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12 results on '"EPIC- InterAct Consortium"'

1. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity

Author

Scott RA, Fall T, Pasko D, Barker A, Sharp SJ, Arriola L, Balkau B, Barricarte A, Barroso I, Boeing H, Clavel Chapelon F, Crowe FL, Dekker JM, Fagherazzi G, Ferrannini E, Forouhi NG, Franks PW, Gavrila D, Giedraitis V, Grioni S, Groop LC, Kaaks R, Key TJ, Kühn T, Lotta LA, Nilsson PM, Overvad K, Palli D, Quirós JR, Rolandsson O, Roswall N, Sacerdote C, Sala N, Sánchez MJ, Schulze MB, Siddiq A, Slimani N, Sluijs I, Spijkerman AM, Tjonneland A, Tumino R, van der A. DL, Yaghootkar H, RISC Study Group, EPIC InterAct Consortium, McCarthy MI, Semple RK, Riboli E, Walker M, Ingelsson E, Frayling TM, Savage DB, Langenberg C, Wareham N.J., PANICO, SALVATORE, Sharp, Stephen [0000-0003-2375-1440], Barroso, Ines [0000-0001-5800-4520], Forouhi, Nita [0000-0002-5041-248X], Semple, Robert [0000-0001-6539-3069], Savage, David [0000-0002-7857-7032], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Scott, Ra, Fall, T, Pasko, D, Barker, A, Sharp, Sj, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel Chapelon, F, Crowe, Fl, Dekker, Jm, Fagherazzi, G, Ferrannini, E, Forouhi, Ng, Franks, Pw, Gavrila, D, Giedraitis, V, Grioni, S, Groop, Lc, Kaaks, R, Key, Tj, Kühn, T, Lotta, La, Nilsson, Pm, Overvad, K, Palli, D, Panico, Salvatore, Quirós, Jr, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, Mj, Schulze, Mb, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, Am, Tjonneland, A, Tumino, R, van der A., Dl, Yaghootkar, H, RISC Study, Group, EPIC InterAct, Consortium, Mccarthy, Mi, Semple, Rk, Riboli, E, Walker, M, Ingelsson, E, Frayling, Tm, Savage, Db, Langenberg, C, and Wareham, N. J.

Subjects
Adult, Male, Genetic Variation, Alanine Transaminase, gamma-Glutamyltransferase, Glucose Tolerance Test, Middle Aged, Overweight, Polymorphism, Single Nucleotide, Body Mass Index, Cohort Studies, Diabetes Mellitus, Type 2, Insulin Secretion, Body Composition, Glucose Clamp Technique, Body Fat Distribution, Humans, Insulin, Female, Genetic Predisposition to Disease, Obesity, Insulin Resistance, Waist Circumference, Aged
Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Published
2014

2. Corrigendum: Rare coding variants and X-linked loci associated with age at menarche

Author

Lunetta, K.L., Day, F.R., Sulem, P., Ruth, K.S., Tung, J.Y., Hinds, D.A., Esko, T., Elks, C.E., Altmaier, E., He, C., Huffman, J.E., Mihailov, E., Porcu, E., Robino, A., Rose, L.M., Schick, U.M., Stolk, L., Teumer, A., Thompson, D.J., Traglia, M., Wang, C.A., Yerges-Armstrong, L.M., Antoniou, A.C., Barbieri, C., Coviello, A.D., Cucca, F., Demerath, E.W., Dunning, A.M., Gandin, I., Grove, M.L., Gudbjartsson, D.F., Hocking, L.J., Hofman, A., Huang, J., Jackson, R.D., Karasik, D., Kriebel, J., Lange, E.M., Lange, L.A., Langenberg, C., Li, X., Luan, J., Mägi, R., Morrison, A.C., Padmanabhan, S., Pirie, A., Polasek, O., Porteous, D.J., Reiner, A.P., Rivadeneira, F., Rudan, I., Sala, C.F., Schlessinger, D., Scott, R.A., Stöckl, D., Visser, J.A., Völker, U., Vozzi, D., Wilson, J.G., Zygmunt, M., EPIC-Interact Consortium (), Generation Scotland Consortium (), Boerwinkle, E., Buring, J.E., Crisponi, L., Easton, D.F., Hayward, C., Hu, F.B., Liu, S., Metspalu, A., Pennell, C.E., Ridker, P.M., Strauch, K., Streeten, E.A., Toniolo, D., Uitterlinden, A.G., Ulivi, S., Völzke, H., Wareham, N.J., Wellons, M., Franceschini, N., Chasman, D.I., Thorsteinsdottir, U., Murray, A., Stefansson, K., Murabito, J.M., Ong, K.K., and Perry, J.R.

Subjects
Adult, Adolescent, Genotype, Mutation, Missense, Immunoglobulins, Cell Cycle Proteins, Penetrance, AMP-Activated Protein Kinases, Autoantigens, White People, Young Adult, Gene Frequency, Genes, X-Linked, Humans, Aged, Menarche, Chromosomes, Human, X, Hypogonadism, Fatty Acids, Age Factors, Genetic Variation, Membrane Proteins, Proteins, RNA-Binding Proteins, Receptors, Neurokinin-3, Middle Aged, Corrigenda, Amides, Phenotype, Codon, Nonsense, Female, RNA Interference, Laminin, Energy Metabolism, Signal Transduction
Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

Published
2015

3. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors

Author

Burgess, Stephen, Scott, Robert A, Timpson, Nicholas J, Davey Smith, George, Thompson, Simon G, EPIC- InterAct Consortium, Burgess, Stephen [0000-0001-5365-8760], Thompson, Simon [0000-0002-5274-7814], and Apollo - University of Cambridge Repository

Subjects
Random Allocation, Risk Factors, Data Interpretation, Statistical, Genetic Variation, Humans, Genetic Predisposition to Disease, Mendelian Randomization Analysis, Sensitivity and Specificity
Abstract

Finding individual-level data for adequately-powered Mendelian randomization analyses may be problematic. As publicly-available summarized data on genetic associations with disease outcomes from large consortia are becoming more abundant, use of published data is an attractive analysis strategy for obtaining precise estimates of the causal effects of risk factors on outcomes. We detail the necessary steps for conducting Mendelian randomization investigations using published data, and present novel statistical methods for combining data on the associations of multiple (correlated or uncorrelated) genetic variants with the risk factor and outcome into a single causal effect estimate. A two-sample analysis strategy may be employed, in which evidence on the gene-risk factor and gene-outcome associations are taken from different data sources. These approaches allow the efficient identification of risk factors that are suitable targets for clinical intervention from published data, although the ability to assess the assumptions necessary for causal inference is diminished. Methods and guidance are illustrated using the example of the causal effect of serum calcium levels on fasting glucose concentrations. The estimated causal effect of a 1 standard deviation (0.13 mmol/L) increase in calcium levels on fasting glucose (mM) using a single lead variant from the CASR gene region is 0.044 (95 % credible interval -0.002, 0.100). In contrast, using our method to account for the correlation between variants, the corresponding estimate using 17 genetic variants is 0.022 (95 % credible interval 0.009, 0.035), a more clearly positive causal effect.

Published
2015

4. Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways

Author

Burgess, Stephen, Daniel, Rhian, Butterworth, Adam S., Thompson, Simon G., the EPIC-InterAct Consortium, Burgess, Stephen [0000-0001-5365-8760], Butterworth, Adam [0000-0002-6915-9015], Thompson, Simon [0000-0002-5274-7814], and Apollo - University of Cambridge Repository

Subjects
Epidemiology, Structural equation modeling, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Mendelian Randomization Methodology, Econometrics, Humans, mediation, 030212 general & internal medicine, 030304 developmental biology, 0303 health sciences, Models, Statistical, Instrumental variable, Estimator, Genetic Variation, Regression analysis, Mendelian Randomization Analysis, General Medicine, R1, Regression, Indirect effect, instrumental variable, Causality, direct effect, Regression Analysis, Psychology, Monte Carlo Method, indirect effect
Abstract

Background: Mendelian randomization uses genetic variants, assumed to be instrumental variables for a particular exposure, to estimate the causal effect of that exposure on an outcome. If the instrumental variable criteria are satisfied, the resulting estimator is consistent even in the presence of unmeasured confounding and reverse causation.\ud \ud Methods: We extend the Mendelian randomization paradigm to investigate more complex networks of relationships between variables, in particular where some of the effect of an exposure on the outcome may operate through an intermediate variable (a mediator). If instrumental variables for the exposure and mediator are available, direct and indirect effects of the exposure on the outcome can be estimated, for example using either a regression-based method or structural equation models. The direction of effect between the exposure and a possible mediator can also be assessed. Methods are illustrated in an applied example considering causal relationships between body mass index, C-reactive protein and uric acid.\ud \ud Results: These estimators are consistent in the presence of unmeasured confounding if, in addition to the instrumental variable assumptions, the effects of both the exposure on the mediator and the mediator on the outcome are homogeneous across individuals and linear without interactions. Nevertheless, a simulation study demonstrates that even considerable heterogeneity in these effects does not lead to bias in the estimates.\ud \ud Conclusions: These methods can be used to estimate direct and indirect causal effects in a mediation setting, and have potential for the investigation of more complex networks between multiple interrelated exposures and disease outcomes.

