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1. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

Author

Vogelezang, S, Bradfield, JP, Ahluwalia, TS, Curtin, JA, Lakka, TA, Grarup, N, Scholz, M, van der Most, PJ, Monnereau, C, Stergiakouli, E, Heiskala, A, Horikoshi, M, Fedko, IO, Vilor-Tejedor, N, Cousminer, DL, Standl, M, Wang, CA, Viikari, J, Geller, F, Íñiguez, C, Pitkänen, N, Chesi, A, Bacelis, J, Yengo, L, Torrent, M, Ntalla, I, Helgeland, Ø, Selzam, S, Vonk, JM, Zafarmand, MH, Heude, B, Farooqi, IS, Alyass, A, Beaumont, RN, Have, CT, Rzehak, P, Bilbao, JR, Schnurr, TM, Barroso, I, Bønnelykke, K, Beilin, LJ, Carstensen, L, Charles, M-A, Chawes, B, Clément, K, Closa-Monasterolo, R, Custovic, A, Eriksson, JG, Escribano, J, Groen-Blokhuis, M, Grote, V, Gruszfeld, D, Hakonarson, H, Hansen, T, Hattersley, AT, Hollensted, M, Hottenga, J-J, Hyppönen, E, Johansson, S, Joro, R, Kähönen, M, Karhunen, V, Kiess, W, Knight, BA, Koletzko, B, Kühnapfel, A, Landgraf, K, Langhendries, J-P, Lehtimäki, T, Leinonen, JT, Li, A, Lindi, V, Lowry, E, Bustamante, M, Medina-Gomez, C, Melbye, M, Michaelsen, KF, Morgen, CS, Mori, TA, Nielsen, TRH, Niinikoski, H, Oldehinkel, AJ, Pahkala, K, Panoutsopoulou, K, Pedersen, O, Pennell, CE, Power, C, Reijneveld, SA, Rivadeneira, F, Simpson, A, Sly, Peter, Stokholm, J, Teo, KK, Thiering, E, Timpson, NJ, Uitterlinden, AG, van Beijsterveldt, CEM, van Schaik, BDC, Vaudel, M, Verduci, E, Vinding, RK, Vogel, M, Zeggini, E, Sebert, S, Lind, MV, Brown, CD, Santa-Marina, L, Reischl, E, Frithioff-Bøjsøe, C, Meyre, D, Wheeler, E, Ong, K, Nohr, EA, Vrijkotte, TGM, Koppelman, GH, Plomin, R, Njølstad, PR, Dedoussis, GD, Froguel, P, Sørensen, TIA, Jacobsson, B, Freathy, RM, Zemel, BS, Raitakari, O, Vrijheid, M, Feenstra, B, Lyytikäinen, L-P, Snieder, H, Kirsten, H, Holt, PG, Heinrich, J, Widén, E, Sunyer, J, Boomsma, DI, Järvelin, M-R, Körner, A, Davey Smith, G, Holm, J-C, Atalay, M, Murray, C, Bisgaard, H, McCarthy, MI, Early Growth Genetics Consortium, Jaddoe, VWV, Grant, SFA, Felix, JF, Vogelezang, S, Bradfield, JP, Ahluwalia, TS, Curtin, JA, Lakka, TA, Grarup, N, Scholz, M, van der Most, PJ, Monnereau, C, Stergiakouli, E, Heiskala, A, Horikoshi, M, Fedko, IO, Vilor-Tejedor, N, Cousminer, DL, Standl, M, Wang, CA, Viikari, J, Geller, F, Íñiguez, C, Pitkänen, N, Chesi, A, Bacelis, J, Yengo, L, Torrent, M, Ntalla, I, Helgeland, Ø, Selzam, S, Vonk, JM, Zafarmand, MH, Heude, B, Farooqi, IS, Alyass, A, Beaumont, RN, Have, CT, Rzehak, P, Bilbao, JR, Schnurr, TM, Barroso, I, Bønnelykke, K, Beilin, LJ, Carstensen, L, Charles, M-A, Chawes, B, Clément, K, Closa-Monasterolo, R, Custovic, A, Eriksson, JG, Escribano, J, Groen-Blokhuis, M, Grote, V, Gruszfeld, D, Hakonarson, H, Hansen, T, Hattersley, AT, Hollensted, M, Hottenga, J-J, Hyppönen, E, Johansson, S, Joro, R, Kähönen, M, Karhunen, V, Kiess, W, Knight, BA, Koletzko, B, Kühnapfel, A, Landgraf, K, Langhendries, J-P, Lehtimäki, T, Leinonen, JT, Li, A, Lindi, V, Lowry, E, Bustamante, M, Medina-Gomez, C, Melbye, M, Michaelsen, KF, Morgen, CS, Mori, TA, Nielsen, TRH, Niinikoski, H, Oldehinkel, AJ, Pahkala, K, Panoutsopoulou, K, Pedersen, O, Pennell, CE, Power, C, Reijneveld, SA, Rivadeneira, F, Simpson, A, Sly, Peter, Stokholm, J, Teo, KK, Thiering, E, Timpson, NJ, Uitterlinden, AG, van Beijsterveldt, CEM, van Schaik, BDC, Vaudel, M, Verduci, E, Vinding, RK, Vogel, M, Zeggini, E, Sebert, S, Lind, MV, Brown, CD, Santa-Marina, L, Reischl, E, Frithioff-Bøjsøe, C, Meyre, D, Wheeler, E, Ong, K, Nohr, EA, Vrijkotte, TGM, Koppelman, GH, Plomin, R, Njølstad, PR, Dedoussis, GD, Froguel, P, Sørensen, TIA, Jacobsson, B, Freathy, RM, Zemel, BS, Raitakari, O, Vrijheid, M, Feenstra, B, Lyytikäinen, L-P, Snieder, H, Kirsten, H, Holt, PG, Heinrich, J, Widén, E, Sunyer, J, Boomsma, DI, Järvelin, M-R, Körner, A, Davey Smith, G, Holm, J-C, Atalay, M, Murray, C, Bisgaard, H, McCarthy, MI, Early Growth Genetics Consortium, Jaddoe, VWV, Grant, SFA, and Felix, JF

