., Korevaar, Tim I.M., Pop, V.J.M., Chaker, L., Goddijn, M., Rijke, Y.B. de, Bisschop, P.H., Broeren, M.A.C., Jaddoe, V.W., Medici, M., Visser, T.J., Steegers, E.A.P., Vrijkotte, T.G., and Peeters, R.P.
Abstract: Contains fulltext : 196373.pdf (publisher's version ) (Closed access), Objective: To investigate a dose dependency of thyroperoxidase antibody (TPOAb) concentrations in relation to thyroid function and premature delivery and define a population-based, pregnancy-specific, functional cutoff for TPOAb positivity. Design: Individual participant meta-analysis of three prospective birth cohorts: the Amsterdam Born Children and their Development study, and the Holistic Approach to Pregnancy. Setting: Population-based studies in the Netherlands (2002 to 2014). Participants: A total of 11,212 pregnant women (<20 weeks' gestation). Main Outcome Measures: Thyrotropin (TSH) and FT4 concentrations, premature delivery. Results: In all cohorts, there was a dose-dependent positive association of TPOAb concentrations with TSH concentrations, as well as a dose-dependent negative association with FT4 concentrations during early pregnancy (all P < 0.0001). There was a dose-dependent association of TPOAb concentrations with the risk of premature delivery, which was also modified by TSH concentrations. Women with TPOAb concentrations from the 92nd percentile upward had a higher TSH and a higher risk of a TSH >2.5 mU/L (range, 19.4% to 51.3%). Stratified analyses showed that women with TPOAb concentrations below manufacturer cutoffs already had a higher risk of premature delivery, especially when TSH concentrations were high or in the high-normal range. Conclusions: This study demonstrated a dose-dependent relationship between TPOAbs and thyroid function as well as the risk of premature delivery. Furthermore, our results indicate that the currently used cutoffs for TPOAb positivity may be too high. Furthermore, the use of a population-based cutoff for TPOAbs may identify women with a clinically relevant extent of thyroid autoimmunity and a higher risk of premature delivery but that would not be considered TPOAb positive or eligible for treatment otherwise.
Published: 2018

34. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author: Teumer, A., Chaker, L., Groeneweg, Stefan, Li, Yong, Munno, Celia Di, Barbieri, C., Galesloot, T.E., Kiemeney, L.A.L.M., Netea-Maier, R.T., Visser, T.J., Medici, M., Teumer, A., Chaker, L., Groeneweg, Stefan, Li, Yong, Munno, Celia Di, Barbieri, C., Galesloot, T.E., Kiemeney, L.A.L.M., Netea-Maier, R.T., Visser, T.J., and Medici, M.
Abstract: Contains fulltext : 197679.pdf (publisher's version ) (Open Access)
Published: 2018

35. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author: Teumer, A. (Alexander), Chaker, L. (Layal), Groeneweg, S. (Stefan), Li, Y. (Yong), Di Munno, C. (Celia), Barbieri, C. (Caterina), Schultheiss, U.T. (Ulla T.), Traglia, M. (Michela), Ahluwalia, T.S. (Tarunveer Singh), Akiyama, M. (Masato), Appel, E.V.R. (Emil Vincent R.), Arking, D.E. (Dan), Arnold, A.M. (Alice), Astrup, A. (Arne), Beekman, M. (Marian), Beilby, J.P. (John), Bekaert, S. (Sofie), Boerwinkle, E. (Eric), Brown, S.J. (Stephen), Buyzere, M. (Marc) de, Campbell, P.J. (Purdey J.), Ceresini, G. (Graziano), Cerqueira, C. (Charlotte), Cucca, F. (Francesco), Deary, I.J. (Ian), Deelen, J. (Joris), Eckardt, K.-U. (Kai-Uwe), Ekici, A.B. (Arif B.), Hagen, K. (Knut), Ferrrucci, L. (Luigi), Fiers, T. (Tom), Fiorillo, E. (Edoardo), Ford, I. (Ian), Fox, C.S. (Caroline), Fuchsberger, C. (Christian), Galesloot, T.E. (Tessel), Gieger, C. (Christian), Gögele, M. (Martin), Grandi, A. (Alessandro) de, Grarup, N. (Niels), Greiser, K.H. (Karin Halina), Haljas, K. (Kadri), Hansen, T. (Torben), Harris, S.E. (Sarah), Heemst, D. (Diana) van, Heijer, M. (Martin) den, Hicks, A.A. (Andrew A.), Hollander, W. (Wouter) den, Homuth, G. (Georg), Hui, J. (Jennie), Ikram, M.A. (Arfan), Ittermann, T. (Till), Jensen, R.A. (Richard A.), Jing, J. (Jiaojiao), Jukema, J.W. (Jan Wouter), Kajantie, E. (Eero), Kamatani, Y. (Yoichiro), Kasbohm, E. (Elisa), Kaufman, J.-M. (Jean-Marc), Kiemeney, L.A. (Lambertus A.), Kloppenburg, M. (Margreet), Kronenberg, F. (Florian), Kubo, M. (Michiaki), Lahti, J. (Jari), Lapauw, B. (Bruno), Li, S. (Shuo), Liewald, D.C.M. (David C. M.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Franke, L. (Lude), van der Harst, P. (Pim), Navis, G. (Gerjan), Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Lim, E.M. (Ee Mun), Linneberg, A. (Allan), Marina, M. (Michela), Mascalzoni, D. (Deborah), Matsuda, K. (Koichi), Medenwald, D. (Daniel), Meisinger, C. (Christa), Meulenbelt, I. (Ingrid), Meyer, T. (Thorsten), Meyer zu Schwabedissen, H.E. (Henriette E.), Mikolajczyk, R. (Rafael), Moed, H. (Heleen), Netea-Maier, R.T. (Romana), Nolte, I.M. (Ilja), Okada, Y. (Yukinori), Pala, M. (Mauro), Penninx, B.W.J.H., Pedersen, O. (Oluf), Petersmann, A. (Astrid), Porcu, E. (Eleonora), Postmus, D. (Douwe), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Ramos, Y.F.M. (Yolande F. M.), Rawal, R. (Rajesh), Redmond, P. (Paul), Richards, J.B. (Brent), Rietzschel, E.R. (Ernst), Rivadeneira Ramirez, F. (Fernando), Roef, G.L. (Greet), Rotter, J.I. (Jerome I.), Sala, C. (Cinzia), Schlessinger, D. (David), Selvin, E. (Elizabeth), Slagboom, P.E. (Eline), Soranzo, N. (Nicole), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Starr, J.M. (John), Stott, D.J. (David. J.), Taes, Y.E. (Youri), Taliun, D. (Daniel), Tanaka, T. (Toshiko), Thuesen, L. (Leif), Tiller, D. (Daniel), Toniolo, D. (Daniela), Uitterlinden, A.G. (Andre G.), Visser, W.E. (Edward), Walsh, J.P. (John P.), Wilson, S.G. (Scott), Wolffenbuttel, B.H.R. (Bruce), Yang, Q. (Qiong Fang), Zheng, H.