Published
2015

5. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Author

Surendran, P., Drenos, F., Young, R., Warren, H., Cook, J.P., Manning, A.K., Grarup, N., Sim, X., Barnes, D.R., Witkowska, K., Staley, J.R., Tragante, V., Tukiainen, T., Yaghootkar, H., Masca, N., Freitag, D.F., Ferreira, T., Giannakopoulou, O., Tinker, A., Harakalova, M., Mihailov, E., Liu, C., Kraja, A.T., Nielsen, S.F., Rasheed, A., Samue, M., Zhao, W., Bonnycastle, L.L., Jackson, A.U., Narisu, N., Swift, A.J., Southam, L., Marten, J., Huyghe, J.R., Stancakova, A., Fava, C., Ohlsson, T., Matchan, A., Stirrups, K.E., Bork-Jensen, J., Gjesing, A.P., Kontto, J., Perola, M., Shaw-Hawkins, S., Havulinna, A.S., Zhang, H., Donnelly, L.A., Groves, C.J., Rayner, N.W., Neville, M.J., Robertson, N.R., Yiorkas, A.M., Herzig, K.H., Kajantie, E., Zhang, W., Willems, S.M., Lannfelt, L., Malerba, G., Soranzo, N., Trabetti, E., Verweij, N., Evangelou, E., Moayyeri, A., Vergnaud, A.C., Nelson, C.P., Poveda, A., Varga, T.V., Caslake, M., Craen, A.J.M. de, Trompet, S., Luan, J., Scott, R.A., Harris, S.E., Liewald, D.C.M., Marioni, R., Menni, C., Farmaki, A.E., Hallmans, G., Renstrom, F., Huffman, J.E., Hassinen, M., Burgess, S., Vasan, R.S., Felix, J.F., Uria-Nickelsen, M., Malarstign, A., Reilly, D.F., Hoek, M., Vogt, T.F., Lin, H.H., Lieb, W., Traylor, M., Markus, H.S., Highland, H.M., Justice, A.E., Marouli, E., Lindstrom, J., Uusitupa, M., Komulainen, P., Lakka, T.A., Rauramaa, R., Polasek, O., Rudan, I., Rolandsson, O., Franks, P.W., Dedoussis, G., Spector, T.D., Jousilahti, P., Mannisto, S., Deary, I.J., Starr, J.M., Langenberg, C., Wareham, N.J., Brown, M.J., Dominiczak, A.F., Connell, J.M., Jukema, J.W., Sattar, N., Ford, I., Packard, C.J., Esko, T., Magi, R., Metspalu, A., Boer, R.A. de, Meer, P. van der, Harst, P. van der, Gambaro, G., Ingelsson, E., Lind, L., Bakker, P.I.W. de, Numans, M.E., Brandslund, I., Christensen, C., Petersen, E.R.B., Korpi-Hyovalti, E., Oksa, H., Chambers, J.C., Kooner, J.S., Blakemore, A.I.F., Franks, S., Jarvelin, M.R., Husemoen, L.L., Linneberg, A., Skaaby, T., Thuesen, B., Karpe, F., Tuomilehto, J., Doney, A.S.F., Morris, A.D., Palmer, C.N.A., Holmen, O.L., Hveem, K., Willer, C.J., Tuomi, T., Groop, L., Karajamaki, A., Palotie, A., Ripatti, S., Salomaa, V., Alam, D.S., Majmnder, A.A.S., Angelantonio, E. di, Chowdhury, R., McCarthy, M.I., Poulter, N., Stanton, A.V., Sever, P., Amouyel, P., Arveiler, D., Blankenberg, S., Ferrieres, J., Kee, F., Kuulasmaa, K., Muller-Nurasyid, M., Veronesi, G., Virtamo, J., Deloukas, P., Elliott, P., Zeggini, E., Kathiresan, S., Melander, O., Kuusisto, J., Laakso, M., Padmanabhan, S., Porteous, D.J., Hayward, C., Scotland, G., Collins, F.S., Mohlke, K.L., Hansen, T., Pedersen, O., Boehnke, M., Stringham, H.M., Frossard, P., Newton-Cheh, C., Tobin, M.D., Nordestgaard, B.G., Caulfield, M.J., Mahajan, A., Morris, A.P., Tomaszewski, M., Samani, N.J., Saleheen, D., Asselbergs, F.W., Lindgren, C.M., Danesh, J., Wain, L.V., Butterworth, A.S., Howson, J.M.M., Munroe, P.B., CHARGE Heart Failure Consortiumm, EchoGen Consortiumm, Metastroke Consortiumm, Giant Consortiumm, EPIC-InterAct Consortium, Lifelines Cohort Study, Wellcome Trust Case Control Consor, Understanding Soc Sci Grp, EPIC-CVD Consortium, CHARGE Exome Chip Blood Pressure C, T2D-GENES Consortium, GoT2DGenes Consortium, ExomeBP Consortium, CHD Exome Consortium, Erasmus MC other, Epidemiology, Internal Medicine, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Surendran, Praveen [0000-0002-4911-6077], Barnes, Daniel [0000-0002-3781-7570], Marten, Jonathan [0000-0001-6916-2014], Johnson, Kathleen [0000-0002-6823-3252], Soranzo, Nicole [0000-0003-1095-3852], Luan, Jian'an [0000-0003-3137-6337], Burgess, Stephen [0000-0001-5365-8760], Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Di Angelantonio, Emanuele [0000-0001-8776-6719], Chowdhury, Rajiv [0000-0003-4881-5690], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Apollo - University of Cambridge Repository, British Heart Foundation, Home Office, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, and Action on Hearing Loss

Subjects
0301 basic medicine, EchoGen Consortium, Population genetics, LOCI, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, 0302 clinical medicine, Settore MED/14 - NEFROLOGIA, Missense mutation, GENE-CENTRIC ARRAY, GoT2DGenes Consortium, AGING RESEARCH, Genetics, education.field_of_study, CHD Exome+ Consortium, CHARGE-Heart Failure Consortium, 11 Medical And Health Sciences, 3. Good health, CARDIOVASCULAR-DISEASE, Hypertension, Medical genetics, HEART, Wellcome Trust Case Control Consortium, EPIC-InterAct Consortium, ExomeBP Consortium, CHARGE, Understanding Society Scientific Group, medicine.medical_specialty, Genotype, Population, Biology, CHARGE+ Exome Chip Blood Pressure Consortium, EPIC-CVD Consortium, Article, 03 medical and health sciences, Lifelines Cohort Study, genome-wide association studies, hypertension, population genetics, Genetic variation, GIANT Consortium, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, education, PLASMA-LEVELS, IDENTIFICATION, Genetic Variation, 06 Biological Sciences, medicine.disease, METASTROKE Consortium, T2D-GENES Consortium, 030104 developmental biology, Blood pressure, Pathophysiology of hypertension, RISK-FACTORS, Developmental Biology, Genome-Wide Association Study, blood pressure, gene
Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ~155,063 samples for independent replication. We identified 30 new blood pressure– or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention. N.P. has received financial support from several pharmaceutical companies that manufacture either blood pressure -lowering or lipid-lowering agents, or both, and consultancy fees. S.K. has received research grants from Merck, Bayer and Aegerion, is on the SAB of Catabasis, Regeneron Genetics Center, Merck and Celera, has equity in San Therapeutics and Catabasis, and performs consulting for Novartis, Aegerion, Bristol Myers Squibb, Sanofi, AstraZeneca and Alnylam. P. Sever has received research awards from Pfizer. A. Malarstig and M.U.-N. are full-time employees of Pfizer. D.F.R. and M. Hoek are full-time employees of Merck. M.J.C. is Chief Scientist for Genomics England, a UK government company. The authors declare no other competing financial interests.

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6. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Author