Abstract

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

Published
2020

2. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

Author

Vogelezang, S. (Suzanne), Bradfield, J. P. (Jonathan P.), Ahluwalia, T. S. (Tarunveer S.), Curtin, J. A. (John A.), Lakka, T. A. (Timo A.), Grarup, N. (Niels), Scholz, M. (Markus), van der Most, P. J. (Peter J.), Monnereau, C. (Claire), Stergiakouli, E. (Evie), Heiskala, A. (Anni), Horikoshi, M. (Momoko), Fedko, I. O. (Iryna O.), Vilor-Tejedor, N. (Natalia), Cousminer, D. L. (Diana L.), Standl, M. (Marie), Wang, C. A. (Carol A.), Viikari, J. (Jorma), Geller, F. (Frank), iniguez, C. (Carmen), Pitkanen, N. (Niina), Chesi, A. (Alessandra), Bacelis, J. (Jonas), Yengo, L. (Loic), Torrent, M. (Maties), Ntalla, I. (Ioanna), Helgeland, O. (Oyvind), Selzam, S. (Saskia), Vonk, J. M. (Judith M.), Zafarmand, M. H. (Mohammed H.), Heude, B. (Barbara), Farooqi, I. S. (Ismaa Sadaf), Alyass, A. (Akram), Beaumont, R. N. (Robin N.), Have, C. T. (Christian T.), Rzehak, P. (Peter), Bilbao, J. R. (Jose Ramon), Schnurr, T. M. (Theresia M.), Barroso, I. (Ines), Bonnelykke, K. (Klaus), Beilin, L. J. (Lawrence J.), Carstensen, L. (Lisbeth), Charles, M.-A. (Marie-Aline), Chawes, B. (Bo), Clement, K. (Karine), Closa-Monasterolo, R. (Ricardo), Custovic, A. (Adnan), Eriksson, J. G. (Johan G.), Escribano, J. (Joaquin), Groen-Blokhuis, M. (Maria), Grote, V. (Veit), Gruszfeld, D. (Dariusz), Hakonarson, H. (Hakon), Hansen, T. (Torben), Hattersley, A. T. (Andrew T.), Hollensted, M. (Mette), Hottenga, J.-J. (Jouke-Jan), Hypponen, E. (Elina), Johansson, S. (Stefan), Joro, R. (Raimo), Kahonen, M. (Mika), Karhunen, V. (Ville), Kiess, W. (Wieland), Knight, B. A. (Bridget A.), Koletzko, B. (Berthold), Kuehnapfel, A. (Andreas), Landgraf, K. (Kathrin), Langhendries, J.-P. (Jean-Paul), Lehtimaki, T. (Terho), Leinonen, J. T. (Jaakko T.), Li, A. (Aihuali), Lindi, V. (Virpi), Lowry, E. (Estelle), Bustamante, M. (Mariona), Medina-Gomez, C. (Carolina), Melbye, M. (Mads), Michaelsen, K. F. (Kim F.), Morgen, C. S. (Camilla S.), Mori, T. A. (Trevor A.), Nielsen, T. R. (Tenna R. H.), Niinikoski, H. (Harri), Oldehinkel, A. J. (Albertine J.), Pahkala, K. (Katja), Panoutsopoulou, K. (Kalliope), Pedersen, O. (Oluf), Pennell, C. E. (Craig E.), Power, C. (Christine), Reijneveld, S. A. (Sijmen A.), Rivadeneira, F. (Fernando), Simpson, A. (Angela), Sly, P. D. (Peter D.), Stokholm, J. (Jakob), Teo, K. K. (Kook K.), Thiering, E. (Elisabeth), Timpson, N. J. (Nicholas J.), Uitterlinden, A. G. (Andre G.), van Beijsterveldt, C. E. (Catharina E. M.), van Schaik, B. D. (Barbera D. C.), Vaudel, M. (Marc), Verduci, E. (Elvira), Vinding, R. K. (Rebecca K.), Vogel, M. (Mandy), Zeggini, E. (Eleftheria), Sebert, S. (Sylvain), Lind, M. V. (Mads V.), Brown, C. D. (Christopher D.), Santa-Marina, L. (Loreto), Reischl, E. (Eva), Frithioff-Bojsoe, C. (Christine), Meyre, D. (David), Wheeler, E. (Eleanor), Ong, K. (Ken), Nohr, E. A. (Ellen A.), Vrijkotte, T. G. (Tanja G. M.), Koppelman, G. H. (Gerard H.), Plomin, R. (Robert), Njolstad, P. R. (Pal R.), Dedoussis, G. D. (George D.), Froguel, P. (Philippe), Sorensen, T. I. (Thorkild I. A.), Jacobsson, B. (Bo), Freathy, R. M. (Rachel M.), Zemel, B. S. (Babette S.), Raitakari, O. (Olli), Vrijheid, M. (Martine), Feenstra, B. (Bjarke), Lyytikainen, L.-P. (Leo-Pekka), Snieder, H. (Harold), Kirsten, H. (Holger), Holt, P. G. (Patrick G.), Heinrich, J. (Joachim), Widen, E. (Elisabeth), Sunyer, J. (Jordi), Boomsma, D. I. (Dorret I.), Jarvelin, M.-R. (Marjo-Riitta), Koerner, A. (Antje), Davey Smith, G. (George), Holm, J.-C. (Jens-Christian), Atalay, M. (Mustafa), Murray, C. (Clare), Bisgaard, H. (Hans), McCarthy, M. I. (Mark I.), Jaddoe, V. W. (Vincent W. V.), Grant, S. F. (Struan F. A.), Felix, J. F. (Janine F.), Vogelezang, S. (Suzanne), Bradfield, J. P. (Jonathan P.), Ahluwalia, T. S. (Tarunveer S.), Curtin, J. A. (John A.), Lakka, T. A. (Timo A.), Grarup, N. (Niels), Scholz, M. (Markus), van der Most, P. J. (Peter J.), Monnereau, C. (Claire), Stergiakouli, E. (Evie), Heiskala, A. (Anni), Horikoshi, M. (Momoko), Fedko, I. O. (Iryna O.), Vilor-Tejedor, N. (Natalia), Cousminer, D. L. (Diana L.), Standl, M. (Marie), Wang, C. A. (Carol A.), Viikari, J. (Jorma), Geller, F. (Frank), iniguez, C. (Carmen), Pitkanen, N. (Niina), Chesi, A. (Alessandra), Bacelis, J. (Jonas), Yengo, L. (Loic), Torrent, M. (Maties), Ntalla, I. (Ioanna), Helgeland, O. (Oyvind), Selzam, S. (Saskia), Vonk, J. M. (Judith M.), Zafarmand, M. H. (Mohammed H.), Heude, B. (Barbara), Farooqi, I. S. (Ismaa Sadaf), Alyass, A. (Akram), Beaumont, R. N. (Robin N.), Have, C. T. (Christian T.), Rzehak, P. (Peter), Bilbao, J. R. (Jose Ramon), Schnurr, T. M. (Theresia M.), Barroso, I. (Ines), Bonnelykke, K. (Klaus), Beilin, L. J. (Lawrence J.), Carstensen, L. (Lisbeth), Charles, M.-A. (Marie-Aline), Chawes, B. (Bo), Clement, K. (Karine), Closa-Monasterolo, R. (Ricardo), Custovic, A. (Adnan), Eriksson, J. G. (Johan G.), Escribano, J. (Joaquin), Groen-Blokhuis, M. (Maria), Grote, V. (Veit), Gruszfeld, D. (Dariusz), Hakonarson, H. (Hakon), Hansen, T. (Torben), Hattersley, A. T. (Andrew T.), Hollensted, M. (Mette), Hottenga, J.-J. (Jouke-Jan), Hypponen, E. (Elina), Johansson, S. (Stefan), Joro, R. (Raimo), Kahonen, M. (Mika), Karhunen, V. (Ville), Kiess, W. (Wieland), Knight, B. A. (Bridget A.), Koletzko, B. (Berthold), Kuehnapfel, A. (Andreas), Landgraf, K. (Kathrin), Langhendries, J.-P. (Jean-Paul), Lehtimaki, T. (Terho), Leinonen, J. T. (Jaakko T.), Li, A. (Aihuali), Lindi, V. (Virpi), Lowry, E. (Estelle), Bustamante, M. (Mariona), Medina-Gomez, C. (Carolina), Melbye, M. (Mads), Michaelsen, K. F. (Kim F.), Morgen, C. S. (Camilla S.), Mori, T. A. (Trevor A.), Nielsen, T. R. (Tenna R. H.), Niinikoski, H. (Harri), Oldehinkel, A. J. (Albertine J.), Pahkala, K. (Katja), Panoutsopoulou, K. (Kalliope), Pedersen, O. (Oluf), Pennell, C. E. (Craig E.), Power, C. (Christine), Reijneveld, S. A. (Sijmen A.), Rivadeneira, F. (Fernando), Simpson, A. (Angela), Sly, P. D. (Peter D.), Stokholm, J. (Jakob), Teo, K. K. (Kook K.), Thiering, E. (Elisabeth), Timpson, N. J. (Nicholas J.), Uitterlinden, A. G. (Andre G.), van Beijsterveldt, C. E. (Catharina E. M.), van Schaik, B. D. (Barbera D. C.), Vaudel, M. (Marc), Verduci, E. (Elvira), Vinding, R. K. (Rebecca K.), Vogel, M. (Mandy), Zeggini, E. (Eleftheria), Sebert, S. (Sylvain), Lind, M. V. (Mads V.), Brown, C. D. (Christopher D.), Santa-Marina, L. (Loreto), Reischl, E. (Eva), Frithioff-Bojsoe, C. (Christine), Meyre, D. (David), Wheeler, E. (Eleanor), Ong, K. (Ken), Nohr, E. A. (Ellen A.), Vrijkotte, T. G. (Tanja G. M.), Koppelman, G. H. (Gerard H.), Plomin, R. (Robert), Njolstad, P. R. (Pal R.), Dedoussis, G. D. (George D.), Froguel, P. (Philippe), Sorensen, T. I. (Thorkild I. A.), Jacobsson, B. (Bo), Freathy, R. M. (Rachel M.), Zemel, B. S. (Babette S.), Raitakari, O. (Olli), Vrijheid, M. (Martine), Feenstra, B. (Bjarke), Lyytikainen, L.-P. (Leo-Pekka), Snieder, H. (Harold), Kirsten, H. (Holger), Holt, P. G. (Patrick G.), Heinrich, J. (Joachim), Widen, E. (Elisabeth), Sunyer, J. (Jordi), Boomsma, D. I. (Dorret I.), Jarvelin, M.-R. (Marjo-Riitta), Koerner, A. (Antje), Davey Smith, G. (George), Holm, J.-C. (Jens-Christian), Atalay, M. (Mustafa), Murray, C. (Clare), Bisgaard, H. (Hans), McCarthy, M. I. (Mark I.), Jaddoe, V. W. (Vincent W. V.), Grant, S. F. (Struan F. A.), and Felix, J. F. (Janine F.)

