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105. Diet in childhood and adult cardiovascular and all cause mortality: the Boyd Orr cohort

Author

Ness, A.R., Maynard, M., Frankel, S., Davey Smith, G., Frobisher, C., Leary, S.D., Emmett, P.M., and Gunnell, D.

Subjects
Antioxidants -- Nutritional aspects, Mortality -- United Kingdom, Mortality -- Causes of, Diet -- Patient outcomes, Children -- Food and nutrition, Children -- Health aspects, Cardiovascular diseases -- Causes of, Cardiovascular diseases -- Patient outcomes, Health
Published
2005

134. Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

Author

Kachuri, L. Saarela, O. Bojesen, S.E. Davey Smith, G. Liu, G. Landi, M.T. Caporaso, N.E. Christiani, D.C. Johansson, M. Panico, S. Overvad, K. Trichopoulou, A. Vineis, P. Scelo, G. Zaridze, D. Wu, X. Albanes, D. Diergaarde, B. Lagiou, P. Macfarlane, G.J. Aldrich, M.C. Tardón, A. Rennert, G. Olshan, A.F. Weissler, M.C. Chen, C. Goodman, G.E. Doherty, J.A. Ness, A.R. Bickeböller, H. Wichmann, H.-E. Risch, A. Field, J.K. Teare, M.D. Kiemeney, L.A. Van Der Heijden, E.H.F.M. Carroll, J.C. Haugen, A. Zienolddiny, S. Skaug, V. Wünsch-Filho, V. Tajara, E.H. Ayoub Moysés, R. Daumas Nunes, F. Lam, S. Eluf-Neto, J. Lacko, M. Peters, W.H.M. Le Marchand, L. Duell, E.J. Andrew, A.S. Franceschi, S. Schabath, M.B. Manjer, J. Arnold, S. Lazarus, P. Mukeriya, A. Swiatkowska, B. Janout, V. Holcatova, I. Stojsic, J. Mates, D. Lissowska, J. Boccia, S. Lesseur, C. Zong, X. McKay, J.D. Brennan, P. Amos, C.I. Hung, R.J.

Abstract

Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci. © 2018 The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Published
2019

135. Genetic architecture of subcortical brain structures in 38,851 individuals

Author

SATIZABAL, C. L., ADAMS, H. H. H., HIBAR, D. P., WHITE, C. C., KNOL, M. J., STEIN, J. L., Scholz, M., Sargurupremraj, Muralidharan, JAHANSHAD, N., ROSHCHUPKIN, G. V., SMITH, A. V., BIS, J. C., JIAN, X., LUCIANO, M., Hofer, E., TEUMER, A., VAN DER LEE, S. J., Yang, J., YANEK, L. R., LEE, T. V., Li, S., Hu, Y., KOH, J. Y., EICHER, J. D., DESRIVIERES, S., ARIAS-VASQUEZ, A., Chauhan, G., ATHANASIU, L., RENTERIA, M. E., Kim, S., HOEHN, D., ARMSTRONG, N. J., Chen, Q., HOLMES, A. J., DEN BRABER, A., KLOSZEWSKA, I., Andersson, M., ESPESETH, T., Grimm, O., ABRAMOVIC, L., ALHUSAINI, S., MILANESCHI, Y., PAPMEYER, M., AXELSSON, T., Ehrlich, S., ROIZ-SANTIANEZ, R., KRAEMER, B., HABERG, A. K., JONES, H. J., Pike, G. B., STEIN, D. J., Stevens, A., BRALTEN, J., VERNOOIJ, M. W., HARRIS, T. B., FILIPPI, I., WITTE, A. V., Guadalupe, T., WITTFELD, K., MOSLEY, T. H., BECKER, J. T., DOAN, N. T., HAGENAARS, S. P., SABA, Y., CUELLAR-PARTIDA, G., Amin, N., HILAL, S., NHO, K., MIRZA-SCHREIBER, N., ARFANAKIS, K., BECKER, D. M., Ames, D., GOLDMAN, A. L., LEE, P. H., Boomsma, D. I., LOVESTONE, S., GIDDALURU, S., LE HELLARD, S., Mattheisen, M., BOHLKEN, M. M., KASPERAVICIUTE, D., SCHMAAL, L., LAWRIE, S. M., Agartz, I., Walton, E., TORDESILLAS-GUTIERREZ, D., DAVIES, G. E., Shin, J., IPSER, J. C., VINKE, L. N., HOOGMAN, M., Jia, T., BURKHARDT, R., Klein, M., Crivello, Fabrice, JANOWITZ, D., CARMICHAEL, O., HAUKVIK, U. K., ARIBISALA, B. S., Schmidt, H., STRIKE, L. T., CHENG, C. Y., RISACHER, S. L., PUTZ, B., FLEISCHMAN, D. A., ASSAREH, A. A., MATTAY, V. S., BUCKNER, R. L., MECOCCI, P., DALE, A. M., Cichon, S., BOKS, M. P., MATARIN, M., PENNINX, Bwjh, CALHOUN, V. D., CHAKRAVARTY, M. M., MARQUAND, A. F., MACARE, C., KHARABIAN MASOULEH, S., OOSTERLAAN, J., Amouyel, P., HEGENSCHEID, K., ROTTER, J. I., SCHORK, A. J., LIEWALD, D. C. M., DE ZUBICARAY, G. I., WONG, T. Y., Shen, L., SAMANN, P. G., BRODATY, H., ROFFMAN, J. L., DE GEUS, E. J. C., TSOLAKI, M., ERK, S., VAN EIJK, K. R., CAVALLERI, G. L., VAN DER WEE, N. J. A., MCINTOSH, A. M., GOLLUB, R. L., BULAYEVA, K. B., Bernard, M., RICHARDS, J. S., HIMALI, J. J., Loeffler, M., ROMMELSE, N., Hoffmann, W., WESTLYE, L. T., VALDES HERNANDEZ, M. C., HANSELL, N. K., VAN ERP, T. G. M., Wolf, C., KWOK, J. B. J., Vellas, B., Heinz, A., OLDE LOOHUIS, L. M., DELANTY, N., HO, B. C., CHING, C. R. K., SHUMSKAYA, E., Singh, B., Hofman, A., VAN DER MEER, D., Homuth, G., PSATY, B. M., BASTIN, M. E., MONTGOMERY, G. W., FOROUD, T. M., REPPERMUND, S., HOTTENGA, J. J., Simmons, A., Meyer-Lindenberg, A., Cahn, W., WHELAN, C. D., VAN DONKELAAR, M. M. J., Yang, Q., HOSTEN, N., GREEN, R. C., THALAMUTHU, A., MOHNKE, S., HULSHOFF POL, H. E., Lin, H., JACK, C. R., Jr., SCHOFIELD, P. R., MUHLEISEN, T. W., MAILLARD, P., POTKIN, S. G., Wen, W., FLETCHER, E., TOGA, A. W., Gruber, O., HUENTELMAN, M., DAVEY SMITH, G., LAUNER, L. J., Nyberg, L., JONSSON, E. G., CRESPO-FACORRO, B., KOEN, N., GREVE, D. N., UITTERLINDEN, A. G., WEINBERGER, D. R., STEEN, V. M., FEDKO, I. O., GROENEWOLD, N. A., Niessen, W. J., TORO, R., Tzourio, Christophe, LONGSTRETH, W. T., Jr., SMOLLER, J. W., VAN TOL, M. J., SUSSMANN, J. E., PAUS, T., Lemaitre, H., SCHROETER, M. L., Mazoyer, B., ANDREASSEN, O. A., Holsboer, F., DEPONDT, C., VELTMAN, D. J., Turner, J. A., PAUSOVA, Z., Schumann, G., Van Rooij, D., Djurovic, S., DEARY, I. J., MCMAHON, K. L., MULLER-MYHSOK, B., BROUWER, R. M., Soininen, H., Pandolfo, M., WASSINK, T. H., CHEUNG, J. W., WOLFERS, T., MARTINOT, J. L., ZWIERS, M. P., Nauck, M., Melle, I., Martin, N. G., Kanai, R., WESTMAN, E., KAHN, R. S., Sisodiya, S. M., White, T., SAREMI, A., van Bokhoven, H., Brunner, H. G., VOLZKE, H., WRIGHT, M. J., VAN 'T ENT, D., NOTHEN, M. M., OPHOFF, R. A., BUITELAAR, J. K., Fernandez, G., SACHDEV, P. S., Rietschel, M., VAN HAREN, N. E. M., Fisher, S. E., BEISER, A. S., Francks, C., SAYKIN, A. J., MATHER, K. A., ROMANCZUK-SEIFERTH, N., HARTMAN, C. A., DeStefano, A. L., HESLENFELD, D. J., WEINER, M. W., Walter, H., HOEKSTRA, P. J., NYQUIST, P. A., Franke, B., BENNETT, D. A., Grabe, H. J., JOHNSON, A. D., Chen, C., VAN DUIJN, C. M., LOPEZ, O. L., FORNAGE, M., WARDLAW, J. M., Schmidt, R., DeCarli, C., DE JAGER, P. L., VILLRINGER, A., Debette, Stephanie, GUDNASON, V., Medland, S. E., SHULMAN, J. M., THOMPSON, P. M., SESHADRI, S., IKRAM, M. K., Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)