Wheeler, E, Leong, A, Liu, C-T, Hivert, M-F, Strawbridge, RJ, Podmore, C, Li, M, Yao, J, Sim, X, Hong, J, Chu, AY, Zhang, W, Wang, X, Chen, P, Maruthur, NM, Porneala, BC, Sharp, SJ, Jia, Y, Kabagambe, EK, Chang, L-C, Chen, W-M, Elks, CE, Evans, DS, Fan, Q, Giulianini, F, Go, MJ, Hottenga, J-J, Hu, Y, Jackson, AU, Kanoni, S, Kim, YJ, Kleber, ME, Ladenvall, C, Lecoeur, C, Lim, S-H, Lu, Y, Mahajan, A, Marzi, C, Nalls, MA, Navarro, P, Nolte, IM, Rose, LM, Rybin, DV, Sanna, S, Shi, Y, Stram, DO, Takeuchi, F, Tan, SP, Van Der Most, PJ, Van Vliet-Ostaptchouk, JV, Wong, A, Yengo, L, Zhao, W, Goel, A, Martinez Larrad, MT, Radke, D, Salo, P, Tanaka, T, Van Iperen, EPA, Abecasis, G, Afaq, S, Alizadeh, BZ, Bertoni, AG, Bonnefond, A, Böttcher, Y, Bottinger, EP, Campbell, H, Carlson, OD, Chen, C-H, Cho, YS, Garvey, WT, Gieger, C, Goodarzi, MO, Grallert, H, Hamsten, A, Hartman, CA, Herder, C, Hsiung, CA, Huang, J, Igase, M, Isono, M, Katsuya, T, Khor, C-C, Kiess, W, Kohara, K, Kovacs, P, Lee, J, Lee, W-J, Lehne, B, Li, H, Liu, J, Lobbens, S, Luan, J, Lyssenko, V, Meitinger, T, Miki, T, Miljkovic, I, Moon, S, Mulas, A, Müller, G, Müller-Nurasyid, M, Nagaraja, R, Nauck, M, Pankow, JS, Polasek, O, Prokopenko, I, Ramos, PS, Rasmussen-Torvik, L, Rathmann, W, Rich, SS, Robertson, NR, Roden, M, Roussel, R, Rudan, I, Scott, RA, Scott, WR, Sennblad, B, Siscovick, DS, Strauch, K, Sun, L, Swertz, M, Tajuddin, SM, Taylor, KD, Teo, Y-Y, Tham, YC, Tönjes, A, Wareham, NJ, Willemsen, G, Wilsgaard, T, Hingorani, AD, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Egan, J, Ferrucci, L, Hovingh, GK, Jula, A, Kivimaki, M, Kumari, M, Njølstad, I, Palmer, CNA, Serrano Ríos, M, Stumvoll, M, Watkins, H, Aung, T, Blüher, M, Boehnke, M, Boomsma, DI, Bornstein, Chambers, JC, Chasman, DI, Chen, Y-DI, Chen, Y-T, Cheng, C-Y, Cucca, F, De Geus, EJC, Deloukas, P, Evans, MK, Fornage, M, Friedlander, Y, Froguel, P, Groop, L, Gross, MD, Harris, TB, Hayward, C, Heng, C-K, Ingelsson, E, Kato, N, Kim, B-J, Koh, W-P, Kooner, JS, Körner, A, Kuh, D, Kuusisto, J, Laakso, M, Lin, X, Liu, Y, Loos, RJF, Magnusson, PKE, März, W, McCarthy, MI, Oldehinkel, AJ, Ong, KK, Pedersen, NL, Pereira, MA, Peters, A, Ridker, PM, Sabanayagam, C, Sale, M, Saleheen, D, Saltevo, J, Schwarz, PE, Sheu, WHH, Snieder, H, Spector, TD, Tabara, Y, Tuomilehto, J, Van Dam, RM, Wilson, JG, Wilson, JF, Wolffenbuttel, BHR, Wong, TY, Wu, J-Y, Yuan, J-M, Zonderman, AB, Soranzo, N, Guo, X, Roberts, DJ, Florez, JC, Sladek, R, Dupuis, J, Morris, AP, Tai, E-S, Selvin, E, Rotter, JI, Langenberg, C, Barroso, I, and Meigs, JB

Subjects
Hemoglobin A, Glycosylated, endocrine system diseases, Diabetes Mellitus, Type 2, phenotype, genetic variation, nutritional and metabolic diseases, humans, 3. Good health, Genome-Wide Association Study, risk
Abstract

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

7. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Author

Surendran, Praveen, Drenos, Fotios, Young, Robin, Warren, Helen, Cook, James P, Manning, Alisa K, Grarup, Niels, Sim, Xueling, Barnes, Daniel R, Witkowska, Kate, Staley, James R, Tragante, Vinicius, Tukiainen, Taru, Yaghootkar, Hanieh, Masca, Nicholas, Freitag, Daniel F, Ferreira, Teresa, Giannakopoulou, Olga, Tinker, Andrew, Harakalova, Magdalena, Mihailov, Evelin, Liu, Chunyu, Kraja, Aldi T, Fallgaard Nielsen, Sune, Rasheed, Asif, Samuel, Maria, Zhao, Wei, Bonnycastle, Lori L, Jackson, Anne U, Narisu, Narisu, Swift, Amy J, Southam, Lorraine, Marten, Jonathan, Huyghe, Jeroen R, Stančáková, Alena, Fava, Cristiano, Ohlsson, Therese, Matchan, Angela, Stirrups, Kathleen E, Bork-Jensen, Jette, Gjesing, Anette P, Kontto, Jukka, Perola, Markus, Shaw-Hawkins, Susan, Havulinna, Aki S, Zhang, He, Donnelly, Louise A, Groves, Christopher J, Rayner, N William, Neville, Matt J, Robertson, Neil R, Yiorkas, Andrianos M, Herzig, Karl-Heinz, Kajantie, Eero, Zhang, Weihua, Willems, Sara M, Lannfelt, Lars, Malerba, Giovanni, Soranzo, Nicole, Trabetti, Elisabetta, Verweij, Niek, Evangelou, Evangelos, Moayyeri, Alireza, Vergnaud, Anne-Claire, Nelson, Christopher P, Poveda, Alaitz, Varga, Tibor V, Caslake, Muriel, De Craen, Anton Jm, Trompet, Stella, Luan, Jian'an, Scott, Robert A, Harris, Sarah E, Liewald, David Cm, Marioni, Riccardo, Menni, Cristina, Farmaki, Aliki-Eleni, Hallmans, Göran, Renström, Frida, Huffman, Jennifer E, Hassinen, Maija, Burgess, Stephen, Vasan, Ramachandran S, Felix, Janine F, CHARGE-Heart Failure Consortium, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F, Hoek, Maarten, Vogt, Thomas, Lin, Honghuang, Lieb, Wolfgang, EchoGen Consortium, Traylor, Matthew, Markus, Hugh F, METASTROKE Consortium, Highland, Heather M, Justice, Anne E, Marouli, Eirini, GIANT Consortium, Lindström, Jaana, Uusitupa, Matti, Komulainen, Pirjo, Lakka, Timo A, Rauramaa, Rainer, Polasek, Ozren, Rudan, Igor, Rolandsson, Olov, Franks, Paul W, Dedoussis, George, Spector, Timothy D, EPIC-InterAct Consortium, Jousilahti, Pekka, Männistö, Satu, Deary, Ian J, Starr, John M, Langenberg, Claudia, Wareham, Nick J, Brown, Morris J, Dominiczak, Anna F, Connell, John M, Jukema, J Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J, Esko, Tõnu, Mägi, Reedik, Metspalu, Andres, De Boer, Rudolf A, Van Der Meer, Peter, Van Der Harst, Pim, Lifelines Cohort Study, Gambaro, Giovanni, Ingelsson, Erik, Lind, Lars, De Bakker, Paul Iw, Numans, Mattijs E, Brandslund, Ivan, Christensen, Cramer, Petersen, Eva Rb, Korpi-Hyövälti, Eeva, Oksa, Heikki, Chambers, John C, Kooner, Jaspal S, Blakemore, Alexandra If, Franks, Steve, Jarvelin, Marjo-Riitta, Husemoen, Lise L, Linneberg, Allan, Skaaby, Tea, Thuesen, Betina, Karpe, Fredrik, Tuomilehto, Jaakko, Doney, Alex Sf, Morris, Andrew D, Palmer, Colin Na, Holmen, Oddgeir Lingaas, Hveem, Kristian, Willer, Cristen J, Tuomi, Tiinamaija, Groop, Leif, Käräjämäki, AnneMari, Palotie, Aarno, Ripatti, Samuli, Salomaa, Veikko, Alam, Dewan S, Shafi Majumder, Abdulla Al, Di Angelantonio, Emanuele, Chowdhury, Rajiv, McCarthy, Mark I, Poulter, Neil, Stanton, Alice V, Sever, Peter, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrières, Jean, Kee, Frank, Kuulasmaa, Kari, Müller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Deloukas, Panos, Wellcome Trust Case Control Consortium, Elliott, Paul, Understanding Society Scientific Group, Zeggini, Eleftheria, Kathiresan, Sekar, Melander, Olle, Kuusisto, Johanna, Laakso, Markku, Padmanabhan, Sandosh, Porteous, David, Hayward, Caroline, Scotland, Generation, Collins, Francis S, Mohlke, Karen L, Hansen, Torben, Pedersen, Oluf, Boehnke, Michael, Stringham, Heather M, EPIC-CVD Consortium, Frossard, Philippe, Newton-Cheh, Christopher, CHARGE+ Exome Chip Blood Pressure Consortium, Tobin, Martin D, Nordestgaard, Børge Grønne, T2D-GENES Consortium, GoT2DGenes Consortium, ExomeBP Consortium, CHD Exome+ Consortium, Caulfield, Mark J, Mahajan, Anubha, Morris, Andrew P, Tomaszewski, Maciej, Samani, Nilesh J, Saleheen, Danish, Asselbergs, Folkert W, Lindgren, Cecilia M, Danesh, John, Wain, Louise V, Butterworth, Adam S, Howson, Joanna Mm, and Munroe, Patricia B

Subjects
Genotype, Hypertension, Genetic Variation, Humans, Blood Pressure, Genetic Predisposition to Disease, 3. Good health, Genome-Wide Association Study
Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

8. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Edwards, Todd L, Ellinghaus, David, Ellinor, Patrick T, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Farooqi, I Sadaf, Faul, Jessica D, Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Ford, Ian, Fornage, Myriam, Franco, Oscar H, Franke, Andre, Franks, Paul W, Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmantas, Gjesing, Anette P, Gordon-Larsen, Penny, Gorski, Mathias, Grabe, Hans-Jörgen, Grant, Struan FA, Grarup, Niels, Griffiths, Helen L, Grove, Megan L, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B, Hattersley, Andrew T, Have, Christian T, Hayward, Caroline, He, Liang, Heard-Costa, Nancy L, Heath, Andrew C, Heid, Iris M, Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Huang, Paul L, Huffman, Jennifer E, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jansson, Jan-Håkan, Jarvik, Gail P, Jensen, Gorm B, Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E, Jørgensen, Torben, Jukema, J Wouter, Kahali, Bratati, Kahn, René S, Kähönen, Mika, Kamstrup, Pia R, Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A, Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kooperberg, Charles, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Ethan M, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Liu, Yongmei, Lo, Ken S, Lophatananon, Artitaya, Lotery, Andrew J, Loukola, Anu, Luan, Jian'an, Lubitz, Steven A, Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L, McCarthy, Mark I, McKean-Cowdin, Roberta, Medland, Sarah E, Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L, Moilanen, Leena, Moitry, Marie, Montgomery, Grant W, Mook-Kanamori, Dennis O, Moore, Carmel, Mori, Trevor A, Morris, Andrew D, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Nalls, Mike A, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Nielsen, Sune F, Nikus, Kjell, Njølstad, Pål R, Nordestgaard, Børge G, Nyholt, Dale R, O'Connel, Jeffrey R, O'Donoghue, Michelle L, Olde Loohuis, Loes M, Ophoff, Roel A, Owen, Katharine R, Packard, Chris J, Padmanabhan, Sandosh, Palmer, Colin NA, Palmer, Nicholette D, Pasterkamp, Gerard, Patel, Aniruddh P, Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Person, Thomas N, Peters, Annette, Petersen, Eva RB, Peyser, Patricia A, Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J, Puolijoki, Hannu, Raitakari, Olli T, Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F, Renström, Frida, Rheinberger, Myriam, Ridker, Paul M, Rioux, John D, Rivas, Manuel A, Roberts, David J, Robertson, Neil R, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo P, Shah, Svati H, Sheu, Wayne H-H, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Albert V, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J, Tada, Hayato, Tansey, Katherine E, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P, Uher, Rudolf, Uitterlinden, André G, Uusitupa, Matti, Laan, Sander W, Duijn, Cornelia M, Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V, Varma, Rohit, Velez Edwards, Digna R, Vermeulen, Sita H, Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wang, Yiqin, Ware, Erin B, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Witte, Daniel R, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Rotter, Jerome I, Pospisilik, John A, Rivadeneira, Fernando, Borecki, Ingrid B, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, North, Kari E, Lindgren, Cecilia M, Hirschhorn, Joel N, and Loos, Ruth JF

Subjects
2. Zero hunger, Adult, Male, Genetic Variation, Proteins, Syndrome, Body Mass Index, Gene Frequency, Animals, Humans, Drosophila, Female, Obesity, Energy Intake, Energy Metabolism
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

9. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. 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A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. 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F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center

Subjects
0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Published
2018
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10. Rare and low-frequency coding variants alter human adult height

Author

Marouli, Eirini, Graff, Mariaelisa, Medina-Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R, Kjaer, Troels R, Fine, Rebecca S, Lu, Yingchang, Schurmann, Claudia, Highland, Heather M, Rueger, Sina, Thorleifsson, Gudmar, Justice, Anne E, Lamparter, David, Stirrups, Kathleen E, Turcot, Valerie, Young, Kristin L, Winkler, Thomas W, Esko, Tonu, Karaderi, Tugce, Locke, Adam E, Masca, Nicholas GD, Ng, Maggie CY, Mudgal, Poorva, Rivas, Manuel A, Vedantam, Sailaja, Mahajan, Anubha, Guo, Xiuqing, Abecasis, Goncalo, Aben, Katja K, Adair, Linda S, Alam, Dewan S, Albrecht, Eva, Allin, Kristine H, Allison, Matthew, Amouyel, Philippe, Appel, Emil V, Arveiler, Dominique, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Banas, Bernhard, Bang, Lia E, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blueher, Matthias, Boeing, Heiner, Boerwinkle, Eric, Boeger, Carsten A, Bonnycastle, Lori L, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Carey, David J, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Galbany, Jordi Corominas, Cox, Amanda J, Cuellar-Partida, Gabriel, Danesh, John, Davies, Gail, de Bakker, Paul IW, de Borst, Gert J, de Denus, Simon, de Groot, Mark CH, de Mutsert, Renee, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, den Hollander, Anneke I, Dennis, Joe G, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dunning, Alison M, Easton, Douglas F, Ebeling, Tapani, Edwards, Todd L, Ellinor, Patrick T, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Faul, Jessica D, Feitosa, Mary F, Feng, Shuang, Ferrannini, Ele, Ferrario, Marco M, Ferrieres, Jean, Florez, Jose C, Ford, Ian, Fornage, Myriam, Franks, Paul W, Frikke-Schmidt, Ruth, Galesloot, Tessel E, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Giri, Ayush, Girotto, Giorgia, Gordon, Scott D, Gordon-Larsen, Penny, Gorski, Mathias, Grarup, Niels, Grove, Megan L, Gudnason, Vilmundur, Gustafsson, Stefan, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B, Hattersley, Andrew T, Hayward, Caroline, He, Liang, Heid, Iris M, Heikkila, Kauko, Helgeland, Oyvind, Hernesniemi, Jussi, Hewitt, Alex W, Hocking, Lynne J, Hollensted, Mette, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hoyng, Carel B, Huang, Paul L, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jansson, Jan-Hakan, Jarvik, Gail P, Jensen, Gorm B, Jhun, Min A, Jia, Yucheng, Jiang, Xuejuan, Johansson, Stefan, Jorgensen, Marit E, Jorgensen, Torben, Jousilahti, Pekka, Jukema, J Wouter, Kahali, Bratati, Kahn, Rene S, Kahonen, Mika, Kamstrup, Pia R, Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Keeman, Renske, Kiemeney, Lambertus A, Kitajima, Hidetoshi, Kluivers, Kirsten B, Kocher, Thomas, Komulainen, Pirjo, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kovacs, Peter, Kriebel, Jennifer, Kuivaniemi, Helena, Kury, Sebastien, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lakka, Timo A, Lange, Ethan M, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Larson, Eric B, Lee, I-Te, Lehtimaki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindstrom, Jaana, Linneberg, Allan, Liu, Yeheng, Liu, Yongmei, Lophatananon, Artitaya, Luan, Jian'an, Lubitz, Steven A, Lyytikainen, Leo-Pekka, Mackey, David A, Madden, Pamela AF, Manning, Alisa K, Mannisto, Satu, Marenne, Gaelle, Marten, Jonathan, Martin, Nicholas G, Mazul, Angela L, Meidtner, Karina, Metspalu, Andres, Mitchell, Paul, Mohlke, Karen L, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew D, Morris, Andrew P, Mueller-Nurasyid, Martina, Munroe, Patricia B, Nalls, Mike A, Nauck, Matthias, Nelson, 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Smith, Albert Vernon, Smith, Jennifer A, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Steinthorsdottir, Valgerdur, Stringham, Heather