Abstract

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

Published
2020

3. Consortium-based genome-wide meta-analysis for childhood dental caries traits

Author

Haworth, S, Shungin, D, van der Tas, JT, Vucic, S, Medina-Gomez, C, Yakimov, V, Feenstra, B, Shaffer, JR, Lee, MK, Standl, M, Thiering, E, Wang, C, Bønnelykke, K, Waage, J, Jessen, LE, Nørrisgaard, PE, Joro, R, Seppälä, I, Raitakari, O, Dudding, T, Grgic, O, Ongkosuwito, E, Vierola, A, Eloranta, A-M, West, NX, Thomas, SJ, McNeil, DW, Levy, SM, Slayton, R, Nohr, EA, Lehtimäki, T, Lakka, T, Bisgaard, H, Pennell, C, Kühnisch, J, Marazita, ML, Melbye, M, Geller, F, Rivadeneira, F, Wolvius, EB, Franks, PW, Johansson, I, Timpson, NJ, Oral and Maxillofacial Surgery, Epidemiology, Erasmus MC other, and Internal Medicine

Subjects
Male, Adolescent, Quantitative Trait Loci, Public Health, Global Health, Social Medicine and Epidemiology, Dental Caries, Phosphoproteins, Polymorphism, Single Nucleotide, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], Dentition, Permanent, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Phenotype, Case-Control Studies, Child, Preschool, Humans, Female, Child, Association Studies Article, Biomarkers, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract

Contains fulltext : 200710.pdf (Publisher’s version ) (Open Access) Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

Published
2018

4. Consortium-based genome-wide meta-analysis for childhood dental caries traits.

Author

Haworth, S., Shungin, D., Tas, J.T. van der, Vucic, S., Medina-Gomez, C., Yakimov, V., Feenstra, B., Shaffer, J.R., Lee, M.K., Standl, M., Thiering, E., Wang, C, Bonnelykke, K., Waage, J., Jessen, L.E., Norrisgaard, P.E., Joro, R., Seppala, I., Raitakari, O., Dudding, T., Grgic, O., Ongkosuwito, E.M., Vierola, A., Eloranta, A.M., West, N.X., Thomas, S.J., McNeil, D.W., Levy, S.M., Slayton, R., Nohr, E.A., Lehtimaki, T., Lakka, T., Bisgaard, H., Pennell, C., Kuhnisch, J., Marazita, M.L., Melbye, M., Geller, F., Rivadeneira, F., Wolvius, E.B., Franks, P.W., Johansson, I., Timpson, N.J., Haworth, S., Shungin, D., Tas, J.T. van der, Vucic, S., Medina-Gomez, C., Yakimov, V., Feenstra, B., Shaffer, J.R., Lee, M.K., Standl, M., Thiering, E., Wang, C, Bonnelykke, K., Waage, J., Jessen, L.E., Norrisgaard, P.E., Joro, R., Seppala, I., Raitakari, O., Dudding, T., Grgic, O., Ongkosuwito, E.M., Vierola, A., Eloranta, A.M., West, N.X., Thomas, S.J., McNeil, D.W., Levy, S.M., Slayton, R., Nohr, E.A., Lehtimaki, T., Lakka, T., Bisgaard, H., Pennell, C., Kuhnisch, J., Marazita, M.L., Melbye, M., Geller, F., Rivadeneira, F., Wolvius, E.B., Franks, P.W., Johansson, I., and Timpson, N.J.