Subjects
nervous system, VINTAGE, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, HEALTHY
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019
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136. Association between fat mass through adolescence and arterial stiffness: a population-based study from The Avon Longitudinal Study of Parents and Children

Author

Dangardt, F. Charakida, M. Georgiopoulos, G. Chiesa, S.T. Rapala, A. Wade, K.H. Hughes, A.D. Timpson, N.J. Pateras, K. Finer, N. Sattar, N. Davey Smith, G. Lawlor, D.A. Deanfield, J.E.

Abstract

Background: The link between adiposity, metabolic abnormalities, and arterial disease progression in children and adolescents remains poorly defined. We aimed to assess whether persistent high adiposity levels are associated with increased arterial stiffness in adolescence and any mediation effects by common metabolic risk factors. Methods: We included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had detailed adiposity measurements between the ages 9–17 years and arterial stiffness (carotid to femoral pulse wave velocity [PWV]) measured at age 17 years. Body-mass index (BMI) and waist-to-height ratio were calculated from weight, height, and waist circumference measurements whereas fat mass was assessed using repeated dual-energy x-ray absorptiometry (DEXA) scans. We used total and trunk fat mass indices (FMIs) to classify participants as normal (75th percentile) FMI. We classified participants as being metabolically unhealthy if they had three or more of the following risk factors: high levels of systolic blood pressure, triglycerides, or glucose (all >75th percentile) or low levels of high-density lipoprotein (

Published
2019

137. Influence of puberty timing on adiposity and cardiometabolic traits: A Mendelian randomisation study

Author

Bell, J, Carslake, D, Wade, K, Richmond, R, Langdon, R, Vincent, E, Holmes, M, Timpson, N, and Davey Smith, G

Subjects
Male, Pediatric Obesity, Magnetic Resonance Spectroscopy, Cardiometabolic traits, Adolescent, Blood Pressure, White People, Body Mass Index, Cohort Studies, Absorptiometry, Photon, Mendelian randomization, Humans, Metabolomics, Amino Acids, Puberty timing, Body mass index, Adiposity, Menarche, DXA, Cholesterol, HDL, Fatty Acids, Puberty, Age Factors, Cholesterol, LDL, Ketones, Mendelian Randomization Analysis, ALSPAC, Phenotype, England, Body Composition, Medicine, Female, ICEP
Abstract

Background Earlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity. Methods and findings One-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry ±based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with −1.38 kg/m2 of BMI at age 18 y (or −0.34 SD units, 95% CI −0.46, −0.23; P = 9.77 × 10−09). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to −0.12 kg/m2 (or −0.03 SDs, 95% CI −0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with −0.77 kg/m2 of pre-pubertal BMI measured at age 8 y (or −0.39 SDs, 95% CI −0.50, −0.29; P = 6.28 × 10−13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by −0.26 y, 95% CI −0.37, −0.16; P = 1.16 × 10−06), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with −0.81 kg/m2 of adult BMI (or −0.17 SD units, 95% CI −0.21, −0.12; P = 4.00 × 10−15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10−15). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors. Conclusions Our results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.

Published
2018
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138. Molecular genetic overlap between migraine and major depressive disorder

Author

Yang, Y, Zhao, H, Boomsma, DI, Ligthart, L, Belin, AC, Davey Smith, G, Esko, T, Freilinger, TM, Folkmann Hansen, T, Arfan Ikram, M, Kallela, M, Kubisch, C, Paraskevi, C, Strachan, DP, Wessman, M, The International Headache Genetics Consortium, van de Maagdenberg, AMJM, Terwindt, GM, and Nyholt, DR

Abstract

Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h2 = 12%) and MDD (h2 = 19%), and a significant cross-disorder genetic correlation (rG = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome-wide significant association (PSNP ≤ 5 × 10−8) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (Pgene-based ≤ 0.05) with both migraine and MDD (Pbinomial-test = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher’s combined gene-based P values that surpassed the genome-wide significance threshold (PFisher’s-combined ≤ 3.6 × 10−6). Pathway analysis of genes with PFisher’s-combined ≤ 1 × 10−3 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD.

Published
2018

139. CETP inhibition and ADCY9 genotype: evidence of a qualitative pharmacogenetic interaction in cardiovascular disease?

Author

Michael V. Holmes and Davey Smith G

Subjects
Oncology, medicine.medical_specialty, Dalcetrapib, Disease, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Genotype, medicine, 10. No inequality, CETP inhibitor, 030304 developmental biology, 0303 health sciences, business.industry, 3. Good health, chemistry, Relative risk, lipids (amino acids, peptides, and proteins), business, Pharmacogenetics, Evacetrapib
Abstract

BackgroundCETP inhibitors raise circulating concentrations of HDL-cholesterol, and potent inhibitors also lower non-HDL-cholesterol and risk of vascular disease. Previous genome-wide pharmacogenetic analysis of a phase III randomized controlled trial (RCT) of the CETP inhibitor, dalcetrapib, found variants in ADCY9 to associate with response to treatment. More recently, findings from a pharmacogenetic analysis of the CETP inhibitor evacetrapib reported a lack of such an association.AimsTo clarify the totality of evidence on whether ADCY9 genotype modifies the treatment response to CETP inhibition on risk of major adverse cardiac events through systematic review and meta-analysis.MethodsWe searched PubMed on 22nd May 2018 to identify RCTs of CETP inhibition that reported vascular disease effect estimates stratified by ADCY9 genotype. Stratum-specific estimates were pooled using fixed effect meta-analysis. Tests of heterogeneity between, and trend across, genotypic strata were assessed using Chi2.ResultsNine studies were identified from PubMed, of which two (dal-OUTCOMES and ACCELERATE) were RCTs reporting the treatment response to CETP inhibition by ADCY9 genotype, and fulfilled the inclusion criteria. In meta-analysis of dal-OUTCOMES and ACCELERATE, treatment with a CETP inhibitor was associated with a relative risk (RR) for major adverse cardiac events of RR 0.80 (95%CI, 0.65-0.99) in carriers of ADCY9 rs1967309 AA. For carriers of AG, the corresponding estimate was a RR of 1.01 (95%CI, 0.89-1.13), and for GG carriers, it was RR 1.21 (95%CI, 1.06-1.40). We identified evidence of heterogeneity (P=0.004) and a trend (P=0.0009) across genotypic groups.ConclusionsIn contrast to the interpretation provided by authors of the analysis based in the ACCELERATE trial, the available evidence lends weak support to a potential interaction of CETP treatment by ADCY9 genotype on risk of major adverse cardiac events. Additional data, e.g. from the ongoing dal-GenE trial focused explicitly on this interaction, should provide further clarity regarding the robustness of this pharmacogenetic effect.