M, Stumvoll, Michael, Surendran, Praveen, 't Hart, Leen M, Tansey, Katherine E, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorsteinsdottir, Unnur, Thuesen, Betina H, Toenjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P, Uher, Rudolf, Uitterlinden, Andre G, Ulivi, Sheila, van der Laan, Sander W, Van Der Leij, Andries R, van Duijn, Cornelia M, van Schoor, Natasja M, van Setten, Jessica, Varbo, Anette, Varga, Tibor V, Varma, Rohit, Edwards, Digna R Velez, Vermeulen, Sita H, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Vozzi, Diego, Walker, Mark, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wang, Yiqin, Wareham, Nicholas J, Warren, Helen R, Wessel, Jennifer, Willems, Sara M, Wilson, James G, Witte, Daniel R, Woods, Michael O, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Rotter, Jerome I, Boehnke, Michael, Kathiresan, Sekar, McCarthy, Mark I, Willer, Cristen J, Stefansson, Kari, Borecki, Ingrid B, Liu, Dajiang J, North, Kari E, Heard-Costa, Nancy L, Pers, Tune H, Lindgren, Cecilia M, Oxvig, Claus, Kutalik, Zoltan, Rivadeneira, Fernando, Loos, Ruth JF, Frayling, Timothy M, Hirschhorn, Joel N, Deloukas, Panos, Lettre, Guillaume, Consortium, EPIC-InterAct, Consortium, EPIC-CVD, Consortium, CHD Exome, Consortium, ExomeBP, Consortium, T2D-Genes, Consortium, GoT2D Genes, Consortium, Global Lipids Genetics, Consortium, ReproGen, Investigators, MAGIC, Marouli, Eirini, Graff, Mariaelisa, Medina Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R., Kjaer, Troels R., Fine, Rebecca S., Lu, Yingchang, Schurmann, Claudia, Highland, Heather M., Rüeger, Sina, 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W., De Borst, Gert J., De Denus, Simon, De Groot, Mark C. H., De Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Den Hollander, Anneke I., Dennis, Joe G., Di Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dunning, Alison M., Easton, Douglas F., Ebeling, Tapani, Edwards, Todd L., Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki Eleni, Faul, Jessica D., Feitosa, Mary F., Feng, Shuang, Ferrannini, Ele, Ferrario, Marco M., Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franks, Paul W., Frikke Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Giri, Ayush, Girotto, Giorgia, Gordon, Scott D., Gordon Larsen, Penny, Gorski, Mathia, Grarup, Niel, Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Hayward, Caroline, He, Liang, Heid, Iris M., Heikkilä, Kauko, Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Hocking, Lynne J., Hollensted, Mette, Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hoyng, Carel B., Huang, Paul L., Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan Håkan, Jarvik, Gail P., Jensen, Gorm B., Jhun, Min A., Jia, Yucheng, Jiang, Xuejuan, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jousilahti, Pekka, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Keeman, Renske, Kiemeney, Lambertus A., Kitajima, Hidetoshi, Kluivers, Kirsten B., Kocher, Thoma, Komulainen, Pirjo, Kontto, Jukka, Kooner, Jaspal S., Kooperberg, Charle, Kovacs, Peter, Kriebel, Jennifer, Kuivaniemi, Helena, Küry, Sébastien, Kuusisto, Johanna, LA BIANCA, Martina, Laakso, Markku, Lakka, Timo A., Lange, Ethan M., Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Larson, Eric B., Lee, I. Te, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li Gao, Ruifang, Lin, Honghuang, Lin, Li An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Yeheng, Liu, Yongmei, Lophatananon, Artitaya, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo Pekka, Mackey, David A., Madden, Pamela A. F., Manning, Alisa K., Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Martin, Nicholas G., Mazul, Angela L., Meidtner, Karina, Metspalu, Andre, Mitchell, Paul, Mohlke, Karen L., Mook Kanamori, Dennis O., Morgan, Anna, Morris, Andrew D., Morris, Andrew P., Müller Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Nauck, Matthia, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Ntalla, Ioanna, O'Connel, Jeffrey R., Oksa, Heikki, Loohuis, Loes M. Olde, Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Person, Thomas N., Pirie, Ailith, Polasek, Ozren, Posthuma, Danielle, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renström, Frida, Ridker, Paul M., Rioux, John D., Robertson, Neil, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sandow, Kevin, Sapkota, Yadav, Sattar, Naveed, Schmidt, Marjanka K., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura Lepe, Marcelo P., Shah, Svati, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert Vernon, Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Steinthorsdottir, Valgerdur, Stringham, Heather M., Stumvoll, Michael, Surendran, Praveen, Hart'T, Leen M., Tansey, Katherine E., Tardif, Jean Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Ulivi, Sheila, Van Der Laan, Sander W., Van Der Leij, Andries R., Van Duijn, Cornelia M., Van Schoor, Natasja M., Van Setten, Jessica, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vozzi, Diego, Walker, Mark, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Wareham, Nicholas J., Warren, Helen R., Wessel, Jennifer, Willems, Sara M., Wilson, James G., Witte, Daniel R., Woods, Michael O., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Rotter, Jerome I., Boehnke, Michael, Kathiresan, Sekar, Mccarthy, Mark I., Willer, Cristen J., Stefansson, Kari, Borecki, Ingrid B., Liu, Dajiang J., North, Kari E., Heard Costa, Nancy L., Pers, Tune H., Lindgren, Cecilia M., Oxvig, Clau, Kutalik, Zoltán, Rivadeneira, Fernando, Loos, Ruth J. F., Frayling, Timothy M., Hirschhorn, Joel N., Deloukas, Pano, Lettre, Guillaume, Pharmacoepidemiology and Clinical Pharmacology, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Neurology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, Action on Hearing Loss, Home Office, National Institutes of Health, Public Health England, EPIC-InterAct Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium, MAGIC Investigators, Physiology, Human genetics, APH - Personalized Medicine, APH - Aging & Later Life, Epidemiology and Data Science, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Male, ReproGen Consortium, Multifactorial Inheritance, Genome-wide association study, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Androgen, ADAMTS Proteins, Gene Frequency, Missing heritability problem, MISSING HERITABILITY, Receptors, 2.1 Biological and endogenous factors, Pregnancy-Associated Plasma Protein-A, Aetiology, Non-U.S. Gov't, Glycosaminoglycans, Genetics, Multidisciplinary, Genome, CHD Exome+ Consortium, Medicine (all), Research Support, Non-U.S. Gov't, T2D-Genes Consortium, Global Lipids Genetics Consortium, Multidisciplinary Sciences, Phenotype, NADPH Oxidase 4, Receptors, Androgen, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Interferon Regulatory Factors, Science & Technology - Other Topics, Intercellular Signaling Peptides and Proteins, Female, Proteoglycans, EPIC-InterAct Consortium, ExomeBP Consortium, Common disease-common variant, Human, Adult, General Science & Technology, Biology, Development, Research Support, Article, GENETIC ARCHITECTURE, N.I.H, 03 medical and health sciences, MAGIC Investigators, Research Support, N.I.H., Extramural, Somatomedins, Genetic variation, MD Multidisciplinary, Journal Article, gene, height, rare, Humans, Hedgehog Proteins, Interleukin-11 Receptor alpha Subunit, Allele, GENOME-WIDE ASSOCIATION, Gene, Allele frequency, Alleles, Genetic association, Genetic association study, Glycoproteins, Science & Technology, MUTATIONS, Genome, Human, ta1184, Human Genome, Extramural, Genetic Variation, NADPH Oxidases, ta3121, Body Height, INTERLEUKIN-11, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], MICE, 030104 developmental biology, GoT2D Genes Consortium, Proteolysis, Procollagen N-Endopeptidase, Cell Adhesion Molecules
Abstract