-F. (Hou-Feng), Cappola, A.R. (Anne), Peeters, R.P. (Robin), Naitza, S. (Silvia), Völzke, H. (Henry), Sanna, S. (Serena), Köttgen, A. (Anna), Visser, T.J. (Theo), Medici, M. (Marco), Teumer, A. (Alexander), Chaker, L. (Layal), Groeneweg, S. (Stefan), Li, Y. (Yong), Di Munno, C. (Celia), Barbieri, C. (Caterina), Schultheiss, U.T. (Ulla T.), Traglia, M. (Michela), Ahluwalia, T.S. (Tarunveer Singh), Akiyama, M. (Masato), Appel, E.V.R. (Emil Vincent R.), Arking, D.E. (Dan), Arnold, A.M. (Alice), Astrup, A. (Arne), Beekman, M. (Marian), Beilby, J.P. (John), Bekaert, S. (Sofie), Boerwinkle, E. (Eric), Brown, S.J. (Stephen), Buyzere, M. (Marc) de, Campbell, P.J. (Purdey J.), Ceresini, G. (Graziano), Cerqueira, C. (Charlotte), Cucca, F. (Francesco), Deary, I.J. (Ian), Deelen, J. (Joris), Eckardt, K.-U. (Kai-Uwe), Ekici, A.B. (Arif B.), Hagen, K. (Knut), Ferrrucci, L. (Luigi), Fiers, T. (Tom), Fiorillo, E. (Edoardo), Ford, I. (Ian), Fox, C.S. (Caroline), Fuchsberger, C. (Christian), Galesloot, T.E. (Tessel), Gieger, C. (Christian), Gögele, M. (Martin), Grandi, A. (Alessandro) de, Grarup, N. (Niels), Greiser, K.H. (Karin Halina), Haljas, K. (Kadri), Hansen, T. (Torben), Harris, S.E. (Sarah), Heemst, D. (Diana) van, Heijer, M. (Martin) den, Hicks, A.A. (Andrew A.), Hollander, W. (Wouter) den, Homuth, G. (Georg), Hui, J. (Jennie), Ikram, M.A. (Arfan), Ittermann, T. (Till), Jensen, R.A. (Richard A.), Jing, J. (Jiaojiao), Jukema, J.W. (Jan Wouter), Kajantie, E. (Eero), Kamatani, Y. (Yoichiro), Kasbohm, E. (Elisa), Kaufman, J.-M. (Jean-Marc), Kiemeney, L.A. (Lambertus A.), Kloppenburg, M. (Margreet), Kronenberg, F. (Florian), Kubo, M. (Michiaki), Lahti, J. (Jari), Lapauw, B. (Bruno), Li, S. (Shuo), Liewald, D.C.M. (David C. M.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Franke, L. (Lude), van der Harst, P. (Pim), Navis, G. (Gerjan), Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Lim, E.M. (Ee Mun), Linneberg, A. (Allan), Marina, M. (Michela), Mascalzoni, D. (Deborah), Matsuda, K. (Koichi), Medenwald, D. (Daniel), Meisinger, C. (Christa), Meulenbelt, I. (Ingrid), Meyer, T. (Thorsten), Meyer zu Schwabedissen, H.E. (Henriette E.), Mikolajczyk, R. (Rafael), Moed, H. (Heleen), Netea-Maier, R.T. (Romana), Nolte, I.M. (Ilja), Okada, Y. (Yukinori), Pala, M. (Mauro), Penninx, B.W.J.H., Pedersen, O. (Oluf), Petersmann, A. (Astrid), Porcu, E. (Eleonora), Postmus, D. (Douwe), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Ramos, Y.F.M. (Yolande F. M.), Rawal, R. (Rajesh), Redmond, P. (Paul), Richards, J.B. (Brent), Rietzschel, E.R. (Ernst), Rivadeneira Ramirez, F. (Fernando), Roef, G.L. (Greet), Rotter, J.I. (Jerome I.), Sala, C. (Cinzia), Schlessinger, D. (David), Selvin, E. (Elizabeth), Slagboom, P.E. (Eline), Soranzo, N. (Nicole), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Starr, J.M. (John), Stott, D.J. (David. J.), Taes, Y.E. (Youri), Taliun, D. (Daniel), Tanaka, T. (Toshiko), Thuesen, L. (Leif), Tiller, D. (Daniel), Toniolo, D. (Daniela), Uitterlinden, A.G. (Andre G.), Visser, W.E. (Edward), Walsh, J.P. (John P.), Wilson, S.G. (Scott), Wolffenbuttel, B.H.R. (Bruce), Yang, Q. (Qiong Fang), Zheng, H.-F. (Hou-Feng), Cappola, A.R. (Anne), Peeters, R.P. (Robin), Naitza, S. (Silvia), Völzke, H. (Henry), Sanna, S. (Serena), Köttgen, A. (Anna), Visser, T.J. (Theo), and Medici, M. (Marco)
Abstract: Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
Published: 2018
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36. Thyroid function and atrial fibrillation: Is there a mediating role for epicardial adipose tissue?