Abstract

Contains fulltext : 200710.pdf (Publisher’s version ) (Open Access), Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

Published
2018

5. Consortium-based genome-wide meta-analysis for childhood dental caries traits

Author

Haworth, S. (Simon), Shungin, D. (Dmitry), Tas, J.T. (Justin) van der, Vučić, S. (Strahinja), Medina-Gomez, M.C. (Carolina), Yakimov, V. (Victor), Feenstra, B. (Bjarke), Shaffer, J.R. (John R), Lee, M.K. (Myoung Keun), Standl, M. (Marie), Thiering, E. (Elisabeth), Wang, C. (Carol), Bønnelykke, K. (Klaus), Waage, J. (Johannes), Jessen, L.E. (Leon E.), Nørrisgaard, P.E. (Pia Elisabeth), Joro, R. (Raimo), Seppälä, I. (Ilkka), Raitakari, O. (Olli), Dudding, T. (Tom), Grgic, O. (Olja), Ongkosuwito, E.M. (Edwin), Vierola, A. (Anu), Eloranta, A.M. (Aino-Maija), West, N.X. (Nicola X.), Thomas, S.J. (Steven J.), McNeil, D.W. (Daniel W.), Levy, S.M. (Steven), Slayton, R. (Rebecca), Nohr, C. (Christian), Lehtimäki, T. (Terho), Lakka, T.A. (Timo), Bisgaard, H. (Hans), Pennell, C.E. (Craig), Kühnisch, J. (Jan), Marazita, M.L. (Mary), Melbye, M. (Mads), Geller, F. (Frank), Rivadeneira Ramirez, F. (Fernando), Wolvius, E.B. (Eppo), Franks, P.W. (Paul), Johansson, I. (Inger), Timpson, N.J. (Nicholas), Haworth, S. (Simon), Shungin, D. (Dmitry), Tas, J.T. (Justin) van der, Vučić, S. (Strahinja), Medina-Gomez, M.C. (Carolina), Yakimov, V. (Victor), Feenstra, B. (Bjarke), Shaffer, J.R. (John R), Lee, M.K. (Myoung Keun), Standl, M. (Marie), Thiering, E. (Elisabeth), Wang, C. (Carol), Bønnelykke, K. (Klaus), Waage, J. (Johannes), Jessen, L.E. (Leon E.), Nørrisgaard, P.E. (Pia Elisabeth), Joro, R. (Raimo), Seppälä, I. (Ilkka), Raitakari, O. (Olli), Dudding, T. (Tom), Grgic, O. (Olja), Ongkosuwito, E.M. (Edwin), Vierola, A. (Anu), Eloranta, A.M. (Aino-Maija), West, N.X. (Nicola X.), Thomas, S.J. (Steven J.), McNeil, D.W. (Daniel W.), Levy, S.M. (Steven), Slayton, R. (Rebecca), Nohr, C. (Christian), Lehtimäki, T. (Terho), Lakka, T.A. (Timo), Bisgaard, H. (Hans), Pennell, C.E. (Craig), Kühnisch, J. (Jan), Marazita, M.L. (Mary), Melbye, M. (Mads), Geller, F. (Frank), Rivadeneira Ramirez, F. (Fernando), Wolvius, E.B. (Eppo), Franks, P.W. (Paul), Johansson, I. (Inger), and Timpson, N.J. (Nicholas)

Abstract

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were c

Published
2018
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6. A novel common variant in DCST2 is associated with length in early life and height in adulthood

Author

van der Valk, R, Kreiner-Møller, E, Kooijman, M, Guxens, M, Stergiakouli, E, Sääf, A, Bradfield, J, Geller, F, Hayes, MG, Cousminer, D, Körner, A, Thiering, E, Curtin, J, Myhre, R, Huikari, V, Joro, R, Kerkhof, M, Warrington, N, Pitkänen, N, Ntalla, I, Horikoshi, M, Veijola, R, Freathy, R, Teo, Y, and Barton, S

Abstract

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Published
2016

7. A novel common variant in DCST2 is associated with length in early life and height in adulthood

Author

van der Valk, R., Kreiner-Møller, E., Kooijman, M., Guxens, M., Stergiakouli, E., Sääf, A., Bradfield, J., Geller, F., Hayes, M., Cousminer, D., Körner, A., Thiering, E., Curtin, J., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N., Pitkänen, N., Ntalla, I., Horikoshi, M., Veijola, R., Freathy, R., Teo, Y., Barton, S., Evans, D., Kemp, J., St Pourcain, B., Ring, S., Davey Smith, G., Bergström, A., Kull, I., Hakonarson, H., Mentch, F., Bisgaard, H., Chawes, B., Stokholm, J., Waage, J., Eriksen, P., Sevelsted, A., Melbye, M., van Duijn, C., Medina-Gomez, C., Hofman, A., de Jongste, J., Taal, H., Uitterlinden, A., Armstrong, L., Eriksson, J., Palotie, A., Bustamante, M., Estivill, X., Gonzalez, J., Llop, S., Kiess, W., Mahajan, A., Flexeder, C., Tiesler, C., Murray, C., Simpson, A., Magnus, P., Sengpiel, V., Hartikainen, A., Keinanen-Kiukaanniemi, S., Lewin, A., Da Silva Couto Alves, A., Blakemore, A., Buxton, J., Kaakinen, M., Rodriguez, A., Sebert, S., Vaarasmaki, M., Lakka, T., Lindi, V., Gehring, U., Postma, D., Ang, W., Newnham, J., Lyytikäinen, L., Pahkala, K., Raitakari, O., Panoutsopoulou, K., Zeggini, E., Boomsma, D., Groen-Blokhuis, M., Ilonen, J., Franke, L., Hirschhorn, J., Pers, T., Liang, L., Huang, J., Hocher, B., Knip, M., Saw, S., Holloway, J., Melén, E., Grant, S., Feenstra, B., Lowe, W., Widén, E., Sergeyev, E., Grallert, H., Custovic, A., Jacobsson, B., Jarvelin, M., Atalay, M., Koppelman, G., Pennell, C., Niinikoski, H., Dedoussis, G., Mccarthy, M., Frayling, T., Sunyer, J., Timpson, N., Rivadeneira, F., Bønnelykke, K., Jaddoe, V., and Early Growth Genetics (EGG) Consortium

Abstract

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Published
2015

8. A novel common variant in DCST2 is associated with length in early life and height in adulthood

Author

van der Valk RJ, Kreiner-Møller E, Kooijman MN, Guxens M, Stergiakouli E, Sääf A, Bradfield JP, Geller F, Hayes MG, Cousminer DL, Körner A, Thiering E, Curtin JA, Myhre R, Huikari V, Joro R, Kerkhof M, Warrington NM, Pitkänen N, Ntalla I, Horikoshi M, Veijola R, Freathy RM, Teo YY, Barton SJ, Evans DM, Kemp JP, St Pourcain B, Ring SM, Davey Smith G, Bergström A, Kull I, Hakonarson H, Mentch FD, Bisgaard H, Chawes B, Stokholm J, Waage J, Eriksen P, Sevelsted A, Melbye M, Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, van Duijn CM, Medina-Gomez C, Hofman A, de Jongste JC, Taal HR, Uitterlinden AG, Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Armstrong LL, Eriksson J, Palotie A, Bustamante M, Estivill X, Gonzalez JR, Llop S, Kiess W, Mahajan A, Flexeder C, Tiesler CM, Murray CS, Simpson A, Magnus P, Sengpiel V, Hartikainen AL, Keinanen-Kiukaanniemi S, Lewin A, Da Silva Couto Alves A, Blakemore AI, Buxton JL, Kaakinen M, Rodriguez A, Sebert S, Vaarasmaki M, Lakka T, Lindi V, Gehring U, Postma DS, Ang W, Newnham JP, Lyytikäinen LP, Pahkala K, Raitakari OT, Panoutsopoulou K, Zeggini E, Boomsma DI, Groen-Blokhuis M, Ilonen J, Franke L, Hirschhorn JN, Pers TH, Liang L, Huang J, Hocher B, Knip M, Saw SM, Holloway JW, Melén E, Grant SF, Feenstra B, Lowe WL, Widén E, Sergeyev E, Grallert H, Custovic A, Jacobsson B, Jarvelin MR, Atalay M, Koppelman GH, Pennell CE, Niinikoski H, Dedoussis GV, Mccarthy MI, Frayling TM, Sunyer J, Timpson NJ, Rivadeneira F, Bønnelykke K, Jaddoe VW, and Early Growth Genetics (EGG) Consortium