Contains fulltext : 169801.pdf (Publisher’s version ) (Closed access) Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Published
2017
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11. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

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Lynne J. Hocking, Caterina Barbieri, Jenny Chang-Claude, David Karasik, Dieter Flesch-Janys, James F. Wilson, Mark S. Goldberg, Henry Voelzke, Archie Campbell, Stig E. Bojesen, David R. Weir, Ailith Pirie, Megan L. Grove, Melissa Wellons, Georg Homuth, Corrado Masciullo, Jennifer A. Brody, Hermann Brenner, Paolo Gasparini, Andrew D. Johnson, Patrick Neven, Graham G. Giles, Peter Kraft, André G. Uitterlinden, Wei Zheng, Alkes L. Price, Anja Rudolph, Arto Mannermaa, Nicholas G. Martin, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Daniela Ruggiero, Toshiko Tanaka, Kathryn L. Lunetta, Julie E. Buring, John R. B. Perry, Robert Winqvist, Laufey Tryggvadottir, Angela Cox, Serena Sanna, Nicola Pirastu, Anna Jakubowska, Paul D.P. Pharoah, David J. Porteous, Dragana Vuckovic, Andrea D. Coviello, Giorgia Girotto, Sara Lindstroem, Patrick Sulem, Astrid Petersmann, Xin Li, Maartje J. Hooning, Lili Milani, Sven Bergmann, Marek Zygmunt, Javier Benitez, Vilmundur Gudnason, Fernando Rivadeneira, Volker Arndt, Marina Ciullo, Caroline Hayward, Sheila Ulivi, Janet E. Olson, Hoda Anton-Culver, Maria Kabisch, Sara Margolin, Vessela N. Kristensen, Patrick F. McArdle, Tanguy Corre, Nora Franceschini, Veli-Matti Kosma, Hiltrud Brauch, Roger L. Milne, Eric Boerwinkle, Matthias W. Beckmann, Charles Kooperberg, Qin Wang, Jessica D. Faul, Stephen J. Chanock, Alexander Teumer, Mark O. Goodarzi, Unnur Thorsteinsdottir, R Maegi, Paul M. Ridker, Antonis C. Antoniou, Ozren Polasek, Daniel F. Gudbjartsson, Barbara McKnight, Melissa E. Garcia, Manjeet K. Bolla, Alanna C. Morrison, Paolo Radice, Xiuqing Guo, Lude L. Franke, Michela Traglia, Marjanka K. Schmidt, Heli Nevanlinna, Teresa Nutile, Cinzia Sala, Pascal Guénel, Jennifer E. Huffman, Stephen T. Turner, Anna Murray, Carl Blomqvist, Margaux F. Keller, Samuel E. Jones, Montserrat Garcia-Closas, Ivana Kolcic, Anne B. Newman, Jan Lubinski, Albert Hofman, Isabel dos-Santos-Silva, Hilary K. Finucane, Anne Lise Børresen-Dale, Alexander P. Reiner, Tim D. Spector, Gonneke Willemsen, John D. Eicher, Douglas F. Easton, Claudia Langenberg, Anthony J. Swerdlow, Natalia Bogdanova, Alison M. Dunning, Giorgio Pistis, Tõnu Esko, Behrooz Z. Alizadeh, Martina Mueller-Nurasyid, Eleonora Porcu, Laura M. Yerges-Armstrong, Leslie J. Raffel, Laura Crisponi, Gonçalo R. Abecasis, Jerome I. Rotter, Yii-Der Ida Chen, Antonietta Robino, Katri Pylkaes, Ken K. Ong, Thibaud Boutin, Elinor J. Sawyer, Daniel I. Chasman, Brian E. Henderson, Frank B. Hu, Leslie Bernstein, Drakoulis Yannoukakos, Tamara B. Harris, Dorret I. Boomsma, Katherine S. Ruth, Jie Yao, Keith Humphreys, Jennifer A. Smith, Elisabeth Altmaier, Ulrike Peters, Doris Stoeckl, Eva Albrecht, Tatijana Zemunik, Jenny A. Visser, Minouk J. Schoemaker, Diego Vozzi, Thilo Doerk, J. Ross Chapman, Irene L. Andrulis, Joanne M. Murabito, Alan F. Wright, Lisette Stolk, Jonathan Marten, Alice M. Arnold, Paolo Peterlongo, Harry Campbell, Natalia Pervjakova, Jingmei Li, Jennifer Kriebel, Alicia Beeghly-Fadiel, Immaculata De Vivo, Jouke-Jan Hottenga, Kari Stefansson, Cornelia M. van Duijn, Brendan Bulik-Sullivan, Evelin Mihailov, Chunyan He, Joe Dennis, Nicholas J. Wareham, Yongmei Liu, Sharon L.R. Kardia, Lynda M. Rose, Felix R. Day, Georgia Chenevix-Trench, Albert V. Smith, David J. Hunter, Sandosh Padmanabhan, Christian Gieger, Konstantin Strauch, Igor Rudan, Jacques Simard, Jian'an Luan, Robert A. Scott, Kyriaki Michailidou, Bruce M. Psaty, Per Hall, Suzette J. Bielinski, Rita K. Schmutzler, Julian Peto, Ellen W. Demerath, Ursula M. Schick, Rossella Sorice, Wei Zhao, Børge G. Nordestgaard, Andres Metspalu, Jonine D. Figueroa, Julia A. Knight, Barbara Burwinkel, Thomas Bruening, Judith Manz, Anna González-Neira, Ilaria Gandin, Ian Tomlinson, Thérèse Truong, Kent D. Taylor, Amanda E. Toland, Deborah J. Thompson, Alfons Meindl, Caroline M. Seynaeve, Benjamin M. Neale, Fergus J. Couch, Mike A. Nalls, Ute Hamann, Kamila Czene, John L. Hopper, Bruce H. R. Wolffenbuttel, Grant W. Montgomery, Hatef Darabi, Daniela Toniolo, Jinyan Huang, Peter Devilee, Cathy E. Elks, David Schlessinger, Luigi Ferrucci, Frank Schmidt, Peter A. Fasching, Diether Lambrechts, Najaf Amin, Day, Felix R, Ruth, Katherine S, Thompson, Deborah J, Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Sulem, Patrick, Bulik Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D, Elks, Cathy E, Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A, Franke, Lude L, Huffman, Jennifer E, Keller, Margaux F, Mcardle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Smith, Jennifer A, Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke Jan, Mangino, Massimo, Smith, Albert V, Tanaka, Toshiko, Abecasis, Gonçalo R, Andrulis, Irene L, Anton Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Arnold, Alice M, Barbieri, CATERINA MARIA, Beckmann, Matthias W, Beeghly Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen Dale, Anne Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thoma, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J, Chapman, J. Ro, Chen, Yii Der Ida, Chenevix Trench, Georgia, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos Santos Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Figueroa, Jonine, Flesch Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E, García Closas, Montserrat, Giles, Graham G, Girotto, Giorgia, Goldberg, Mark S, González Neira, Anna, Goodarzi, Mark O, Grove, Megan L, Gudbjartsson, Daniel F, Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A, Hall, Per, Hamann, Ute, Henderson, Brian E, Hocking, Lynne J, Hofman, Albert, Homuth, Georg, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Huang, Jinyan, Humphreys, Keith, Hunter, David J, Jakubowska, Anna, Jones, Samuel E, Kabisch, Maria, Karasik, David, Knight, Julia A, Kolcic, Ivana, Kooperberg, Charle, Kosma, Veli Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindström, Sara, Liu, Yongmei, Luan, Jian'An, Lubinski, Jan, Mägi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G, Masciullo, Corrado, Meindl, Alfon, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L, Müller Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M, Nevanlinna, Heli, Neven, Patrick, Newman, Anne B, Nordestgaard, Børge G, Olson, Janet E, Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P, Pirastu, Nicola, Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M, Pylkäs, Katri, Radice, Paolo, Raffel, Leslie J, Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F, Sanna, Serena, Sawyer, Elinor J, Schlessinger, David, Schmidt, Marjanka K, Schmidt, Frank, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Robert A, Seynaeve, Caroline M, Simard, Jacque, Sorice, Rossella, Southey, Melissa C, Stöckl, Dori, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D, Thorsteinsdottir, Unnur, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Tryggvadottir, Laufey, Turner, Stephen T, Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F, Winqvist, Robert, Wolffenbuttel, Bruce B. H. R, Wright, Alan F, Yannoukakos, Drakouli, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I, Buring, Julie E, Ferrucci, Luigi, Montgomery, Grant W, Gudnason, Vilmundur, Spector, Tim D, van Duijn, Cornelia M, Alizadeh, Behrooz Z, Ciullo, Marina, Crisponi, Laura, Easton, Douglas F, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B, Hayward, Caroline, Kardia, Sharon L. R, Kraft, Peter, Mcknight, Barbara, Metspalu, Andre, Morrison, Alanna C, Reiner, Alex P, Ridker, Paul M, Rotter, Jerome I, Toniolo, Daniela, Uitterlinden, André G, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J, Weir, David R, Yerges Armstrong, Laura M, Price, Alkes L, Stefansson, Kari, Visser, Jenny A, Ong, Ken K, Chang Claude, Jenny, Murabito, Joanne M, Perry, John R. B, Murray, Anna, Internal Medicine, Epidemiology, Medical Oncology, Clinical Genetics, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, PRACTICAL Consortium, kConFab Investigators, AOCS Investigators, EPIC-InterAct Consortium, LifeLines Cohort Study, Generation, Scotland, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Subjects
Netherlands Twin Register (NTR), Aging, DNA Repair, LOCI, Genome-wide association study, BLOOD-PRESSURE, Disease, CHROMOSOMAL INSTABILITY, Bioinformatics, HOMOLOGOUS RECOMBINATION, PREMATURE OVARIAN FAILURE, Genotype, BRCA2 MUTATION CARRIERS, WIDE ASSOCIATION, Gene Regulatory Networks, NATURAL MENOPAUSE, Genetics, education.field_of_study, menopause, DDR, BODY-MASS INDEX, CELL-TYPES, BRCA1 Protein, Reproduction, BRCA1-mediated DNA repair, Age Factors, Obstetrics and Gynecology, General Medicine, Genomics, Middle Aged, 3. Good health, Menopause, Phenotype, Female, medicine.symptom, Signal Transduction, Delayed puberty, Adult, DNA repair, Population, Hypothalamus, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Lower risk, DDR, Article, Breast cancer, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Genetic association, Models, Genetic, business.industry, Genetic Variation, medicine.disease, Aging/genetics, BRCA1 Protein/genetics, Breast Neoplasms/genetics, Gene Regulatory Networks/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Genomics/methods, Hypothalamus/metabolism, Menopause/genetics, Reproduction/genetics, Signal Transduction/genetics, business, Genome-Wide Association Study
Abstract

Menopause timing has a major impact on infertility and risk of disease. Younger age at natural (nonsurgical) menopause (ANM) is associated with a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes and a lower risk of breast cancer. Late menopause is associated with a higher risk of breast cancer. It is well known that the age at which women go through menopause is partly determined by genes, but the underlying mechanisms are poorly understood. Genome-wide association studies have identified 18 common genetic variants associated with ANM. These variants explain less than 5% of the variation in ANM compared with the 21% explained by all common variants on genome-wide association study arrays. This genome-wide association study was the collaborative effort of researchers from 177 institutions worldwide. The study was designed to investigate genetic variants associated with timing of menopause among a population of approximately 70,000 women of European ancestry. A dual strategy was used to identify both common and, for the first time, low-frequency coding variants associated with ANM. The causal relationship between ANM and breast cancer was investigated using a Mendelian randomization approach. Combined analysis identified 1208 single-nucleotide polymorphisms (SNPs) of a total of approximately 2.6 million that reached the genome-wide significance threshold for association with ANM. Forty-four regions with common variants were identified; among these 44 loci were 2 rare low-frequency missense alleles of large effect. A majority of ANM SNPs were enriched in DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal relationship between delayed ANM and breast cancer risk; there was approximately 6% increase in risk per year; P = 3 × 10-14); increased risk with delayed menopause appeared to be mediated primarily by prolonged sex hormone exposure in a woman’s lifetime, not DDR mechanisms. This is the first study to confirm the link between early and late menopause and breast cancer risk using genetic information. Age at natural menopause genetic variants influence breast cancer risk primarily through variation in menopause timing. Although carrying higher numbers of ANM-increasing variants and enrichment in DDR genes are associated with a modest increase in breast cancer risk, the major mechanism for increased risk appears to be prolonged estrogen and/or progesterone exposure due to delayed menopause.