Published
2018
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142. Genome-wide analyses using UK biobank data povide new therapeutic targets for osteoarthritis

Author

Hatzikotoulas, K., primary, Tachmazidou, I., additional, Southam, L., additional, Esparza-Gordillo, J., additional, Haberland, V., additional, Zheng, J., additional, Johnson, T., additional, Koprulu, M., additional, Zengini, E., additional, Steinberg, J., additional, Wilkinson, J., additional, Bhatnagar, S., additional, Hoffman, J., additional, Buchan, N., additional, Süveges, D., additional, Yerges-Armstrong, L., additional, Davey-Smith, G., additional, Gaunt, T., additional, Scott, R., additional, McCarthy, L., additional, and Zeggini, E., additional

Published
2019
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144. Covariate-adjusted measures of discrimination for survival data

Author

White, Ian R, Rapsomaniki, Eleni, Wannamethee, S. G., Morris, R. W., Willeit, J., Willeit, P., Santer, P., Kiechl, S., Wald, N., Ebrahim, S., Lawlor, D. A., Gallacher, J., Yarnell, J. W. G., Ben Shlomo, Y., Casiglia, Edoardo, Tikhonoff, V., Sutherland, S. E., Nietert, P. J., Keil, J. E., Bachman, D. L., Psaty, B. M., Cushman, M., Nordestgaard, B. G., Tybjærg Hansen, A., Frikke Schmidt, R., Giampaoli, S., Palmieri, L., Panico, S., Pilotto, L., Vanuzzo, D., Simons, L. A., Friedlander, Y., Mccallum, J., Price, J. F., Mclachlan, S., Taylor, J. O., Guralnik, J. M., Wallace, R. B., Kohout, F. J., Cornoni Huntley, J. C., Blazer, D. G., Phillips, C. L., Wareham, N. J., Khaw, K. T., Brenner, H., Schöttker, B., Müller, H. T., Rothenbacher, D., Nissinen, A., Donfrancesco, C., Harald, K., Jousilahti, P. R., Vartiainen, E., Salomaa, V., D'Agostino, R. B., Wolf, P. A., Vasan, R. S., Daimon, M., Oizumi, T., Kayama, T., Kato, T., Chetrit, A., Dankner, R., Lubin, F., Welin, L., Svärdsudd, K., Eriksson, H., Lappas, G., Lissner, L., Mehlig, K., Björkelund, C., Nagel, D., Kiyohara, Y., Arima, H., Ninomiya, T., Hata, J., Rodriguez, B., Dekker, J. M., Nijpels, G., Stehouwer, C. D. A., Iso, H., Kitamura, A., Yamagishi, K., Noda, H., Goldbourt, U., Kauhanen, J., Salonen, J. T., Tuomainen, T. P., Meade, T. W., Destavola, B. L., Blokstra, A., Verschuren, W. M. M., de Boer, I. H., Folsom, A. R., Koenig, W., Meisinger, C., Peters, A., Bueno de Mesquita, H. B., Rosengren, A., Wilhelmsen, L., Kuller, L. H., Grandits, G., Cooper, J. A., Bauer, K. A., Davidson, K. W., Kirkland, S., Shaffer, J. A., Shimbo, D., Sato, S., Dullaart, R. P. F., Bakker, S. J. L., Gansevoort, R. T., Ducimetiere, P., Amouyel, P., Arveiler, D., Evans, A., Ferrières, J., Schulte, H., Assmann, G., Jukema, J. W., Westendorp, R. G. J., Sattar, N., Cantin, B., Lamarche, B., Després, J. P., Null, E. Barrett Connor, Wingard, D. L., Daniels, L. B., Gudnason, V., Aspelund, T., Trevisan, M., Hofman, A., Franco, O. H., Tunstall Pedoe, H., Tavendale, R., Lowe, G. D. O., Woodward, M., Howard, W. J., Howard, B. V., Zhang, Y., Best, L. G., Umans, J., Davey Smith, G., Onat, A., Nakagawa, H., Sakurai, M., Nakamura, K., Morikawa, Y., Njølstad, I., Mathiesen, E. B., Wilsgaard, T., Sundström, J., Gaziano, J. M., Ridker, P. M., Marmot, M., Clarke, R., Collins, R., Fletcher, A., Brunner, E., Shipley, M., Kivimaki, M., Buring, J., Rifai, N., Cook, N., Ford, I., Robertson, M., Marín Ibañez, A., Feskens, E. J. M., Geleijnse, J. M., MUMC+: HVC Pieken Maastricht Studie (9), Interne Geneeskunde, MUMC+: MA Interne Geneeskunde (3), RS: FHML non-thematic output, Apollo - University of Cambridge Repository, White, Ian R, Rapsomaniki, Eleni, and Panico, Salvatore

Subjects
Statistics and Probability, Male, Biometry, C-index, D-index, Discrimination, Analysis of Variance, Cardiovascular Diseases, Clinical Trials as Topic, Discriminant Analysis, Female, Humans, Middle Aged, Risk Factors, Survival Analysis, Medicine (all), Statistics, Probability and Uncertainty, 01 natural sciences, Article, Unit (housing), 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Survival data, Cardiovascular Disease, Covariate, Statistics, 030212 general & internal medicine, 0101 mathematics, 10. No inequality, Prognostic models, Survival analysis, Medicine(all), Proportional hazards model, Risk Factor, General Medicine, Probability and Uncertainty, Discriminant Analysi, Demography, Human
Abstract

Discrimination statistics describe the ability of a survival model to assign higher risks to individuals who experience earlier events: examples are Harrell's C-index and Royston and Sauerbrei's D, which we call the D-index. Prognostic covariates whose distributions are controlled by the study design (e.g. age and sex) influence discrimination and can make it difficult to compare model discrimination between studies. Although covariate adjustment is a standard procedure for quantifying disease-risk factor associations, there are no covariate adjustment methods for discrimination statistics in censored survival data.To develop extensions of the C-index and D-index that describe the prognostic ability of a model adjusted for one or more covariate(s).We define a covariate-adjusted C-index and D-index for censored survival data, propose several estimators, and investigate their performance in simulation studies and in data from a large individual participant data meta-analysis, the Emerging Risk Factors Collaboration.The proposed methods perform well in simulations. In the Emerging Risk Factors Collaboration data, the age-adjusted C-index and D-index were substantially smaller than unadjusted values. The study-specific standard deviation of baseline age was strongly associated with the unadjusted C-index and D-index but not significantly associated with the age-adjusted indices.The proposed estimators improve meta-analysis comparisons, are easy to implement and give a more meaningful clinical interpretation.? 2014 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Published
2015
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145. Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