Subjects
Genetic variants, DCST2, Single nucleotide polymorphisms (SNPs), Skeletal growth, Adult height, Early growth
Abstract

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height. R.M.F. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant 085541/Z/08/Z). T.H.P. is supported by The Danish Council for Independent Research Medical Sciences (FSS) The Alfred Benzon Foundation. B.F. is supported by an Oak Foundation fellowship. M.M. is a Wellcome Trust Senior Investigator (Wellcome Trust grant 090532) and a NIHR Senior Investigator. T.M.F. is supported by the European Research Council grant: SZ-245 50371- GLUCOSEGENES-FP7-IDEAS-ERC. F.R. (VIDI 016.136.367) and V.W.V.J. (VIDI 016.136.361) received grants from the Netherlands Organization for Health Research and Development.

Published
2015

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

Author

Horikoshi, M. (Momoko), Beaumont, R.N. (Robin N.), Day, F.R. (Felix), Warrington, N.M. (Nicole), Kooijman, M.N. (Marjolein), Fernandez-Tajes, J. (Juan), Feenstra, B. (Bjarke), Van Zuydam, N.R. (Natalie R.), Gaulton, K. (Kyle), Grarup, N. (Niels), Bradfield, J.P. (Jonathan), Strachan, D.P. (David), Li-Gao, R. (Ruifang), Ahluwalia, T.S. (Tarunveer Singh), Kreiner, E. (Eskil), Rueedi, R. (Rico), Lyytikäinen, L.-P. (Leo-Pekka), Cousminer, D.L. (Diana), Wu, Y. (Ying), Thiering, E. (Elisabeth), Wang, C.A. (Carol A.), Have, C.T. (Christian T.), Hottenga, J.J. (Jouke Jan), Vilor-Tejedor, N. (Natàlia), Joshi, P.K. (Peter), Boh, E.T.H. (Eileen Tai Hui), Ntalla, I. (Ioanna), Pitkanen, N. (Niina), Mahajan, A. (Anubha), Leeuwen, E.M. (Elisa) van, Joro, R. (Raimo), Lagou, V. (Vasiliki), Nodzenski, M. (Michael), Diver, L.A. (Louise A.), Zondervan, K.T. (Krina), Bustamante, M. (Mariona), Marques-Vidal, P. (Pedro), Mercader, J.M. (Josep), Bennett, A.J. (Amanda), Rahmioglu, N. (Nilufer), Nyholt, D.R. (Dale), Ma, R.C.W. (Ronald C. W.), Tam, C.H.T. (Claudia H. T.), Tam, W.H. (Wing Hung), Ganesh, S.K. (Santhi), Rooij, F.J.A. (Frank) van, Jones, S.E. (Samuel E.), Loh, P.-R. (Po-Ru), Ruth, K.S. (Katherine S.), Tuke, M.A. (Marcus A.), Tyrrell, A.W.R., Wood, A.R. (Andrew), Yaghootkar, H. (Hanieh), Scholtens, D.M. (Denise M.), Paternoster, L. (Lavinia), Prokopenko, I. (Inga), Kovacs, P. (Peter), Atalay, M. (Mustafa), Willems, S.M. (Sara), Panoutsopoulou, K. (Kalliope), Wang, X. (Xu), Carstensen, L. (Lisbeth), Geller, F. (Frank), Schraut, K.E. (Katharina E.), Murcia, M. (Mario), Beijsterveldt, C.E.M. (Toos) van, Willemsen, G.A.H.M. (Gonneke), Appel, E.V.R. (Emil V. R.), Fonvig, C.E. (Cilius E.), Trier, C. (Caecilie), Tiesler, C.M.T. (Carla M. T.), Standl, E. (Eberhard), Kutalik, Z. (Zoltán), Bonàs-Guarch, S. (Silvia), Hougaard, D.M. (David), Sánchez, F. (Friman), Torrents, D. (David), Waage, J. (Johannes), Hollegaard, M.V. (Mads V), Haan, H.G. (Hugoline) de, Rosendaal, F.R. (Frits), Medina-Gomez, C. (Carolina), Ring, S.M. (Susan), Hemani, G., Mcmahon, G. (George), Robertson, N.R. (Neil), Groves, C.J. (Christopher), Langenberg, C. (Claudia), Luan, J. (Jian'An), Scott, R.A. (Robert), Zhao, J.H. (Jing Hua), Mentch, F.D. (Frank), MacKenzie, S.M. (Scott M.), Reynolds, R.M. (Rebecca), Lowe Jr., W.L. (William), Tönjes, A. (Anke), Stumvoll, M. (Michael), Lindi, V. (Virpi), Lakka, T.A. (Timo), Duijn, C.M. (Cornelia) van, Kieß, W. (Wieland), KöRner, A. (Antje), Sørensen, T.I.A. (Thorkild), Niinikoski, H. (Harri), Pahkala, K. (Katja), Raitakari, O.T. (Olli T.), Zeggini, E. (Eleftheria), Dedoussis, G.V. (George), Teo, Y.Y. (Yik Ying), Saw, S.-M. (Seang-Mei), Melbye, M. (Mads), Campbell, H. (Harry), Wilson, J.F. (James F.), Vrijheid, M. (Martine), Geus, E.J.C. (Eco) de, Boomsma, D.I. (Dorret), Kadarmideen, H.N. (Haja N.), Holm, J.-C. (Jens-Christian), Hansen, T. (T.), Sebert, S. (Sylvain), Hattersley, A.T. (Andrew), Beilin, L.J. (Lawrence), Newnham, J.P. (John), Pennell, C.E. (Craig), Heinrich, J. (Joachim), Adair, L.S. (Linda), Borja, J.B. (Judith), Mohlke, K.L. (Karen), Hagen, K. (Knut), Widen, E. (Elisabeth), Kähönen, M. (Mika), Viikari, J. (Jorma), Lehtimäki, T. (Terho), Vollenweider, P. (Peter), Bønnelykke, K. (Klaus), Bisgaard, H. (Hans), Mook-Kanamori, D.O. (Dennis), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Pisinger, C. (Charlotta), Pedersen, O. (Oluf), Power, C. (Christopher), Hypponen, E. (Elina), Wareham, N.J. (Nick), Hakonarson, H. (Hakon), Davies, E. (Eleanor), Walker, B.R. (Brian R.), Jaddoe, V.W.V. (Vincent), Jarvelin, M.