Published
2015
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12. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author

Wessel, Jennifer, Chu, Audrey Y, Willems, Sara M, Wang, Shuai, Yaghootkar, Hanieh, Brody, Jennifer A, Dauriz, Marco, Hivert, Marie-France, Raghavan, Sridharan, Lipovich, Leonard, Hidalgo, Bertha, Fox, Keolu, Huffman, Jennifer E, An, Ping, Lu, Yingchang, Rasmussen-Torvik, Laura J, Grarup, Niels, Ehm, Margaret G, Li, Li, Baldridge, Abigail S, Stančáková, Alena, Abrol, Ravinder, Besse, Céline, Boland, Anne, Bork-Jensen, Jette, Fornage, Myriam, Freitag, Daniel F, Garcia, Melissa E, Guo, Xiuqing, Hara, Kazuo, Isaacs, Aaron, Jakobsdottir, Johanna, Lange, Leslie A, Layton, Jill C, Li, Man, Hua Zhao, Jing, Meidtner, Karina, Morrison, Alanna C, Nalls, Mike A, Peters, Marjolein J, Sabater-Lleal, Maria, Schurmann, Claudia, Silveira, Angela, Smith, Albert V, Southam, Lorraine, Stoiber, Marcus H, Strawbridge, Rona J., Taylor, Kent D, Varga, Tibor V, Allin, Kristine H, Amin, Najaf, Aponte, Jennifer L, Aung, Tin, Barbieri, Caterina, Bihlmeyer, Nathan A, Boehnke, Michael, Bombieri, Cristina, Bowden, Donald W, Burns, Sean M, Chen, Yuning, Chen, Yii-DerI, Cheng, Ching-Yu, Correa, Adolfo, Czajkowski, Jacek, Dehghan, Abbas, Ehret, Georg B, Eiriksdottir, Gudny, Escher, Stefan A, Farmaki, Aliki-Eleni, Frånberg, Mattias, Gambaro, Giovanni, Giulianini, Franco, Goddard, William A, Goel, Anuj, Gottesman, Omri, Grove, Megan L, Gustafsson, Stefan, Hai, Yang, Hallmans, Göran, Heo, Jiyoung, Hoffmann, Per, Ikram, Mohammad K, Jensen, Richard A, Jørgensen, Marit E, Jørgensen, Torben, Karaleftheri, Maria, Khor, Chiea C, Kirkpatrick, Andrea, Kraja, Aldi T, Kuusisto, Johanna, Lange, Ethan M, Lee, I T, Lee, Wen-Jane, Leong, Aaron, Liao, Jiemin, Liu, Chunyu, Liu, Yongmei, Lindgren, Cecilia M, Linneberg, Allan, Malerba, Giovanni, Mamakou, Vasiliki, Marouli, Eirini, Maruthur, Nisa M, Matchan, Angela, McKean-Cowdin, Roberta, McLeod, Olga, Metcalf, Ginger A, Mohlke, Karen L, Muzny, Donna M, Ntalla, Ioanna, Palmer, Nicholette D, Pasko, Dorota, Peter, Andreas, Rayner, Nigel W, Renström, Frida, Rice, Ken, Sala, Cinzia F, Sennblad, Bengt, Serafetinidis, Ioannis, Smith, Jennifer A, Soranzo, Nicole, Speliotes, Elizabeth K, Stahl, Eli A, Stirrups, Kathleen, Tentolouris, Nikos, Thanopoulou, Anastasia, Torres, Mina, Traglia, Michela, Tsafantakis, Emmanouil, Javad, Sundas, Yanek, Lisa R, Zengini, Eleni, Becker, Diane M, Bis, Joshua C, Brown, James B, Adrienne Cupples, L, Hansen, Torben, Ingelsson, Erik, Karter, Andrew J, Lorenzo, Carlos, Mathias, Rasika A, Norris, Jill M, Peloso, Gina M, Sheu, Wayne H.-H., Toniolo, Daniela, Vaidya, Dhananjay, Varma, Rohit, Wagenknecht, Lynne E, Boeing, Heiner, Bottinger, Erwin P, Dedoussis, George, Deloukas, Panos, Ferrannini, Ele, Franco, Oscar H, Franks, Paul W, Gibbs, Richard A, Gudnason, Vilmundur, Hamsten, Anders, Harris, Tamara B, Hattersley, Andrew T, Hayward, Caroline, Hofman, Albert, Jansson, Jan-Håkan, Langenberg, Claudia, Launer, Lenore J, Levy, Daniel, Oostra, Ben A, O’Donnell, Christopher J, O’Rahilly, Stephen, Padmanabhan, Sandosh, Pankow, James S, Polasek, Ozren, Province, Michael A, Rich, Stephen S, Ridker, Paul M, Rudan, Igor, Schulze, Matthias B, Smith, Blair H, Uitterlinden, André G, Walker, Mark, Watkins, Hugh, Wong, Tien Y, Zeggini, Eleftheria, Sharp, Stephen J, Forouhi, Nita G, Kerrison, Nicola D, Lucarelli, Debora ME, Sims, Matt, Barroso, Inês, McCarthy, Mark I, Arriola, Larraitz, Balkau, Beverley, Barricarte, Aurelio, Gonzalez, Carlos, Grioni, Sara, Kaaks, Rudolf, Key, Timothy J, Navarro, Carmen, Nilsson, Peter M, Overvad, Kim, Palli, Domenico, Panico, Salvatore, Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Sánchez, María–José, Slimani, Nadia, Tjonneland, Anne, Tumino, Rosario, van der A, Daphne L, van der Schouw, Yvonne T, Riboli, Elio, Laakso, Markku, Borecki, Ingrid B, Chasman, Daniel I, Pedersen, Oluf, Psaty, Bruce M, Shyong Tai, E, van Duijn, Cornelia M, Wareham, Nicholas J, Waterworth, Dawn M, Boerwinkle, Eric, Linda Kao, W H, Florez, Jose C, Loos, Ruth J.F., Wilson, James G, Frayling, Timothy M, Siscovick, David S, Dupuis, Josée, Rotter, Jerome I, Meigs, James B, Scott, Robert A, Goodarzi, Mark O, Jennifer Wessel, Audrey Y. Chu, Sara M. Willems, Shuai Wang, Hanieh Yaghootkar, Jennifer A. Brody, Marco Dauriz, Marie France Hivert, Sridharan Raghavan, Leonard Lipovich, Bertha Hidalgo, Keolu Fox, Jennifer E. Huffman, Ping An, Yingchang Lu, Laura J. Rasmussen Torvik, Niels Grarup, Margaret G. Ehm, Li Li, Abigail S. Baldridge, Alena Stančáková, Ravinder Abrol, Céline Besse, Anne Boland, Jette Bork Jensen, Myriam Fornage, Daniel F. Freitag, Melissa E. Garcia, Xiuqing Guo, Kazuo Hara, Aaron Isaacs, Johanna Jakobsdottir, Leslie A. Lange, Jill C. Layton, Man Li, Jing Hua Zhao, Karina Meidtner, Alanna C. Morrison, Mike A. Nalls, Marjolein J. Peter, Maria Sabater Lleal, Claudia Schurmann, Angela Silveira, Albert V. Smith, Lorraine Southam, Marcus H. Stoiber, Rona J. Strawbridge, Kent D. Taylor, Tibor V. Varga, Kristine H. Allin, Najaf Amin, Jennifer L. Aponte, Tin, Aung, Barbieri, CATERINA MARIA, Nathan A. Bihlmeyer, Michael Boehnke, Cristina Bombieri, Donald W. Bowden, Sean M. Burns, Yuning Chen, Yii DerI Chen, Ching Yu Cheng, Adolfo Correa, Jacek Czajkowski, Abbas Dehghan, Georg B. Ehret, Gudny Eiriksdottir, Stefan A. Escher, Aliki Eleni Farmaki, Mattias Frånberg, Giovanni Gambaro, Franco Giulianini, William A. Goddard, Anuj Goel, Omri Gottesman, Megan L. Grove, Stefan Gustafsson, Yang Hai, Göran Hallmans, Jiyoung Heo, Per Hoffmann, Mohammad K. Ikram, Richard A. Jensen, Marit E. Jørgensen, Torben Jørgensen, Maria Karaleftheri, Chiea C. Khor, Andrea Kirkpatrick, Aldi T. Kraja, Johanna Kuusisto, Ethan M. Lange, I. T. Lee, Wen Jane Lee, Aaron Leong, Jiemin Liao, Chunyu Liu, Yongmei Liu, Cecilia M. Lindgren, Allan Linneberg, Giovanni Malerba, Vasiliki Mamakou, Eirini Marouli, Nisa M. Maruthur, Angela Matchan, Roberta McKean Cowdin, Olga McLeod, Ginger A. Metcalf, Karen L. Mohlke, Donna M. Muzny, Ioanna Ntalla, Nicholette D. Palmer, Dorota Pasko, Andreas Peter, Nigel W. Rayner, Frida Renström, Ken Rice, Cinzia F. Sala, Bengt Sennblad, Ioannis Serafetinidis, Jennifer A. Smith, Nicole Soranzo, Elizabeth K. Speliote, Eli A. Stahl, Kathleen Stirrup, Nikos Tentolouris, Anastasia Thanopoulou, Mina Torres, Michela Traglia, Emmanouil Tsafantakis, Sundas Javad, Lisa R. Yanek, Eleni