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Hinney, A., Kesselmeier, M., Huckins, Laura M, Hauser, Joanna, Karhunen, Leila, Meulenbelt, Ingrid, Slagboom, P Eline, Tortorella, Alfonso, Maj, Mario, Dedoussis, George, Dikeos, Dimitris, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Southam, Lorraine, Tsitsika, Artemis, Papezova, Hana, Slachtova, Lenka, Martaskova, Debora, Kennedy, James L, Levitan, Robert D, Yilmaz, Zeynep, Huemer, Julia, Koubek, Doris, Merl, Elisabeth, Rayner, N William, Wagner, Gudrun, Lichtenstein, Paul, Breen, Gerome, Cohen-Woods, Sarah, Farmer, Anne, McGuffin, Peter, Cichon, Sven, Giegling, Ina, Herms, Stefan, Rujescu, Dan, Tachmazidou, Ioanna, Schreiber, Stefan, Wichmann, H-Erich, Dina, Christian, Sladek, Rob, Gambaro, Giovanni, Soranzo, Nicole, Julia, Antonio, Marsal, Sara, Rabionet, Raquel, Gaborieau, Valerie, Klump, Kelly L, Dick, Danielle M, Palotie, Aarno, Ripatti, Samuli, Widén, Elisabeth, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri, Reinvang, Ivar, Steen, Vidar M, Hellard, Stephanie Le, Treasure, Janet, Mattingsdal, Morten, Ntalla, Ioanna, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Navratilova, Marie, Gallinger, Steven, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Lewis, Cathryn M, Carlberg, Laura, Schosser, Alexandra, Alfredsson, Lars, Ding, Bo, Klareskog, Lars, Padyukov, Leonid, Finan, Chris, Kalsi, Gursharan, Roberts, Marion, Logan, Darren W, Schmidt, Ulrike, Peltonen, Leena, Ritchie, Graham R S, Barrett, Jeff C, Estivill, Xavier, Hinney, Anke, Sullivan, Patrick F, Collier, David A, Zeggini, Eleftheria, Bulik, Cynthia M, Anderson, Carl A, Tozzi, Federica, Barrett, Jeffrey C, Floyd, James A B, Franklin, Christopher S, McGinnis, Ralph, Sambrook, Jennifer, Stephens, Jonathan, Ouwehand, Willem H, McArdle, Wendy L, iezebrink, Kirsty, Ring, Susan M, Strachan, David P, Alexander, Graeme, Conlon, Peter J, Dominiczak, Anna, Duncanson, Audrey, Hill, Adrian, Langford, Cordelia, Jall, S., Hebebrand, Johannes, Lord, Graham, Maxwell, Alexander P, Morgan, Linda, Sandford, Richard N, Sheerin, Neil, Vannberg, Frederik O, Blackburn, Hannah, Chen, Wei-Min, Edkins, Sarah, Gorwood, Philip, Gillman, Mathew, Gray, Emma, Hunt, Sarah E, Nengut-Gumuscu, Suna, Potter, Simon, Rich, Stephen S, Simpkin, Douglas, Whittaker, Pamela, Heid, I. 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J., Dominiczak, A., Duncanson, A., Hill, A., Langford, C., Lord, G., Maxwell, A. P., Morgan, L., Sandford, R. N., Sheerin, N., Vannberg, F. O., Chen, W. -M., Edkins, S., Gillman, M., Gray, E., Hunt, S. E., Nengut, S. -G., Potter, S., Rich, S. S., Simpkin, D., Whittaker, P., Adair, L. S., Ang, W., Atalay, M., van Beijsterveldt, T., Bergen, N., Benke, K., Berry, D. J., Boomsma, D. I., Bradfield, J. P., Charoen, P., Coin, L., Cooper, C., Cousminer, D. L., Das, S., Elliott, P., Evans, D. M., Feenstra, B., Flexeder, C., Frayling, T., Freathy, R. M., Gaillard, R., Geller, F., Groen-Blokhuis, M., Goh, L. K., Guxens, M., Hattersley, A. T., Haworth, C. M., Hadley, D., Heinrich, J., Hirschhorn, J. N., Hocher, B., Holloway, J. W., Holst, C., Hottenga, J. J., Horikoshi, M., Huikari, V., Hypponen, E., Iniguez, C., Jaddoe, V. W., Jarvelin, M. R., Kaakinen, M., Kilpelainen, T. O., Kirin, M., Kowgier, M., Lakka, H. M., Lakka, T. A., Lange, L. A., Lawlor, D. A., Lehtimaki, T., Lewin, A., Lindgren, C., Lindi, V., Maggi, R., Marsh, J., Mccarthy, M. I., Melbye, M., Middeldorp, C., Millwood, I., Mohlke, K. L., Mook-Kanamori, D. O., Murray, J. C., Nivard, M., Nohr, E. A., Oken, E., Ong, K. K., O'Reilly, P. F., Palmer, L. J., Panoutsopoulou, K., Pararajasingham, J., Pearson, E. R., Pennell, C. E., Power, C., Price, T. S., Prokopenko, I., Raitakari, O. T., Rodriguez, A., Salem, R. M., Saw, S. M., Sebert, S., Siitonen, N., Simell, O., Sorensen, T. I., Sovio, U., Pourcain, B. S., Sunyer, J., Taal, H. R., Teo, Y. Y., Thiering, E., Tiesler, C., Timpson, N. J., Uitterlinden, A. G., Valcarcel, B., Warrington, N. M., White, S., Willemsen, G., Wilson, J. F., Yaghootkar, H., Elks, C. E., Perry, J. R., Sulem, P., Chasman, D. I., Franceschini, N., He, C., Lunetta, K. L., Visser, J. A., Byrne, E. M., Gudbjartsson, D. F., Koller, D. L., Kutalik, Z., Lin, P., Mangino, M., Marongiu, M., Smith, A. V., Stolk, L., van Wingerden, S. H., Zhao, J. H., Albrecht, E., Corre, T., Ingelsson, E., Hayward, C., Magnusson, P. K., Smith, E. N., Ulivi, S., Warrington, M., Zgaga, L., Alavere, H., Amin, N., Aspelund, T., Bandinelli, S., Barroso, I., Berenson, G. S., Bergmann, S., Boerwinkle, E., Buring, J. E., Busonero, F., Campbell, H., Chanock, S. J., Cornelis, M. C., Couper, D., Coviello, A. D., D'Adamo, P., de Faire, U., de Geus, E. J., Deloukas, P., Doring, A., Davey Smith, G., Easton, D. F., Eiriksdottir, G., Emilsson, V., Eriksson, J., Ferrucci, L., Folsom, A. R., Foroud, T., Garcia, M., Gasparini, P., Gieger, C., Gudnason, V., Hall, P., Hankinson, S. E., Ferreli, L., Heath, A. C., Hernandez, D. G., Hofman, A., Hu, F. B., Illig, T., Karasik, D., Khaw, K. T., Kiel, D. P., Kolcic, I., Kraft, P., Launer, L. J., Laven, J. S., Li, S., Liu, J., Levy, D., Martin, N. G., Mooser, V., Murray, S. S., Nalls, M. A., Navarro, P., Nelis, M., Ness, A. R., Northstone, K., Oostra, B. A., Peacock, M., Pare, G., Parker, A. N., Pedersen, N. L., Pharoah, P., Polasek, O., Plump, A. S., Pouta, A., Porcu, E., Rafnar, T., Rice, J. P., Rivadeneira, F., Rudan, I., Sala, C., Salomaa, V., Sanna, S., Schlessinger, D., Scuteri, A., Segre, A. V., Shuldiner, A. R., Srinivasan, S. R., Tammesoo, M. L., Tikkanen, E., Toniolo, D., Tsui, K., Tryggvadottir, L., Tyrer, J., Uda, M., van Dam, R. M., van Meurs, J. B., Vollenweider, P., Waeber, G., Wareham, N. J., Waterworth, D. M., Weedon, M. N., Wright, A. F., Young, L., Zhai, G., Zhuang, W. V., Bierut, L. J., Boyd, H. A., Crisponi, L., Demerath, E. W., van Duijn, C. M., Econs, M. J., Harris, T. B., Hunter, D. J., Loos, R. J., Ridker, P. M., Spector, T. D., Streeten, E. A., Stefansson, K., Thorsteinsdottir, U., Murabito, J. M., Murray, A., Brandt, H., Crawford, S., Crow, S., Fichter, M. M., Halmi, K. A., Johnson, C., La Via, M., Mitchell, J., Strober, M., Rotondo, A., Woodside, D. B., Keel, P., Lilenfeld, L., Plotnicov, K., Magistretti, P., Montgomery, G. W., Blackburn, H., Schork, N. J., Hinney, Anke, Kesselmeier, Miriam, Jall, Sigrid, Volckmar, Anna-Lena, Föcker, Manuel, Hebebrand, J, GCAN, WTCCC3, GIANT, EGG, Price Foundation Collaborative Group, Children’s Hospital of Philadelphia/Price Foundation, Cardiology, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Hinney, A, Kesselmeier, M, Jall, S, Volckmar, Al, Focker, M, Antel, J, Gcan, Wtccc3, Heid, Im, Winkler, Tw, Grant, Sfa, Giant, Manunta, P, Sfa, Grant, Egg, Guo, Y, Bergen, Aw, Kaye, W, Berrettini, W, Hakonarson, H, Price Foundation Collaborative, Group, Children’s Hospital of Philadelphia/Price, Foundation, Herpertz-Dahlmann, B, de Zwaan, M, Herzog, W, Ehrlich, S, Zipfel, S, Egberts, Km, Adan, R, Brandys, M, van Elburg, A, Perica, Vb, Franklin, C, Tschop, Mh, Zeggini, E, Bulik, Cm, Collier, D, Scherag, A, Muller, Td, Animal Ecology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Volckmar, A-L, Föcker, M, Gcan, Wtccc, Gasparini, P, D'Adamo, A, Children’S Hospital of Philadelphia/Price, Foundation, Boraska Perica, V, Tschöp, Mh, and Müller, Td