-R. (Marjo-Riitta), Grant, S.F.A. (Struan), Vaag, A.A. (Allan A.), Lawlor, D.A. (Debbie), Frayling, T.M. (Timothy), Smith, A.V. (Davey), Morris, A.P. (Andrew), Ong, K.K. (Ken), Felix, J.F. (Janine), Timpson, N.J. (Nicholas), Perry, J.R.B. (John), Evans, D.M. (David), McCarthy, M.I. (Mark), Freathy, R.M. (Rachel), Horikoshi, M. (Momoko), Beaumont, R.N. (Robin N.), Day, F.R. (Felix), Warrington, N.M. (Nicole), Kooijman, M.N. (Marjolein), Fernandez-Tajes, J. (Juan), Feenstra, B. (Bjarke), Van Zuydam, N.R. (Natalie R.), Gaulton, K. (Kyle), Grarup, N. (Niels), Bradfield, J.P. (Jonathan), Strachan, D.P. (David), Li-Gao, R. (Ruifang), Ahluwalia, T.S. (Tarunveer Singh), Kreiner, E. (Eskil), Rueedi, R. (Rico), Lyytikäinen, L.-P. (Leo-Pekka), Cousminer, D.L. (Diana), Wu, Y. (Ying), Thiering, E. (Elisabeth), Wang, C.A. (Carol A.), Have, C.T. (Christian T.), Hottenga, J.J. (Jouke Jan), Vilor-Tejedor, N. (Natàlia), Joshi, P.K. (Peter), Boh, E.T.H. (Eileen Tai Hui), Ntalla, I. (Ioanna), Pitkanen, N. (Niina), Mahajan, A. (Anubha), Leeuwen, E.M. (Elisa) van, Joro, R. (Raimo), Lagou, V. (Vasiliki), Nodzenski, M. (Michael), Diver, L.A. (Louise A.), Zondervan, K.T. (Krina), Bustamante, M. (Mariona), Marques-Vidal, P. (Pedro), Mercader, J.M. (Josep), Bennett, A.J. (Amanda), Rahmioglu, N. (Nilufer), Nyholt, D.R. (Dale), Ma, R.C.W. (Ronald C. W.), Tam, C.H.T. (Claudia H. T.), Tam, W.H. (Wing Hung), Ganesh, S.K. (Santhi), Rooij, F.J.A. (Frank) van, Jones, S.E. (Samuel E.), Loh, P.-R. (Po-Ru), Ruth, K.S. (Katherine S.), Tuke, M.A. (Marcus A.), Tyrrell, A.W.R., Wood, A.R. (Andrew), Yaghootkar, H. (Hanieh), Scholtens, D.M. (Denise M.), Paternoster, L. (Lavinia), Prokopenko, I. (Inga), Kovacs, P. (Peter), Atalay, M. (Mustafa), Willems, S.M. (Sara), Panoutsopoulou, K. (Kalliope), Wang, X. (Xu), Carstensen, L. (Lisbeth), Geller, F. (Frank), Schraut, K.E. (Katharina E.), Murcia, M. (Mario), Beijsterveldt, C.E.M. (Toos) van, Willemsen, G.A.H.M. (Gonneke), Appel, E.V.R. (Emil V. R.), Fonvig, C.E. (Cilius E.), Trier, C. (Caecilie), Tiesler, C.M.T. (Carla M. T.), Standl, E. (Eberhard), Kutalik, Z. (Zoltán), Bonàs-Guarch, S. (Silvia), Hougaard, D.M. (David), Sánchez, F. (Friman), Torrents, D. (David), Waage, J. (Johannes), Hollegaard, M.V. (Mads V), Haan, H.G. (Hugoline) de, Rosendaal, F.R. (Frits), Medina-Gomez, C. (Carolina), Ring, S.M. (Susan), Hemani, G., Mcmahon, G. (George), Robertson, N.R. (Neil), Groves, C.J. (Christopher), Langenberg, C. (Claudia), Luan, J. (Jian'An), Scott, R.A. (Robert), Zhao, J.H. (Jing Hua), Mentch, F.D. (Frank), MacKenzie, S.M. (Scott M.), Reynolds, R.M. (Rebecca), Lowe Jr., W.L. (William), Tönjes, A. (Anke), Stumvoll, M. (Michael), Lindi, V. (Virpi), Lakka, T.A. (Timo), Duijn, C.M. (Cornelia) van, Kieß, W. (Wieland), KöRner, A. (Antje), Sørensen, T.I.A. (Thorkild), Niinikoski, H. (Harri), Pahkala, K. (Katja), Raitakari, O.T. (Olli T.), Zeggini, E. (Eleftheria), Dedoussis, G.V. (George), Teo, Y.Y. (Yik Ying), Saw, S.-M. (Seang-Mei), Melbye, M. (Mads), Campbell, H. (Harry), Wilson, J.F. (James F.), Vrijheid, M. (Martine), Geus, E.J.C. (Eco) de, Boomsma, D.I. (Dorret), Kadarmideen, H.N. (Haja N.), Holm, J.-C. (Jens-Christian), Hansen, T. (T.), Sebert, S. (Sylvain), Hattersley, A.T. (Andrew), Beilin, L.J. (Lawrence), Newnham, J.P. (John), Pennell, C.E. (Craig), Heinrich, J. (Joachim), Adair, L.S. (Linda), Borja, J.B. (Judith), Mohlke, K.L. (Karen), Hagen, K. (Knut), Widen, E. (Elisabeth), Kähönen, M. (Mika), Viikari, J. (Jorma), Lehtimäki, T. (Terho), Vollenweider, P. (Peter), Bønnelykke, K. (Klaus), Bisgaard, H. (Hans), Mook-Kanamori, D.O. (Dennis), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Pisinger, C. (Charlotta), Pedersen, O. (Oluf), Power, C. (Christopher), Hypponen, E. (Elina), Wareham, N.J. (Nick), Hakonarson, H. (Hakon), Davies, E. (Eleanor), Walker, B.R. (Brian R.), Jaddoe, V.W.V. (Vincent), Jarvelin, M.-R. (Marjo-Riitta), Grant, S.F.A. (Struan), Vaag, A.A. (Allan A.), Lawlor, D.A. (Debbie), Frayling, T.M. (Timothy), Smith, A.V. (Davey), Morris, A.P. (Andrew), Ong, K.K. (Ken), Felix, J.F. (Janine), Timpson, N.J. (Nicholas), Perry, J.R.B. (John), Evans, D.M. (David), McCarthy, M.I. (Mark), and Freathy, R.M. (Rachel)

Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg =-0.22, P = 5.5 × 10-13), T2D (Rg =-0.27, P = 1.1 × 10-6) and coronary artery disease (Rg =-0.30, P = 6.5 × 10-9). In addition, using large-cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Published
2016
Full Text
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10. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