Zengini, Diane M. Becker, Joshua C. Bi, James B. Brown, L. Adrienne Cupple, Torben Hansen, Erik Ingelsson, Andrew J. Karter, Carlos Lorenzo, Rasika A. Mathias, Jill M. Norri, Gina M. Peloso, Wayne H. H. Sheu, Daniela Toniolo, Dhananjay Vaidya, Rohit Varma, Lynne E. Wagenknecht, Heiner Boeing, Erwin P. Bottinger, George Dedoussis, Panos Delouka, Ele Ferrannini, Oscar H. Franco, Paul W. Franks, Richard A. Gibb, Vilmundur Gudnason, Anders Hamsten, Tamara B. Harris, Andrew T. Hattersley, Caroline Hayward, Albert Hofman, Jan Håkan Jansson, Claudia Langenberg, Lenore J. Launer, Daniel Levy, Ben A. Oostra, Christopher J. O’Donnell, Stephen O’Rahilly, Sandosh Padmanabhan, James S. Pankow, Ozren Polasek, Michael A. Province, Stephen S. Rich, Paul M. Ridker, Igor Rudan, Matthias B. Schulze, Blair H. Smith, André G. Uitterlinden, Mark Walker, Hugh Watkins, Tien Y. Wong, Eleftheria Zeggini, The EPIC InterAct Consortium, Markku Laakso, Ingrid B. Borecki, Daniel I. Chasman, Oluf Pedersen, Bruce M. Psaty, E. Shyong Tai, Cornelia M. van Duijn, Nicholas J. Wareham, Dawn M. Waterworth, Eric Boerwinkle, W. H. Linda Kao, Jose C. Florez, Ruth J. F. Loos, James G. Wilson, Timothy M. Frayling, David S. Siscovick, Josée Dupuis, Jerome I. Rotter, James B. Meigs, Robert A. Scott, Mark O., Goodarzi, Wessel, Jennifer, Chu, Audrey Y, Willems, Sara M, Wang, Shuai, Yaghootkar, Hanieh, Brody, Jennifer A, Dauriz, Marco, Hivert, Marie France, Raghavan, Sridharan, Lipovich, Leonard, Hidalgo, Bertha, Fox, Keolu, Huffman, Jennifer E, An, Ping, Lu, Yingchang, Rasmussen Torvik, Laura J, Grarup, Niel, Ehm, Margaret G, Li, Li, Baldridge, Abigail S, Stančáková, Alena, Abrol, Ravinder, Besse, Céline, Boland, Anne, Bork Jensen, Jette, Fornage, Myriam, Freitag, Daniel F, Garcia, Melissa E, Guo, Xiuqing, Hara, Kazuo, Isaacs, Aaron, Jakobsdottir, Johanna, Lange, Leslie A, Layton, Jill C, Li, Man, Hua Zhao, Jing, Meidtner, Karina, Morrison, Alanna C, Nalls, Mike A, Peters, Marjolein J, Sabater Lleal, Maria, Schurmann, Claudia, Silveira, Angela, Smith, Albert V, Southam, Lorraine, Stoiber, Marcus H, Strawbridge, Rona J, Taylor, Kent D, Varga, Tibor V, Allin, Kristine H, Amin, Najaf, Aponte, Jennifer L, Aung, Tin, Barbieri, Caterina, Bihlmeyer, Nathan A, Boehnke, Michael, Bombieri, Cristina, Bowden, Donald W, Burns, Sean M, Chen, Yuning, Chen, Yii DerI, Cheng, Ching Yu, Correa, Adolfo, Czajkowski, Jacek, Dehghan, Abba, Ehret, Georg B, Eiriksdottir, Gudny, Escher, Stefan A, Farmaki, Aliki Eleni, Frånberg, Mattia, Gambaro, Giovanni, Giulianini, Franco, Goddard, William A, Goel, Anuj, Gottesman, Omri, Grove, Megan L, Gustafsson, Stefan, Hai, Yang, Hallmans, Göran, Heo, Jiyoung, Hoffmann, Per, Ikram, Mohammad K, Jensen, Richard A, Jørgensen, Marit E, Jørgensen, Torben, Karaleftheri, Maria, Khor, Chiea C, Kirkpatrick, Andrea, Kraja, Aldi T, Kuusisto, Johanna, Lange, Ethan M, Lee, I. T, Lee, Wen Jane, Leong, Aaron, Liao, Jiemin, Liu, Chunyu, Liu, Yongmei, Lindgren, Cecilia M, Linneberg, Allan, Malerba, Giovanni, Mamakou, Vasiliki, Marouli, Eirini, Maruthur, Nisa M, Matchan, Angela, McKean Cowdin, Roberta, Mcleod, Olga, Metcalf, Ginger A, Mohlke, Karen L, Muzny, Donna M, Ntalla, Ioanna, Palmer, Nicholette D, Pasko, Dorota, Peter, Andrea, Rayner, Nigel W, Renström, Frida, Rice, Ken, Sala, Cinzia F, Sennblad, Bengt, Serafetinidis, Ioanni, Smith, Jennifer A, Soranzo, Nicole, Speliotes, Elizabeth K, Stahl, Eli A, Stirrups, Kathleen, Tentolouris, Niko, Thanopoulou, Anastasia, Torres, Mina, Traglia, Michela, Tsafantakis, Emmanouil, Javad, Sunda, Yanek, Lisa R, Zengini, Eleni, Becker, Diane M, Bis, Joshua C, Brown, James B, Cupples, L. Adrienne, Hansen, Torben, Ingelsson, Erik, Karter, Andrew J, Lorenzo, Carlo, Mathias, Rasika A, Norris, Jill M, Peloso, Gina M, Sheu, Wayne H. H, Toniolo, Daniela, Vaidya, Dhananjay, Varma, Rohit, Wagenknecht, Lynne E, Boeing, Heiner, Bottinger, Erwin P, Dedoussis, George, Deloukas, Pano, Ferrannini, Ele, Franco, Oscar H, Franks, Paul W, Gibbs, Richard A, Gudnason, Vilmundur, Hamsten, Ander, Harris, Tamara B, Hattersley, Andrew T, Hayward, Caroline, Hofman, Albert, Jansson, Jan Håkan, Langenberg, Claudia, Launer, Lenore J, Levy, Daniel, Oostra, Ben A, O'Donnell, Christopher J, O'Rahilly, Stephen, Padmanabhan, Sandosh, Pankow, James S, Polasek, Ozren, Province, Michael A, Rich, Stephen S, Ridker, Paul M, Rudan, Igor, Schulze, Matthias B, Smith, Blair H, Uitterlinden, André G, Walker, Mark, Watkins, Hugh, Wong, Tien Y, Zeggini, Eleftheria, Laakso, Markku, Borecki, Ingrid B, Chasman, Daniel I, Pedersen, Oluf, Psaty, Bruce M, Tai, E. Shyong, van Duijn, Cornelia M, Wareham, Nicholas J, Waterworth, Dawn M, Boerwinkle, Eric, Kao, W. H. Linda, Florez, Jose C, Loos, Ruth J. F, Wilson, James G, Frayling, Timothy M, Siscovick, David S, Dupuis, Josée, Rotter, Jerome I, Meigs, James B, Scott, Robert A, Goodarzi, Mark O., Panico, Salvatore, Soranzo, Nicole [0000-0003-1095-3852], Johnson, Kathleen [0000-0002-6823-3252], Langenberg, Claudia [0000-0002-5017-7344], O'Rahilly, Stephen [0000-0003-2199-4449], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Epidemiology, Surgery, Internal Medicine, Radiology & Nuclear Medicine, Clinical Genetics, Obstetrics & Gynecology, and Cell biology

Subjects
Blood Glucose, diabetes, exome chip, SEQUENCING DATA, European Continental Ancestry Group, Black People, Genetic Association Studie, Endocrinology and Diabetes, TRIGLYCERIDE LEVELS, Polymorphism, Single Nucleotide, Article, White People, Glucagon-Like Peptide-1 Receptor, Cohort Studies, SDG 3 - Good Health and Well-being, Mutation Rate, GLYCEMIC TRAITS, Humans, Settore MED/14 - NEFROLOGIA, Insulin, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genetic Association Studies, African Continental Ancestry Group, Oligonucleotide Array Sequence Analysis, PLASMA-GLUCOSE, INSULIN-RESISTANCE, epidemiology/genetics, Science & Technology, GLUCAGON-LIKE PEPTIDE-1, Diabetes, Genetic Variation, GERMLINE MUTATIONS, Fasting, epidemiology/genetics, Cohort Studies, Exome, diabetes, Multidisciplinary Sciences, RECEPTOR GENE, Diabetes Mellitus, Type 2, Genetic Loci, Endokrinologi och diabetes, CODING VARIATION, Glucose-6-Phosphatase, Science & Technology - Other Topics, exome chip, Human
Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility., Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.

Published
2015

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