Subjects
Netherlands Twin Register (NTR), Male, Anorexia Nervosa, Genome-wide association study, Cardiovascular, Linkage Disequilibrium, Body Mass Index, 0302 clinical medicine, Databases, Genetic, WTCCC3, Aetiology, Cancer, 0303 health sciences, Loci, Genetic Predisposition to Disease/genetics, Cross-disorder, Anorèxia nerviosa, anorexia nervosa (AN), Shared, 3. Good health, Psychiatry and Mental health, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Human, Alleles, Body Weight, Female, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Obesity, Polymorphism, Single Nucleotide, Risk Factors, Molecular Biology, Psychiatry and Mental Health, Cellular and Molecular Neuroscience, medicine.medical_specialty, Locus (genetics), Single-nucleotide polymorphism, ta3111, Article, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, Genetics, EGG, Polymorphism, Children’s Hospital of Philadelphia/Price Foundation, body mass index (BMI), genome-wide association meta-analysis (GWAMA), Prevention, ta1184, medicine.disease, 030104 developmental biology, Endocrinology, diagnostic markers, Body mass index, Genètica, 030217 neurology & neurosurgery, 0301 basic medicine, Linkage disequilibrium, GIANT, Medizin, Obesity/genetics, Overweight, Medical and Health Sciences, Oral and gastrointestinal, Anorexia Nervosa/genetics, 2.1 Biological and endogenous factors, Psychiatry, 2. Zero hunger, Allele, Eating disorder, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, Price Foundation Collaborative Group, Stroke, psychiatric disorders, Gene Frequency/genetics, medicine.symptom, Databases, Internal medicine, Body Weight/genetics, medicine, Journal Article, Linkage Disequilibrium/genetics, ddc:610, Metabolic and endocrine, Nutrition, 030304 developmental biology, GCAN, business.industry, Risk Factor, Human Genome, Psychology and Cognitive Sciences, Bulimia nervosa, business
Abstract

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values

Published
2017
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146. Genetic architecture of subcortical brain structures in 38,851 individuals