Author: Bos, D. (Daniel), Bano, A. (Arjola), Hofman, A. (Albert), VanderWeele, T.J. (Tyler J.), Kavousi, M. (Maryam), Franco, O.H. (Oscar H.), Vernooij, M.W. (Meike), Peeters, R.P. (Robin), Ikram, M.A. (Arfan), Chaker, L. (Layal), Bos, D. (Daniel), Bano, A. (Arjola), Hofman, A. (Albert), VanderWeele, T.J. (Tyler J.), Kavousi, M. (Maryam), Franco, O.H. (Oscar H.), Vernooij, M.W. (Meike), Peeters, R.P. (Robin), Ikram, M.A. (Arfan), and Chaker, L. (Layal)
Abstract: Background: The underlying mechanism of the association between thyroid function and atrial fibrillation (AF) is poorly understood, but epicardial adipose tissue (EAT) could be a promising mediator. Methods: In the 1995 participants (mean age 64.5 years) from the population-based Rotterdam Study, we measured thyroid function (thyroid-stimulating hormone, free thyroxine [FT4]) and performed computed tomography to quantify EAT volumes. All participants were followed for the occurrence of AF. We assessed associations of thyroid-stimulating hormone and FT4 with EAT and AF and performed causal mediation analysis to decompose the overall effect of thyroid function on AF with EAT as mediator. Results: Higher FT4 levels were associated with larger EAT volumes in persons with large waist circumferences, defined by sex-specific cutoffs (0.08 mL more EAT per 1-SD increase in FT4, 95% CI: 0.02, 0.14), but not in persons with a normal waist circumference. In persons with a large waist circumference, higher FT4 levels were associated with a higher AF risk (hazard ratio 1.50, 95% CI: 1.22, 1.83). We found no evidence of a mediating role of EAT in the association of thyroid function with AF (mediated interaction 1.6%, pure indirect effect 3.2%). The estimate of reference interaction of EAT with thyroid function on AF risk was more substantial (10.8%), but statistically nonsignificant. Conclusions: Higher FT4 levels are associated with larger EAT volumes in persons with abdominal obesity. We report no mediating role of EAT in the association of thyroid function with AF, but found evidence for a suggested interaction of FT4 with EAT volumes on AF risk.
Published: 2018
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37. Thyroid Function and Premature Delivery in TPO Antibody-Negative Women: The Added Value of hCG

Author: Korevaar, T.I.M. (Tim), Steegers, E.A.P. (Eric), Chaker, L. (Layal), Medici, M. (Marco), Jaddoe, V.W.V. (Vincent), Visser, T.J. (Theo), Rijke, Y.B. (Yolanda) de, Peeters, R.P. (Robin), Korevaar, T.I.M. (Tim), Steegers, E.A.P. (Eric), Chaker, L. (Layal), Medici, M. (Marco), Jaddoe, V.W.V. (Vincent), Visser, T.J. (Theo), Rijke, Y.B. (Yolanda) de, and Peeters, R.P. (Robin)
Abstract: Conclusion: In TPOAb-negative women with high-normal TSH concentrations, only women with high hCG concentrations had a higher risk of premature delivery or pPROM. These results suggest a lower thyroidal response to hCG stimulation is also associated with premature delivery in TPOAb-negative women and that an additional measurement of hCG may improve thyroid-related risk assessments during pregnancy.Context: Human chorionic gonadotropin (hCG) stimulates thyroid function during pregnancy. We recently showed that thyroid autoimmunity severely attenuated the thyroidal response to hCG stimulation and that this may underlie the higher risk of premature delivery in thyroperoxidase antibody (TPOAb)-positive women. We hypothesized that a lower thyroidal response to hCG stimulation in TPOAb-negative women is also associated with a higher risk of premature delivery and preterm premature rupture of membranes (pPROM).Design, Setting, and Participants: Thyrotropin (TSH), free thyroxine (FT4), and hCG concentrations were available in 5644 TPOAb-negative women from a prospective cohort. We tested for interaction between TSH or FT4 and hCG in linear regression models for duration of pregnancy and logistic regression models for premature delivery/pPROM. Accordingly, analyses were stratified per TSH percentile (TSH ≥ 85th percentile) and hCG per 10,000 IU/L.Results: Women with high TSH and low hCG concentrations did not have a higher risk of premature delivery or pPROM, with protective effect estimates. In contrast, women with a high TSH concentration despite a high hCG concentration had twofold to 10-fold higher risk of premature delivery (Pdifference = 0.022) and an up to fourfold higher risk of pPROM (Pdifference = 0.079). hCG concentrations were not associated with premature delivery or pPROM.
Published: 2017
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38. Glandula Thyreoidea et Senescens