Author

Felix, J.F. (Janine), Bradfield, J.P. (Jonathan), Poppelaars-Monnereau, C. (Claire), Valk, R.J.P. (Ralf) van der, Stergiakouli, E. (Evie), Chesi, A. (Alessandra), Gaillard, R. (Romy), Feenstra, B. (Bjarke), Thiering, E. (Elisabeth), Kreiner-Møller, E. (Eskil), Mahajan, A. (Anubha), Pitkänen, N. (Niina), Joro, R. (Raimo), Cavadino, A. (Alana), Huikari, V. (Ville), Franks, S. (Steve), Groen-Blokhuis, M. (Maria), Cousminer, D.L. (Diana), Marsh, J.A. (Julie), Lehtimäki, T. (Terho), Curtin, J.A. (John), Vioque, J. (Jesus), Ahluwalia, T.S. (Tarunveer Singh), Myhre, R. (Ronny), Price, T.S. (Thomas), Vilor-Tejedor, N. (Natalia), Yengo, L. (Loic), Grarup, N. (Niels), Ntalla, I. (Ioanna), Ang, W.Q. (Wei), Atalay, M. (Mustafa), Bisgaard, H. (Hans), Blakemore, A.I.F. (Alexandra), Bonnefond, A. (Amélie), Carstensen, L. (Lisbeth), Eriksson, J.G. (Johan G.), Flexeder, C. (Claudia), Franke, L. (Lude), Geller, F. (Frank), Geserick, M. (Mandy), Hartikainen, A.L., Haworth, C.M.A. (Claire M.), Hirschhorn, J.N. (Joel N.), Hofman, A. (Albert), Holm, J.-C. (Jens-Christian), Horikoshi, M. (Momoko), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Kadarmideen, H.N. (Haja N.), Kähönen, M. (Mika), Kiess, W. (Wieland), Lakka, T.A. (Timo), Lewin, A. (Alex), Liang, L. (Liming), Lyytikäinen, L.-P. (Leo-Pekka), Ma, B. (Baoshan), Magnus, P. (Per), McCormack, S.E. (Shana E.), Mcmahon, G. (George), Mentch, F.D. (Frank), Middeldorp, C.M. (Christel), Murray, C.S. (Clare S.), Pahkala, K. (Katja), Pers, T.H. (Tune), Pfäffle, R. (Roland), Postma, D.S. (Dirkje), Power, C. (Christine), Simpson, A. (Angela), Sengpiel, V. (Verena), Tiesler, C. (Carla), Torrent, M. (Maties), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Vinding, R. (Rebecca), Waage, J. (Johannes), Wardle, J. (Jane), Zeggini, E. (Eleftheria), Zemel, B.S. (Babette S.), Dedoussis, G.V. (George), Pedersen, O. (Oluf), Froguel, P. (Philippe), Sunyer, J. (Jordi), Plomin, R. (Robert), Jacobsson, B. (Bo), Hansen, T. (Torben), Gonzalez, J.R. (Juan R.), Custovic, A. (Adnan), Raitakari, O.T. (Olli T.), Pennell, C.E. (Craig), Widén, E. (Elisabeth), Boomsma, D.I. (Dorret), Koppelman, G.H. (Gerard), Sebert, S. (Sylvain), Jarvelin, M.-R. (Marjo-Riitta), Hypponen, E. (Elina), McCarthy, M.I. (Mark), Lindi, V. (Virpi), Harri, N. (Niinikoski), Körner, A. (Antje), Bønnelykke, K. (Klaus), Heinrich, J. (Joachim), Melbye, M. (Mads), Rivadeneira Ramirez, F. (Fernando), Hakonarson, H. (Hakon), Ring, S.M. (Susan), Smith, A.V. (Davey), Sørensen, T.I.A. (Thorkild I.A.), Timpson, N.J. (Nicholas), Grant, S.F.A. (Struan), Jaddoe, V.W.V. (Vincent), Kalkwarf, H.J. (Heidi J.), Lappe, J.M. (Joan M.), Gilsanz, V. (Vicente), Oberfield, S.E. (Sharon E.), Shepherd, J.A. (John A.), Kelly, A. (Andrea), Felix, J.F. (Janine), Bradfield, J.P. (Jonathan), Poppelaars-Monnereau, C. (Claire), Valk, R.J.P. (Ralf) van der, Stergiakouli, E. (Evie), Chesi, A. (Alessandra), Gaillard, R. (Romy), Feenstra, B. (Bjarke), Thiering, E. (Elisabeth), Kreiner-Møller, E. (Eskil), Mahajan, A. (Anubha), Pitkänen, N. (Niina), Joro, R. (Raimo), Cavadino, A. (Alana), Huikari, V. (Ville), Franks, S. (Steve), Groen-Blokhuis, M. (Maria), Cousminer, D.L. (Diana), Marsh, J.A. (Julie), Lehtimäki, T. (Terho), Curtin, J.A. (John), Vioque, J. (Jesus), Ahluwalia, T.S. (Tarunveer Singh), Myhre, R. (Ronny), Price, T.S. (Thomas), Vilor-Tejedor, N. (Natalia), Yengo, L. (Loic), Grarup, N. (Niels), Ntalla, I. (Ioanna), Ang, W.Q. (Wei), Atalay, M. (Mustafa), Bisgaard, H. (Hans), Blakemore, A.I.F. (Alexandra), Bonnefond, A. (Amélie), Carstensen, L. (Lisbeth), Eriksson, J.G. (Johan G.), Flexeder, C. (Claudia), Franke, L. (Lude), Geller, F. (Frank), Geserick, M. (Mandy), Hartikainen, A.L., Haworth, C.M.A. (Claire M.), Hirschhorn, J.N. (Joel N.), Hofman, A. (Albert), Holm, J.-C. (Jens-Christian), Horikoshi, M. (Momoko), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Kadarmideen, H.N. (Haja N.), Kähönen, M. (Mika), Kiess, W. (Wieland), Lakka, T.A. (Timo), Lewin, A. (Alex), Liang, L. (Liming), Lyytikäinen, L.-P. (Leo-Pekka), Ma, B. (Baoshan), Magnus, P. (Per), McCormack, S.E. (Shana E.), Mcmahon, G. (George), Mentch, F.D. (Frank), Middeldorp, C.M. (Christel), Murray, C.S. (Clare S.), Pahkala, K. (Katja), Pers, T.H. (Tune), Pfäffle, R. (Roland), Postma, D.S. (Dirkje), Power, C. (Christine), Simpson, A. (Angela), Sengpiel, V. (Verena), Tiesler, C. (Carla), Torrent, M. (Maties), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Vinding, R. (Rebecca), Waage, J. (Johannes), Wardle, J. (Jane), Zeggini, E. (Eleftheria), Zemel, B.S. (Babette S.), Dedoussis, G.V. (George), Pedersen, O. (Oluf), Froguel, P. (Philippe), Sunyer, J. (Jordi), Plomin, R. (Robert), Jacobsson, B. (Bo), Hansen, T. (Torben), Gonzalez, J.R. (Juan R.), Custovic, A. (Adnan), Raitakari, O.T. (Olli T.), Pennell, C.E. (Craig), Widén, E. (Elisabeth), Boomsma, D.I. (Dorret), Koppelman, G.H. (Gerard), Sebert, S. (Sylvain), Jarvelin, M.-R. (Marjo-Riitta), Hypponen, E. (Elina), McCarthy, M.I. (Mark), Lindi, V. (Virpi), Harri, N. (Niinikoski), Körner, A. (Antje), Bønnelykke, K. (Klaus), Heinrich, J. (Joachim), Melbye, M. (Mads), Rivadeneira Ramirez, F. (Fernando), Hakonarson, H. (Hakon), Ring, S.M. (Susan), Smith, A.V. (Davey), Sørensen, T.I.A. (Thorkild I.A.), Timpson, N.J. (Nicholas), Grant, S.F.A. (Struan), Jaddoe, V.W.V. (Vincent), Kalkwarf, H.J. (Heidi J.), Lappe, J.M. (Joan M.), Gilsanz, V. (Vicente), Oberfield, S.E. (Sharon E.), Shepherd, J.A. (John A.), and Kelly, A. (Andrea)