Author

Satizabal, C.L., Adams, H.H.H., Hibar, D.P., White, C.C., Knol, M.J., Stein, J.L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G.V., Smith, A.V., Bis, J.C., Jian, X., Luciano, M., Hofer, E., Teumer, A., van der Lee, S.J., Yang, J., Yanek, L.R., Lee, T.V., Li, S., Hu, Y., Koh, J.Y., Eicher, J.D., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M.E., Kim, S., Hoehn, D., Armstrong, N.J., Chen, Q., Holmes, A.J., den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A.K., Jones, H.J., Pike, G.B., Stein, D.J., Stevens, A., Bralten, J., Vernooij, M.W., Harris, T.B., Filippi, I., Witte, A.V., Guadalupe, T., Wittfeld, K., Mosley, T.H., Becker, J.T., Doan, N.T., Hagenaars, S.P., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Mirza-Schreiber, N., Arfanakis, K., Becker, D.M., Ames, D., Goldman, A.L., Lee, P.H., Boomsma, D.I., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M.M., Kasperaviciute, D., Schmaal, L., Lawrie, S.M., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G.E., Shin, J., Ipser, J.C., Vinke, L.N., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U.K., Aribisala, B.S., Schmidt, H., Strike, L.T., Cheng, C-Y, Risacher, S.L., Pütz, B., Fleischman, D.A., Assareh, A.A., Mattay, V.S., Buckner, R.L., Mecocci, P., Dale, A.M., Cichon, S., Boks, M.P., Matarin, M., Penninx, B.W.J.H., Calhoun, V.D., Chakravarty, M.M., Marquand, A.F., Macare, C., Kharabian Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J.I., Schork, A.J., Liewald, D.C.M., de Zubicaray, G.I., Wong, T.Y., Shen, L., Sämann, P.G., Brodaty, H., Roffman, J.L., de Geus, E.J.C., Tsolaki, M., Erk, S., van Eijk, K.R., Cavalleri, G.L., van der Wee, N.J.A., McIntosh, A.M., Gollub, R.L., Bulayeva, K.B., Bernard, M., Richards, J.S., Himali, J.J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L.T., Valdés Hernández, M.C., Hansell, N.K., Van Erp, T.G.M., Wolf, C., Kwok, J.B.J., Vellas, B., Heinz, A., Olde Loohuis, L.M., Delanty, N., Ho, B-C., Ching, C.R.K., Shumskaya, E., Singh, B., Hofman, A., van der Meer, D., Homuth, G., Psaty, B.M., Bastin, M.E., Montgomery, G.W., Foroud, T.M., Reppermund, S., Hottenga, J-J, Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C.D., van Donkelaar, M.M.J., Yang, Q., Hosten, N., Green, R.C., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H.E., Lin, H., Jack, C.R., Schofield, P.R., Mühleisen, T.W., Maillard, P., Potkin, S.G., Wen, W., Fletcher, E., Toga, A.W., Gruber, O., Huentelman, M., Davey Smith, G., Launer, L.J., Nyberg, L., Jönsson, E.G., Crespo-Facorro, B., Koen, N., Greve, D.N., Uitterlinden, A.G., Weinberger, D.R., Steen, V.M., Fedko, I.O., Groenewold, N.A., Niessen, W.J., Toro, R., Tzourio, C., Longstreth, W.T., Ikram, M.K., Smoller, J.W., van Tol, M-J, Sussmann, J.E., Paus, T., Lemaitre, H., Schroeter, M.L., Mazoyer, B., Andreassen, O.A., Holsboer, F., Depondt, C., Veltman, D.J., Turner, J.A., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I.J., McMahon, K.L., Müller-Myhsok, B., Brouwer, R.M., Soininen, H., Pandolfo, M., Wassink, T.H., Cheung, J.W., Wolfers, T., Martinot, J-L, Zwiers, M.P., Nauck, M., Melle, I., Martin, N.G., Kanai, R., Westman, E., Kahn, R.S., Sisodiya, S.M., White, T., Saremi, A., van Bokhoven, H., Brunner, H.G., Völzke, H., Wright, M.J., van ‘t Ent, D., Nöthen, M.M., Ophoff, R.A., Buitelaar, J.K., Fernández, G., Sachdev, P.S., Rietschel, M., van Haren, N.E.M., Fisher, S.E., Beiser, A.S., Francks, C., Saykin, A.J., Mather, K.A., Romanczuk-Seiferth, N., Hartman, C.A., DeStefano, A.L., Heslenfeld, D.J., Weiner, M.W., Walter, H., Hoekstra, P.J., Nyquist, P.A., Franke, B., Bennett, D.A., Grabe, H.J., Johnson, A.D., Chen, C., van Duijn, C.M., Lopez, O.L., Fornage, M., Wardlaw, J.M., Schmidt, R., DeCarli, C., De Jager, P.L., Villringer, A., Debette, S., Gudnason, V., Medland, S.E., Shulman, J.M., Thompson, P.M., Seshadri, S., Ikram, M.A., Satizabal, C.L., Adams, H.H.H., Hibar, D.P., White, C.C., Knol, M.J., Stein, J.L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G.V., Smith, A.V., Bis, J.C., Jian, X., Luciano, M., Hofer, E., Teumer, A., van der Lee, S.J., Yang, J., Yanek, L.R., Lee, T.V., Li, S., Hu, Y., Koh, J.Y., Eicher, J.D., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M.E., Kim, S., Hoehn, D., Armstrong, N.J., Chen, Q., Holmes, A.J., den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A.K., Jones, H.J., Pike, G.B., Stein, D.J., Stevens, A., Bralten, J., Vernooij, M.W., Harris, T.B., Filippi, I., Witte, A.V., Guadalupe, T., Wittfeld, K., Mosley, T.H., Becker, J.T., Doan, N.T., Hagenaars, S.P., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Mirza-Schreiber, N., Arfanakis, K., Becker, D.M., Ames, D., Goldman, A.L., Lee, P.H., Boomsma, D.I., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M.M., Kasperaviciute, D., Schmaal, L., Lawrie, S.M., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G.E., Shin, J., Ipser, J.C., Vinke, L.N., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U.K., Aribisala, B.S., Schmidt, H., Strike, L.T., Cheng, C-Y, Risacher, S.L., Pütz, B., Fleischman, D.A., Assareh, A.A., Mattay, V.S., Buckner, R.L., Mecocci, P., Dale, A.M., Cichon, S., Boks, M.P., Matarin, M., Penninx, B.W.J.H., Calhoun, V.D., Chakravarty, M.M., Marquand, A.F., Macare, C., Kharabian Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J.I., Schork, A.J., Liewald, D.C.M., de Zubicaray, G.I., Wong, T.Y., Shen, L., Sämann, P.G., Brodaty, H., Roffman, J.L., de Geus, E.J.C., Tsolaki, M., Erk, S., van Eijk, K.R., Cavalleri, G.L., van der Wee, N.J.A., McIntosh, A.M., Gollub, R.L., Bulayeva, K.B., Bernard, M., Richards, J.S., Himali, J.J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L.T., Valdés Hernández, M.C., Hansell, N.K., Van Erp, T.G.M., Wolf, C., Kwok, J.B.J., Vellas, B., Heinz, A., Olde Loohuis, L.M., Delanty, N., Ho, B-C., Ching, C.R.K., Shumskaya, E., Singh, B., Hofman, A., van der Meer, D., Homuth, G., Psaty, B.M., Bastin, M.E., Montgomery, G.W., Foroud, T.M., Reppermund, S., Hottenga, J-J, Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C.D., van Donkelaar, M.M.J., Yang, Q., Hosten, N., Green, R.C., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H.E., Lin, H., Jack, C.R., Schofield, P.R., Mühleisen, T.W., Maillard, P., Potkin, S.G., Wen, W., Fletcher, E., Toga, A.W., Gruber, O., Huentelman, M., Davey Smith, G., Launer, L.J., Nyberg, L., Jönsson, E.G., Crespo-Facorro, B., Koen, N., Greve, D.N., Uitterlinden, A.G., Weinberger, D.R., Steen, V.M., Fedko, I.O., Groenewold, N.A., Niessen, W.J., Toro, R., Tzourio, C., Longstreth, W.T., Ikram, M.K., Smoller, J.W., van Tol, M-J, Sussmann, J.E., Paus, T., Lemaitre, H., Schroeter, M.L., Mazoyer, B., Andreassen, O.A., Holsboer, F., Depondt, C., Veltman, D.J., Turner, J.A., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I.J., McMahon, K.L., Müller-Myhsok, B., Brouwer, R.M., Soininen, H., Pandolfo, M., Wassink, T.H., Cheung, J.W., Wolfers, T., Martinot, J-L, Zwiers, M.P., Nauck, M., Melle, I., Martin, N.G., Kanai, R., Westman, E., Kahn, R.S., Sisodiya, S.M., White, T., Saremi, A., van Bokhoven, H., Brunner, H.G., Völzke, H., Wright, M.J., van ‘t Ent, D., Nöthen, M.M., Ophoff, R.A., Buitelaar, J.K., Fernández, G., Sachdev, P.S., Rietschel, M., van Haren, N.E.M., Fisher, S.E., Beiser, A.S., Francks, C., Saykin, A.J., Mather, K.A., Romanczuk-Seiferth, N., Hartman, C.A., DeStefano, A.L., Heslenfeld, D.J., Weiner, M.W., Walter, H., Hoekstra, P.J., Nyquist, P.A., Franke, B., Bennett, D.A., Grabe, H.J., Johnson, A.D., Chen, C., van Duijn, C.M., Lopez, O.L., Fornage, M., Wardlaw, J.M., Schmidt, R., DeCarli, C., De Jager, P.L., Villringer, A., Debette, S., Gudnason, V., Medland, S.E., Shulman, J.M., Thompson, P.M., Seshadri, S., and Ikram, M.A.