Author: Chaker, L. (Layal) and Chaker, L. (Layal)
Abstract: Thyroid hormone action is crucial for the function of virtually all organs and tissues, but transport and metabolism of thyroid hormone is organ- and cell specific. Thyroid dysfunction is very common in the general population and prevalence can be up to 20% in elderly. Due to the large variation in clinical presentation and general absence of symptom specificity, the definition of thyroid dysfunction is predominantly biochemical, defined by the serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4). This is despite the fact that thyroid diseases are associated with several clinical long-term consequences such as risk cardiovascular disease and dementia. Because clinical thyroid disease is generally treated, long-term consequences of thyroid dysfunction have been mainly studied in the context of subclinical thyroid disorders. Some of these associations with mainly cardiovascular disease have also shown to extend within the currently defined reference ranges. Therefore a debate concerning the accuracy and usefulness in terms of clinical care and prevention of the reference ranges has emerged. The
Published: 2017

39. Thyroid function and risk of type 2 diabetes: A population-based prospective cohort study

Author: Chaker, L. (Layal), Ligthart, S. (Symen), Korevaar, T.I.M. (Tim), Hofman, A. (Albert), Franco, O.H. (Oscar), Peeters, R.P. (Robin), Dehghan, A. (Abbas), Chaker, L. (Layal), Ligthart, S. (Symen), Korevaar, T.I.M. (Tim), Hofman, A. (Albert), Franco, O.H. (Oscar), Peeters, R.P. (Robin), and Dehghan, A. (Abbas)
Abstract: __Background:__ The association of thyroid function with risk of type 2 diabetes remains elusive. We aimed to investigate the association of thyroid function with incident diabetes and progression from prediabetes to diabetes in a population-based prospective cohort study. __Methods:__ We included 8452 participants (mean age 65 years) with thyroid function measurement, defined by thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and longitudinal assessment of diabetes incidence. Cox-models were used to investigate the association of TSH and FT4 with diabetes and progression from prediabetes to diabetes. Multivariable models were adjusted for age, sex, high-density lipoprotein cholesterol, and glucose at
Published: 2016
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40. Erratum: Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms

Author: Amin, N, primary, Jovanova, O, additional, Adams, H H H, additional, Dehghan, A, additional, Kavousi, M, additional, Vernooij, M W, additional, Peeters, R P, additional, de Vrij, F M S, additional, van der Lee, S J, additional, van Rooij, J G J, additional, van Leeuwen, E M, additional, Chaker, L, additional, Demirkan, A, additional, Hofman, A, additional, Brouwer, R W W, additional, Kraaij, R, additional, Willems van Dijk, K, additional, Hankemeier, T, additional, van Ijcken, W F J, additional, Uitterlinden, A G, additional, Niessen, W J, additional, Franco, O H, additional, Kushner, S A, additional, Ikram, M A, additional, Tiemeier, H, additional, and van Duijn, C M, additional
Published: 2016
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41. Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms

Author: Amin, N, primary, Jovanova, O, additional, Adams, H H H, additional, Dehghan, A, additional, Kavousi, M, additional, Vernooij, M W, additional, Peeters, R P, additional, de Vrij, F M S, additional, van der Lee, S J, additional, van Rooij, J G J, additional, van Leeuwen, E M, additional, Chaker, L, additional, Demirkan, A, additional, Hofman, A, additional, Brouwer, R W W, additional, Kraaij, R, additional, Willems van Dijk, K, additional, Hankemeier, T, additional, van Ijcken, W F J, additional, Uitterlinden, A G, additional, Niessen, W J, additional, Franco, O H, additional, Kushner, S A, additional, Ikram, M A, additional, Tiemeier, H, additional, and van Duijn, C M, additional
Published: 2016
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42. The global impact of non-communicable diseases on macro-economic productivity: a systematic review