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019

147. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals

Author

Deelen, J. (Joris), Kettunen, J. (Johannes), Fischer, K. (Krista), Spek, A. (Ashley) van der, Trompet, S. (Stella), Kastenmuller, G. (Gabi), Boyd, A. (Andy), Zierer, J. (Jonas), Akker, E.B. (Erik) van den, Ala-Korpela, M. (Mika), Amin, N. (Najaf), Demirkan, A. (Ayse), Ghanbari, M. (Mohsen), Heemst, D. (Diana) van, Ikram, M.A. (Arfan), Klinken, J.B. (Jan Bert) van, Mooijaart, S.P. (Simon), Peters, A. (Annette), Salomaa, V. (Veikko), Sattar, N. (Naveed), Spector, T.D. (Timothy), Tiemeier, H.W. (Henning), Verhoeven, A. (Aswin), Waldenberger, M. (Melanie), Würtz, P. (Peter), Davey Smith, G. (George), Metspalu, A. (Andres), Perola, M. (Markus), Menni, C. (Cristina), Geleijnse, J.M. (Johanna M.), Drenos, F. (Fotios), Beekman, M. (Marian), Jukema, J.W. (Jan Wouter), Duijn, C.M. (Cornelia) van, Slagboom, P.E. (Eline), Deelen, J. (Joris), Kettunen, J. (Johannes), Fischer, K. (Krista), Spek, A. (Ashley) van der, Trompet, S. (Stella), Kastenmuller, G. (Gabi), Boyd, A. (Andy), Zierer, J. (Jonas), Akker, E.B. (Erik) van den, Ala-Korpela, M. (Mika), Amin, N. (Najaf), Demirkan, A. (Ayse), Ghanbari, M. (Mohsen), Heemst, D. (Diana) van, Ikram, M.A. (Arfan), Klinken, J.B. (Jan Bert) van, Mooijaart, S.P. (Simon), Peters, A. (Annette), Salomaa, V. (Veikko), Sattar, N. (Naveed), Spector, T.D. (Timothy), Tiemeier, H.W. (Henning), Verhoeven, A. (Aswin), Waldenberger, M. (Melanie), Würtz, P. (Peter), Davey Smith, G. (George), Metspalu, A. (Andres), Perola, M. (Markus), Menni, C. (Cristina), Geleijnse, J.M. (Johanna M.), Drenos, F. (Fotios), Beekman, M. (Marian), Jukema, J.W. (Jan Wouter), Duijn, C.M. (Cornelia) van, and Slagboom, P.E. (Eline)

Abstract

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18–109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.

Published
2019
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148. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.

Author

Küpers, LK, Monnereau, C, Sharp, GC, Yousefi, P, Salas, LA, Ghantous, A, Page, CM, Reese, SE, Wilcox, AJ, Czamara, D, Starling, AP, Novoloaca, A, Lent, S, Roy, R, Hoyo, C, Breton, CV, Allard, C, Just, AC, Bakulski, KM, Holloway, JW, Everson, TM, Xu, C-J, Huang, R-C, van der Plaat, DA, Wielscher, M, Merid, SK, Ullemar, V, Rezwan, FI, Lahti, J, van Dongen, J, Langie, SAS, Richardson, TG, Magnus, MC, Nohr, EA, Xu, Z, Duijts, L, Zhao, S, Zhang, W, Plusquin, M, DeMeo, DL, Solomon, O, Heimovaara, JH, Jima, DD, Gao, L, Bustamante, M, Perron, P, Wright, RO, Hertz-Picciotto, I, Zhang, H, Karagas, MR, Gehring, U, Marsit, CJ, Beilin, LJ, Vonk, JM, Jarvelin, M-R, Bergström, A, Örtqvist, AK, Ewart, S, Villa, PM, Moore, SE, Willemsen, G, Standaert, ARL, Håberg, SE, Sørensen, TIA, Taylor, JA, Räikkönen, K, Yang, IV, Kechris, K, Nawrot, TS, Silver, MJ, Gong, YY, Richiardi, L, Kogevinas, M, Litonjua, AA, Eskenazi, B, Huen, K, Mbarek, H, Maguire, RL, Dwyer, T, Vrijheid, M, Bouchard, L, Baccarelli, AA, Croen, LA, Karmaus, W, Anderson, D, de Vries, M, Sebert, S, Kere, J, Karlsson, R, Arshad, SH, Hämäläinen, E, Routledge, MN, Boomsma, DI, Feinberg, AP, Newschaffer, CJ, Govarts, E, Moisse, M, Fallin, MD, Melén, E, Prentice, AM, Kajantie, E, Almqvist, C, Oken, E, Dabelea, D, Boezen, HM, Melton, PE, Wright, RJ, Koppelman, GH, Trevisi, L, Hivert, M-F, Sunyer, J, Munthe-Kaas, MC, Murphy, SK, Corpeleijn, E, Wiemels, J, Holland, N, Herceg, Z, Binder, EB, Davey Smith, G, Jaddoe, VWV, Lie, RT, Nystad, W, London, SJ, Lawlor, DA, Relton, CL, Snieder, H, Felix, JF, Küpers, LK, Monnereau, C, Sharp, GC, Yousefi, P, Salas, LA, Ghantous, A, Page, CM, Reese, SE, Wilcox, AJ, Czamara, D, Starling, AP, Novoloaca, A, Lent, S, Roy, R, Hoyo, C, Breton, CV, Allard, C, Just, AC, Bakulski, KM, Holloway, JW, Everson, TM, Xu, C-J, Huang, R-C, van der Plaat, DA, Wielscher, M, Merid, SK, Ullemar, V, Rezwan, FI, Lahti, J, van Dongen, J, Langie, SAS, Richardson, TG, Magnus, MC, Nohr, EA, Xu, Z, Duijts, L, Zhao, S, Zhang, W, Plusquin, M, DeMeo, DL, Solomon, O, Heimovaara, JH, Jima, DD, Gao, L, Bustamante, M, Perron, P, Wright, RO, Hertz-Picciotto, I, Zhang, H, Karagas, MR, Gehring, U, Marsit, CJ, Beilin, LJ, Vonk, JM, Jarvelin, M-R, Bergström, A, Örtqvist, AK, Ewart, S, Villa, PM, Moore, SE, Willemsen, G, Standaert, ARL, Håberg, SE, Sørensen, TIA, Taylor, JA, Räikkönen, K, Yang, IV, Kechris, K, Nawrot, TS, Silver, MJ, Gong, YY, Richiardi, L, Kogevinas, M, Litonjua, AA, Eskenazi, B, Huen, K, Mbarek, H, Maguire, RL, Dwyer, T, Vrijheid, M, Bouchard, L, Baccarelli, AA, Croen, LA, Karmaus, W, Anderson, D, de Vries, M, Sebert, S, Kere, J, Karlsson, R, Arshad, SH, Hämäläinen, E, Routledge, MN, Boomsma, DI, Feinberg, AP, Newschaffer, CJ, Govarts, E, Moisse, M, Fallin, MD, Melén, E, Prentice, AM, Kajantie, E, Almqvist, C, Oken, E, Dabelea, D, Boezen, HM, Melton, PE, Wright, RJ, Koppelman, GH, Trevisi, L, Hivert, M-F, Sunyer, J, Munthe-Kaas, MC, Murphy, SK, Corpeleijn, E, Wiemels, J, Holland, N, Herceg, Z, Binder, EB, Davey Smith, G, Jaddoe, VWV, Lie, RT, Nystad, W, London, SJ, Lawlor, DA, Relton, CL, Snieder, H, and Felix, JF

Abstract

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

Published
2019

149. Migraine polygenic risk score associates with efficacy of migraine-specific drugs

Author

Kogelman, L. J. (Lisette J. A.), Esserlind, A.-L. (Ann-Louise), Christensen, A. F. (Anne Francke), Awasthi, S. (Swapnil), Ripke, S. (Stephan), Ingason, A. (Andres), Davidsson, O. B. (Olafur B.), Erikstrup, C. (Christian), Hjalgrim, H. (Henrik), Ullum, H. (Henrik), Olesen, J. (Jes), Hansen, T. F. (Thomas Folkmann), Gudbjartsson, D. (Daniel), Gastafsson, O. (Omar), Stefansson, K. (Kari), Stefansson, H. (Hreinn), Porsteinsdottir, U. (Unnur), Andersen, S. (Steffen), Banasik, K. (Karina), Brunak, S. (Soren), Buil, A. (Alfonso), Burgdorf, K. (Kristoffer), Gregor, J. (Jemec), Jennum, P. (Poul), Nielsen, K. R. (Kasper Rene), Nyegaard, M. (Mette), Paarup, H. M. (Helene Mariana), Pedersen, O. B. (Ole Birger), Sorensen, E. (Erik), Werge, T. (Thomas), Anttila, V. (Verneri), Artto, V. (Ville), Belin, A. C. (Andrea Carmine), de Boer, I. (Irene), Boomsma, D. I. (Dorret, I), Borte, S. (Sigrid), Chasman, D. I. (Daniel, I), Cherkas, L. (Lynn), Cormand, B. (Bru), Cuenca-Leon, E. (Ester), Davey-Smith, G. (George), Dichgans, M. (Martin), van Duijn, C. (Cornelia), Esko, T. (Tonu), Ferrari, M. (Michel), Frants, R. R. (Rune R.), Freilinger, T. (Tobias), Furlotte, N. (Nick), Gormley, P. (Padhraig), Griffiths, L. (Lyn), Hamalainen, E. (Eija), Hiekkala, M. (Marjo), Ikram, M. A. (M. Arfan), Järvelin, M.-R. (Marjo-Riitta), Kajanne, R. (Risto), Kallela, M. (Mikko), Kaprio, J. (Jaakko), Kaunisto, M. (Mari), Kubisch, C. (Christian), Kurki, M. (Mitja), Kurth, T. (Tobias), Launer, L. (Lenore), Lehtimaki, T. (Terho), Lessel, D. (Davor), Ligthart, L. (Lannie), Litterman, N. (Nadia), van den Maagdenberg, A. (Arn), Macaya, A. (Alfons), Malik, R. (Rainer), Mangino, M. (Massimo), McMahon, G. (George), Muller-Myhsok, B. (Bertram), Neale, B. M. (Benjamin M.), Northover, C. (Carrie), Nyholt, D. R. (Dale R.), Palotie, A. (Aarno), Palta, P. (Priit), Pedersen, L. (Linda), Pedersen, N. (Nancy), Posthuma, D. (Danielle), Pozo-Rosich, P. (Patricia), Pressman, A. (Alice), Raitakari, O. (Olli), Schurks, M. (Markus), Sintas, C. (Celia), Steinberg, S. (Stacy), Strachan, D. (David), Terwindt, G. (Gisela), Vila-Pueyo, M. (Marta), Wessman, M. (Maija), Winsvold, B. S. (Bendik S.), Zhao, H. (Huiying), Zwart, J.-A. (John-Anker), Kogelman, L. J. (Lisette J. A.), Esserlind, A.-L. (Ann-Louise), Christensen, A. F. (Anne Francke), Awasthi, S. (Swapnil), Ripke, S. (Stephan), Ingason, A. (Andres), Davidsson, O. B. (Olafur B.), Erikstrup, C. (Christian), Hjalgrim, H. (Henrik), Ullum, H. (Henrik), Olesen, J. (Jes), Hansen, T. F. (Thomas Folkmann), Gudbjartsson, D. (Daniel), Gastafsson, O. (Omar), Stefansson, K. (Kari), Stefansson, H. (Hreinn), Porsteinsdottir, U. (Unnur), Andersen, S. (Steffen), Banasik, K. (Karina), Brunak, S. (Soren), Buil, A. (Alfonso), Burgdorf, K. (Kristoffer), Gregor, J. (Jemec), Jennum, P. (Poul), Nielsen, K. R. (Kasper Rene), Nyegaard, M. (Mette), Paarup, H. M. (Helene Mariana), Pedersen, O. B. (Ole Birger), Sorensen, E. (Erik), Werge, T. (Thomas), Anttila, V. (Verneri), Artto, V. (Ville), Belin, A. C. (Andrea Carmine), de Boer, I. (Irene), Boomsma, D. I. (Dorret, I), Borte, S. (Sigrid), Chasman, D. I. (Daniel, I), Cherkas, L. (Lynn), Cormand, B. (Bru), Cuenca-Leon, E. (Ester), Davey-Smith, G. (George), Dichgans, M. (Martin), van Duijn, C. (Cornelia), Esko, T. (Tonu), Ferrari, M. (Michel), Frants, R. R. (Rune R.), Freilinger, T. (Tobias), Furlotte, N. (Nick), Gormley, P. (Padhraig), Griffiths, L. (Lyn), Hamalainen, E. (Eija), Hiekkala, M. (Marjo), Ikram, M. A. (M. Arfan), Järvelin, M.-R. (Marjo-Riitta), Kajanne, R. (Risto), Kallela, M. (Mikko), Kaprio, J. (Jaakko), Kaunisto, M. (Mari), Kubisch, C. (Christian), Kurki, M. (Mitja), Kurth, T. (Tobias), Launer, L. (Lenore), Lehtimaki, T. (Terho), Lessel, D. (Davor), Ligthart, L. (Lannie), Litterman, N. (Nadia), van den Maagdenberg, A. (Arn), Macaya, A. (Alfons), Malik, R. (Rainer), Mangino, M. (Massimo), McMahon, G. (George), Muller-Myhsok, B. (Bertram), Neale, B. M. (Benjamin M.), Northover, C. (Carrie), Nyholt, D. R. (Dale R.), Palotie, A. (Aarno), Palta, P. (Priit), Pedersen, L. (Linda), Pedersen, N. (Nancy), Posthuma, D. (Danielle), Pozo-Rosich, P. (Patricia), Pressman, A. (Alice), Raitakari, O. (Olli), Schurks, M. (Markus), Sintas, C. (Celia), Steinberg, S. (Stacy), Strachan, D. (David), Terwindt, G. (Gisela), Vila-Pueyo, M. (Marta), Wessman, M. (Maija), Winsvold, B. S. (Bendik S.), Zhao, H. (Huiying), and Zwart, J.-A. (John-Anker)

Abstract

Objective: To assess whether the polygenic risk score (PRS) for migraine is associated with acute and/or prophylactic migraine treatment response. Methods: We interviewed 2,219 unrelated patients at the Danish Headache Center using a semistructured interview to diagnose migraine and assess acute and prophylactic drug response. All patients were genotyped. A PRS was calculated with the linkage disequilibrium pred algorithm using summary statistics from the most recent migraine genome-wide association study comprising ∼375,000 cases and controls. The PRS was scaled to a unit corresponding to a twofold increase in migraine risk, using 929 unrelated Danish controls as reference. The association of the PRS with treatment response was assessed by logistic regression, and the predictive power of the model by area under the curve using a case-control design with treatment response as outcome. Results: A twofold increase in migraine risk associates with positive response to migraine-specific acute treatment (odds ratio [OR] = 1.25 [95% confidence interval (CI) = 1.05–1.49]). The association between migraine risk and migraine-specific acute treatment was replicated in an independent cohort consisting of 5,616 triptan users with prescription history (OR = 3.20 [95% CI = 1.26–8.14]). No association was found for acute treatment with non–migraine-specific weak analgesics and prophylactic treatment response. Conclusions: The migraine PRS can significantly identify subgroups of patients with a higher-than-average likelihood of a positive response to triptans, which provides a first step toward genetics-based precision medicine in migraine.

Published
2019

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

Author

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

Abstract

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

Published
2019

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