Author: Chaker, L. (Layal), Falla, A. (Abby), Lee, S.J. (Sven) van der, Muka, T. (Taulant), Imo, D. (David), Jaspers, L. (Loes), Colpani, V. (Veronica), Mendis, S. (Shanthi), Chowdhury, R. (Rajiv), Bramer, W.M. (Wichor), Pazoki, R. (Raha), Franco, O.H. (Oscar), Chaker, L. (Layal), Falla, A. (Abby), Lee, S.J. (Sven) van der, Muka, T. (Taulant), Imo, D. (David), Jaspers, L. (Loes), Colpani, V. (Veronica), Mendis, S. (Shanthi), Chowdhury, R. (Rajiv), Bramer, W.M. (Wichor), Pazoki, R. (Raha), and Franco, O.H. (Oscar)
Abstract: Non-communicable diseases (NCDs) have large economic impact at multiple levels. To systematically review the literature investigating the economic impact of NCDs [including coronary heart disease (CHD), stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on macro-economic productivity. Systematic search, up to November 6th 2014, of medical databases (Medline, Embase and Google Scholar) without language restrictions. To identify additional publications, we searched the reference lists of retrieved studies and contacted authors in the field. Randomized controlled trials, cohort, case–control, cross-sectional, ecological studies and modelling studies carried out in adults (>18 years old) were included. Two independent reviewers performed all abstract and full text selection. Disagreements were resolved through consensus or consulting a third reviewer. Two independent reviewers extracted data using a predesigned data collection form. Main outcome measure was the impact of the selected NCDs on productivity, measured i
Published: 2015
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43. Thyroid function and age-related macular degeneration: A prospective population-based cohort study - the Rotterdam Study

Author: Chaker, L. (Layal), Buitendijk, G.H.S. (Gabrielle), Dehghan, A. (Abbas), Medici, M. (Marco), Hofman, A. (Albert), Vingerling, J.R. (Hans), Franco, O.H. (Oscar), Klaver, C.C.W. (Caroline), Peeters, R.P. (Robin), Chaker, L. (Layal), Buitendijk, G.H.S. (Gabrielle), Dehghan, A. (Abbas), Medici, M. (Marco), Hofman, A. (Albert), Vingerling, J.R. (Hans), Franco, O.H. (Oscar), Klaver, C.C.W. (Caroline), and Peeters, R.P. (Robin)
Abstract: Background: In animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related macular degeneration (AMD) has not been investigated in the general population. Methods: Participants of age ≥55 years from the Rotterdam Study with thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and AMD assessment were included. We conducted age- and sex-adjusted Cox proportional hazards models to explore the association of TSH or FT4 with AMD, in the full range and in those with TSH (0.4-4.0 mIU/L) and/or FT4 in normal range (11-25 pmol/L). Cox proportional hazards models were performed for the association of TSH or FT4 with retinal pigment alterations (RPA), as an early marker of retinal changes. Multivariable models additionally included cardiovascular risk factors and thyroid peroxidase antibodies positivity. We also performed stratification by age and sex. A bidirectional look-up in genome-wide association study (GWAS) data for thyroid parameters and AMD was performed. Single nucleotide polymorphisms (SNPs) that are significantly associated with both phenotypes were identified. Results: We included 5,573 participants with a median follow-up of 6.9 years (interquartile range 4.4-10.8 years). During follow-up 805 people developed AMD. TSH levels were not associated with increased risk of AMD. Within normal range of FT4, participants in the highest FT4 quintile had a 1.34-fold increased risk of developing AMD, compared to individuals in the middle group (95% confidence interval [CI] 1.07-1.66). Higher FT4 values in the full range were associated with a higher risk of AMD (hazard ratio 1.04, CI, 1.01-1.06 per 1 pmol/L increase). Higher FT4 levels were similarly associated with a higher risk of RPA. Restricting analyses to euthyroid individuals, additional multivariable models, and stratificati
Published: 2015
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44. A genetic risk score for thyroid peroxidase antibodies associates with clinical thyroid disease in community-based populations

Author: Schultheiss, U.T. (Ulla T.), Teumer, A. (Alexander), Medici, M. (Marco), Li, Y. (Yong), Daya, N. (Natalie), Chaker, L. (Layal), Homuth, G. (Georg), Uitterlinden, A.G. (André), Nauck, M. (Matthias), Hofman, A. (Albert), Selvin, E. (Elizabeth), Völzke, H. (Henry), Peeters, R.P. (Robin), Köttgen, A. (Anna), Schultheiss, U.T. (Ulla T.), Teumer, A. (Alexander), Medici, M. (Marco), Li, Y. (Yong), Daya, N. (Natalie), Chaker, L. (Layal), Homuth, G. (Georg), Uitterlinden, A.G. (André), Nauck, M. (Matthias), Hofman, A. (Albert), Selvin, E. (Elizabeth), Völzke, H. (Henry), Peeters, R.P. (Robin), and Köttgen, A. (Anna)
Abstract: Copyright
Published: 2015
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45. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis

Author: Chaker, L. (Layal), Baumgartner, C. (Christine), Elzen, W.P.J. (Wendy) den, Ikram, M.A. (Arfan), Blum, M.R. (Manuel), Collet, T.-H. (Tinh-Hai), Bakker, S.J.L. (Stephan), Dehghan, A. (Abbas), Drechsler, C. (Christiane), Luben, R.N. (Robert), Hofman, A. (Albert), Portegies, M.L.P. (Marileen), Medici, M. (Marco), Iervasi, G. (Giorgio), Stott, D.J. (David. J.), Ford, I. (Ian), Bremner, A.P. (Alexandra P.), Wanner, C. (Christoph), Ferrucci, L. (Luigi), Newman, A.B. (Anne B.), Dullaart, R.P.F. (Robin), Sgarbi, J.A. (José A.), Ceresini, G. (Graziano), Maciel, R.M.B. (Rui M. B.), Westendorp, R.G.J. (Rudi), Jukema, J.W. (Jan Wouter), Imaizumi, M. (Misa), Franklyn, J.A. (Jayne), Bauer, D.C. (Douglas C.), Walsh, J.P. (John), Razvi, S. (Salman), Khaw, K.T., Cappola, A.R. (Anne), Völzke, H. (Henry), Franco, O.H. (Oscar), Gussekloo, J. (Jacobijn), Rodondi, N. (Nicolas), Peeters, R.P. (Robin), Chaker, L. (Layal), Baumgartner, C. (Christine), Elzen, W.P.J. (Wendy) den, Ikram, M.A. (Arfan), Blum, M.R. (Manuel), Collet, T.-H. (Tinh-Hai), Bakker, S.J.L. (Stephan), Dehghan, A. (Abbas), Drechsler, C. (Christiane), Luben, R.N. (Robert), Hofman, A. (Albert), Portegies, M.L.P. (Marileen), Medici, M. (Marco), Iervasi, G. (Giorgio), Stott, D.J. (David. J.), Ford, I. (Ian), Bremner, A.P. (Alexandra P.), Wanner, C. (Christoph), Ferrucci, L. (Luigi), Newman, A.B. (Anne B.), Dullaart, R.P.F. (Robin), Sgarbi, J.A. (José A.), Ceresini, G. (Graziano), Maciel, R.M.B. (Rui M. B.), Westendorp, R.G.J. (Rudi), Jukema, J.W. (Jan Wouter), Imaizumi, M. (Misa), Franklyn, J.A. (Jayne), Bauer, D.C. (Douglas C.), Walsh, J.P. (John), Razvi, S. (Salman), Khaw, K.T., Cappola, A.R. (Anne), Völzke, H. (Henry), Franco, O.H. (Oscar), Gussekloo, J. (Jacobijn), Rodondi, N. (Nicolas), and Peeters, R.P. (Robin)
Abstract: Copyright
Published: 2015
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46. Association kyste de la poche de Rathke et hypophysite auto-immune est-elle possible ?

Author: Achir, S., primary, Chaker, L., additional, Foudil, D., additional, and Mimouni, S., additional
Published: 2015
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47. Faux anévrisme de la voie d’éjection du ventricule droit compliquant une endocardite infectieuse après réparation d’une cardiopathie congénitale

Author: Chaker, L., Drissa, M.A., and Drissa, H.
Published: 2010
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48. Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease

Author: Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S.J., Jensen, R.A., Rawal, R., Roef, G.L., Plantinga, T.S., Vermeulen, S., Lahti, J., Simmonds, M.J., Husemoen, L.L., Freathy, R.M., Shields, B.M., Pietzner, D., Nagy, R., Broer, L., Chaker, L., Korevaar, T.I., Plia, M.G., Sala, C., Volker, U., Richards, J.B., Sweep, C.G.J., Gieger, C., Corre, T., Kajantie, E., Thuesen, B., Taes, Y.E., Visser, W.E., Hattersley, A.T., Kratzsch, J., Hamilton, A., Li, W., Homuth, G., Lobina, M., Mariotti, S., Soranzo, N., Cocca, M., Nauck, M., Spielhagen, C., Ross, A., Arnold, A., Bunt, M. van de, Liyanarachchi, S., Heier, M., Grabe, H.J., Masciullo, C., Galesloot, T.E., Lim, E.M., Reischl, E., Leedman, P.J., Lai, S., Delitala, A., Bremner, A.P., Philips, D.I., Beilby, J.P., Mulas, A., Vocale, M., Abecasis, G., Forsen, T., James, A., Widen, E., Hui, J., Prokisch, H., Rietzschel, E.E., Palotie, A., Feddema, P., Fletcher, S.J., Schramm, K., Rotter, J.I., Kluttig, A., Radke, D., Traglia, M., Surdulescu, G.L., He, H., Franklyn, J.A., Tiller, D., Vaidya, B., Meyer, T., Jorgensen, T., Eriksson, J.G., O'Leary, P.C., Wichmann, E., Hermus, A.R.M.M., Psaty, B.M., Ittermann, T., Hofman, A., Bosi, E., Schlessinger, D., Wallaschofski, H., Pirastu, N., Aulchenko, Y.S., Chapelle, A. dela, Netea-Maier, R.T., Gough, S.C., Meyer Zu Schwabedissen, H., Frayling, T.M., Kaufman, J.M., Smit, J.W.A., Kiemeney, B., et al., Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S.J., Jensen, R.A., Rawal, R., Roef, G.L., Plantinga, T.S., Vermeulen, S., Lahti, J., Simmonds, M.J., Husemoen, L.L., Freathy, R.M., Shields, B.M., Pietzner, D., Nagy, R., Broer, L., Chaker, L., Korevaar, T.I., Plia, M.G., Sala, C., Volker, U., Richards, J.B., Sweep, C.G.J., Gieger, C., Corre, T., Kajantie, E., Thuesen, B., Taes, Y.E., Visser, W.E., Hattersley, A.T., Kratzsch, J., Hamilton, A., Li, W., Homuth, G., Lobina, M., Mariotti, S., Soranzo, N., Cocca, M., Nauck, M., Spielhagen, C., Ross, A., Arnold, A., Bunt, M. van de, Liyanarachchi, S., Heier, M., Grabe, H.J., Masciullo, C., Galesloot, T.E., Lim, E.M., Reischl, E., Leedman, P.J., Lai, S., Delitala, A., Bremner, A.P., Philips, D.I., Beilby, J.P., Mulas, A., Vocale, M., Abecasis, G., Forsen, T., James, A., Widen, E., Hui, J., Prokisch, H., Rietzschel, E.E., Palotie, A., Feddema, P., Fletcher, S.J., Schramm, K., Rotter, J.I., Kluttig, A., Radke, D., Traglia, M., Surdulescu, G.L., He, H., Franklyn, J.A., Tiller, D., Vaidya, B., Meyer, T., Jorgensen, T., Eriksson, J.G., O'Leary, P.C., Wichmann, E., Hermus, A.R.M.M., Psaty, B.M., Ittermann, T., Hofman, A., Bosi, E., Schlessinger, D., Wallaschofski, H., Pirastu, N., Aulchenko, Y.S., Chapelle, A. dela, Netea-Maier, R.T., Gough, S.C., Meyer Zu Schwabedissen, H., Frayling, T.M., Kaufman, J.M., Smit, J.W.A., Kiemeney, B., and et al.
Abstract: Contains fulltext : 138209.pdf (publisher's version ) (Open Access), Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5x10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1x10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9x10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5x10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2x10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2x10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9x10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmu
Published: 2014

49. Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Author: Medici, M. (Marco), Porcu, E. (Eleonora), Pistis, G. (Giorgio), Teumer, A. (Alexander), Brown, S.J. (Stephen), Jensen, R.A. (Richard), Rawal, R. (Rajesh), Roef, G.L. (Greet), Plantinga, T.S. (Theo S.), Vermeulen, S.H.H.M. (Sita), Lahti, J. (Jari), Simmonds, M.C. (Mark), Husemoen, L.L.N. (Lise Lotte), Freathy, R.M. (Rachel), Shields, B.M. (Beverley), Pietzner, D. (Diana), Nagy, R. (Rebecca), Broer, L. (Linda), Chaker, L. (Layal), Korevaar, T.I.M. (Tim), Plia, M.G. (Maria Grazia), Sala, C. (Cinzia), Völker, U. (Uwe), Richards, J.B. (Brent), Sweep, F.C. (Fred), Gieger, C. (Christian), Corre, T. (Tanguy), Kajantie, E. (Eero), Thuesen, L. (Leif), Taes, Y.E. (Youri), Visser, W.E. (Edward), Hattersley, A.T. (Andrew), Kratzsch, J. (Jürgen), Hamilton, A. (Amy), Li, W. (Wei), Homuth, G. (Georg), Lobina, M. (Monia), Mariotti, S. (Stefano), Soranzo, N. (Nicole), Cocca, M. (Massimiliano), Nauck, M. (Matthias), Spielhagen, C. (Christin), Ross, H.A. (Alec), Arnold, A.M. (Alice), Bunt, M. (Martijn) van de, Liyanarachchi, S. (Sandya), Heier, M. (Margit), Grabe, H.J. (Hans Jörgen), Masciullo, C. (Corrado), Galesloot, T.E. (Tessel), Lim, E.M. (Ee Mun), Reischl, G. (Gunilla), Leedman, P.J. (Peter), Lai, S. (Sandra), Delitala, A. (Alessandro), Bremner, A. (Alexandra), Philips, D.I.W. (David I.), Beilby, J.P. (John), Mulas, A. (Antonella), Vocale, M. (Matteo), Abecasis, G.R. (Gonçalo), Forsen, T. (Tom), James, A. (Alan), Widen, E. (Elisabeth), Hui, J. (Jennie), Prokisch, H. (Holger), Rietzschel, E.E. (Ernst), Palotie, A. (Aarno), Feddema, W. (Wouter), Fletcher, S.J. (Stephen), Schramm, K. (Katharina), Rotter, J.I. (Jerome), Kluttig, A. (Alexander), Radke, D. (Dörte), Traglia, M. (Michela), Surdulescu, G. (Gabriela), He, H. (Hao), Franklyn, J.A. (Jayne), Tiller, D. (Daniel), Vaidya, B. (Bijay), Meyer, T. (Thorsten), Jorgensen, T. (Torben), Hagen, K. (Knut), O'Leary, P.C. (Peter), Wichmann, E. (Eric), Hermus, A.R.M.M. (Ad), Psaty, B.M. (Bruce), Ittermann, T. (Till), Hofman, A. (Albert), Bosi, E. (Emanuele), Schlessinger, D. (David), Wallaschofski, H. (Henri), Pirastu, N. (Nicola), Aulchenko, Y.S. (Yurii), de la Chapelle, A. (Albert), Netea-Maier, R.T. (Romana), Gough, J.E. (Julie), Meyer zu Schwabedissen, H. (Henriette), Frayling, T.M. (Timothy), Kaufman, J.-M. (Jean-Marc), Linneberg, A. (Allan), Räikkönen, K. (Katri), Smit, J.W.A. (Jan), Kiemeney, L.A.L.M. (Bart), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Walsh, J.P. (John), Meisinger, C. (Christa), Heijer, M. (Martin) den, Visser, T.J. (Theo), Spector, T.D. (Timothy), Wilson, S.G. (Scott), Völzke, H. (Henry), Cappola, A.R. (Anne), Toniolo, D. (Daniela), Sanna, S. (Serena), Naitza, S. (Silvia), Peeters, R.P. (Robin), Medici, M. (Marco), Porcu, E. (Eleonora), Pistis, G. (Giorgio), Teumer, A. (Alexander), Brown, S.J. (Stephen), Jensen, R.A. (Richard), Rawal, R. (Rajesh), Roef, G.L. (Greet), Plantinga, T.S. (Theo S.), Vermeulen, S.H.H.M. (Sita), Lahti, J. (Jari), Simmonds, M.C. (Mark), Husemoen, L.L.N. (Lise Lotte), Freathy, R.M. (Rachel), Shields, B.M. (Beverley), Pietzner, D. (Diana), Nagy, R. (Rebecca), Broer, L. (Linda), Chaker, L. (Layal), Korevaar, T.I.M. (Tim), Plia, M.G. (Maria Grazia), Sala, C. (Cinzia), Völker, U. (Uwe), Richards, J.B. (Brent), Sweep, F.C. (Fred), Gieger, C. (Christian), Corre, T. (Tanguy), Kajantie, E. (Eero), Thuesen, L. (Leif), Taes, Y.E. (Youri), Visser, W.E. (Edward), Hattersley, A.T. (Andrew), Kratzsch, J. (Jürgen), Hamilton, A. (Amy), Li, W. (Wei), Homuth, G. (Georg), Lobina, M. (Monia), Mariotti, S. (Stefano), Soranzo, N. (Nicole), Cocca, M. (Massimiliano), Nauck, M. (Matthias), Spielhagen, C. (Christin), Ross, H.A. (Alec), Arnold, A.M. (Alice), Bunt, M. (Martijn) van de, Liyanarachchi, S. (Sandya), Heier, M. (Margit), Grabe, H.J. (Hans Jörgen), Masciullo, C. (Corrado), Galesloot, T.E. (Tessel), Lim, E.M. (Ee Mun), Reischl, G. (Gunilla), Leedman, P.J. (Peter), Lai, S. (Sandra), Delitala, A. (Alessandro), Bremner, A. (Alexandra), Philips, D.I.W. (David I.), Beilby, J.P. (John), Mulas, A. (Antonella), Vocale, M. (Matteo), Abecasis, G.R. (Gonçalo), Forsen, T. (Tom), James, A. (Alan), Widen, E. (Elisabeth), Hui, J. (Jennie), Prokisch, H. (Holger), Rietzschel, E.E. (Ernst), Palotie, A. (Aarno), Feddema, W. (Wouter), Fletcher, S.J. (Stephen), Schramm, K. (Katharina), Rotter, J.I. (Jerome), Kluttig, A. (Alexander), Radke, D. (Dörte), Traglia, M. (Michela), Surdulescu, G. (Gabriela), He, H. (Hao), Franklyn, J.A. (Jayne), Tiller, D. (Daniel), Vaidya, B. (Bijay), Meyer, T. (Thorsten), Jorgensen, T. (Torben), Hagen, K. (Knut), O'Leary, P.C. (Peter), Wichmann, E. (Eric), Hermus, A.R.M.M. (Ad), Psaty, B.M. (Bruce), Ittermann, T. (Till), Hofman, A. (Albert), Bosi, E. (Emanuele), Schlessinger, D. (David), Wallaschofski, H. (Henri), Pirastu, N. (Nicola), Aulchenko, Y.S. (Yurii), de la Chapelle, A. (Albert), Netea-Maier, R.T. (Romana), Gough, J.E. (Julie), Meyer zu Schwabedissen, H. (Henriette), Frayling, T.M. (Timothy), Kaufman, J.-M. (Jean-Marc), Linneberg, A. (Allan), Räikkönen, K. (Katri), Smit, J.W.A. (Jan), Kiemeney, L.A.L.M. (Bart), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Walsh, J.P. (John), Meisinger, C. (Christa), Heijer, M. (Martin) den, Visser, T.J. (Theo), Spector, T.D. (Timothy), Wilson, S.G. (Scott), Völzke, H. (Henry), Cappola, A.R. (Anne), Toniolo, D. (Daniela), Sanna, S. (Serena), Naitza, S. (Silvia), and Peeters, R.P. (Robin)
Abstract: Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10-8) were detected at T
Published: 2014
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50. Exome-sequencing in a large population-based study reveals a rare Asn396Servariant in the LIPGgene associated with depressive symptoms

Author: Amin, N, Jovanova, O, Adams, H H H, Dehghan, A, Kavousi, M, Vernooij, M W, Peeters, R P, de Vrij, F M S, van der Lee, S J, van Rooij, J G J, van Leeuwen, E M, Chaker, L, Demirkan, A, Hofman, A, Brouwer, R W W, Kraaij, R, Willems van Dijk, K, Hankemeier, T, van Ijcken, W F J, Uitterlinden, A G, Niessen, W J, Franco, O H, Kushner, S A, Ikram, M A, Tiemeier, H, and van Duijn, C M
Abstract: Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Sermutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10−08, β=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser(P-value=7.1 × 10−03, β=2.55) with depressive symptoms. LIPGis predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Servariant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 1−02) and a higher risk of Alzheimer’s disease (odds ration=2.01; P-value=2.8 × 10−02) compared with the non-carriers. Together, these findings implicate the Asn396Servariant of LIPGin the pathogenesis of depressive symptoms in the general population.
Published: 2017
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