Abstract

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown.We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores.We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10-8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10-10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in streng

Published
2016
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11. A novel common variant in DCST2 is associated with length in early life and height in adulthood

Author

Rj, Valk, Kreiner-Møller E, Mn, Kooijman, Guxens M, Stergiakouli E, Sääf A, Jp, Bradfield, Geller F, Mg, Hayes, Dl, Cousminer, Körner A, Thiering E, Ja, Curtin, Myhre R, Huikari V, Joro R, Kerkhof M, Nm, Warrington, Pitkänen N, Ntalla I, Horikoshi M, Veijola R, Rm, Freathy, Yy, Teo, Sj, Barton, Dm, Evans, Jp, Kemp, St Pourcain B, Sm, Ring, Gd, Smith, Bergström A, Kull I, Hakonarson H, Fd, Mentch, Bisgaard H, Chawes B, Stokholm J, Waage J, Eriksen P, Sevelsted A, Melbye M, Cm, Duijn, Medina-Gomez C, Hofman A, Jc, Jongste, Hr, Taal, Ag, Uitterlinden, Ll, Armstrong, Eriksson J, Palotie A, Bustamante M, Estivill X, Jr, Gonzalez, Llop S, Kiess W, Mahajan A, Flexeder C, Cm, Tiesler, Cs, Murray, Simpson A, Magnus P, Sengpiel V, Al, Hartikainen, Keinanen-Kiukaanniemi S, Lewin A, Da Silva Couto Alves A, Ai, Blakemore, Jl, Buxton, Kaakinen M, Rodriguez A, Sebert S, Vaarasmaki M, Lakka T, Lindi V, Gehring U, Ds, Postma, Ang W, Jp, Newnham, Lp, Lyytikäinen, Pahkala K, Ot, Raitakari, Panoutsopoulou K, Zeggini E, Di, Boomsma, Groen-Blokhuis M, Ilonen J, Franke L, Jn, Hirschhorn, Th, Pers, Liang L, Huang J, Hocher B, Knip M, Sm, Saw, Jw, Holloway, Melén E, Sf, Grant, Feenstra B, Wl, Lowe, Widén E, Sergeyev E, Grallert H, Adnan Custovic, Jacobsson B, Jarvelin MR, Atalay M, Gh, Koppelman, Ce, Pennell, Niinikoski H, Gv, Dedoussis, Mi, Mccarthy, Tm, Frayling, Sunyer J, Nj, Timpson, Rivadeneira F, Bønnelykke K, Vw, Jaddoe, Medical Research Council (MRC), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Pediatrics, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, Gastroenterology & Hepatology, Epidemiology, Internal Medicine, and Medical Oncology

Subjects
Netherlands Twin Register (NTR), Adult, Biochemistry & Molecular Biology, Genotype, Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Quantitative Trait Loci, LOCI, Polymorphism, Single Nucleotide, DISEASE, Quantitative Trait, Heritable, Early Growth Genetics (EGG) Consortium, Databases, Genetic, Psychology, GLUCOCEREBROSIDASE MUTATIONS, TOOL, Humans, LOW-BIRTH-WEIGHT, GENOME-WIDE ASSOCIATION, DC-STAMP, Alleles, Genetic Association Studies, Medicinsk genetik, Adaptor Proteins, Signal Transducing, Genetics & Heredity, Psykologi, Science & Technology, IMPUTED DATA, Association Studies Articles, Age Factors, Infant, Newborn, Computational Biology, Genetic Variation, Membrane Proteins, Reproducibility of Results, 11 Medical And Health Sciences, 06 Biological Sciences, GENE, Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, C420 Human Genetics, Body Height, Phenotype, Institut für Ernährungswissenschaft, epidemiology, Medical Genetics, Life Sciences & Biomedicine, biological, GROWTH-RETARDATION
Abstract

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

12. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis.

Author

Medina-Gomez C, Mullin BH, Chesi A, Prijatelj V, Kemp JP, Shochat-Carvalho C, Trajanoska K, Wang C, Joro R, Evans TE, Schraut KE, Li-Gao R, Ahluwalia TS, Zillikens MC, Zhu K, Mook-Kanamori DO, Evans DS, Nethander M, Knol MJ, Thorleifsson G, Prokic I, Zemel B, Broer L, McGuigan FE, van Schoor NM, Reppe S, Pawlak MA, Ralston SH, van der Velde N, Lorentzon M, Stefansson K, Adams HHH, Wilson SG, Ikram MA, Walsh JP, Lakka TA, Gautvik KM, Wilson JF, Orwoll ES, van Duijn CM, Bønnelykke K, Uitterlinden AG, Styrkársdóttir U, Akesson KE, Spector TD, Tobias JH, Ohlsson C, Felix JF, Bisgaard H, Grant SFA, Richards JB, Evans DM, van der Eerden B, van de Peppel J, Ackert-Bicknell C, Karasik D, Kague E, and Rivadeneira F

Subjects
Animals, Genome-Wide Association Study, Zebrafish genetics, Skull, Transcription Factors genetics, Bone Density genetics, Craniosynostoses genetics
Abstract

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases., (© 2023. The Author(s).)

Published
2023
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13. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

Author

Vogelezang S, Bradfield JP, Ahluwalia TS, Curtin JA, Lakka TA, Grarup N, Scholz M, van der Most PJ, Monnereau C, Stergiakouli E, Heiskala A, Horikoshi M, Fedko IO, Vilor-Tejedor N, Cousminer DL, Standl M, Wang CA, Viikari J, Geller F, Íñiguez C, Pitkänen N, Chesi A, Bacelis J, Yengo L, Torrent M, Ntalla I, Helgeland Ø, Selzam S, Vonk JM, Zafarmand MH, Heude B, Farooqi IS, Alyass A, Beaumont RN, Have CT, Rzehak P, Bilbao JR, Schnurr TM, Barroso I, Bønnelykke K, Beilin LJ, Carstensen L, Charles MA, Chawes B, Clément K, Closa-Monasterolo R, Custovic A, Eriksson JG, Escribano J, Groen-Blokhuis M, Grote V, Gruszfeld D, Hakonarson H, Hansen T, Hattersley AT, Hollensted M, Hottenga JJ, Hyppönen E, Johansson S, Joro R, Kähönen M, Karhunen V, Kiess W, Knight BA, Koletzko B, Kühnapfel A, Landgraf K, Langhendries JP, Lehtimäki T, Leinonen JT, Li A, Lindi V, Lowry E, Bustamante M, Medina-Gomez C, Melbye M, Michaelsen KF, Morgen CS, Mori TA, Nielsen TRH, Niinikoski H, Oldehinkel AJ, Pahkala K, Panoutsopoulou K, Pedersen O, Pennell CE, Power C, Reijneveld SA, Rivadeneira F, Simpson A, Sly PD, Stokholm J, Teo KK, Thiering E, Timpson NJ, Uitterlinden AG, van Beijsterveldt CEM, van Schaik BDC, Vaudel M, Verduci E, Vinding RK, Vogel M, Zeggini E, Sebert S, Lind MV, Brown CD, Santa-Marina L, Reischl E, Frithioff-Bøjsøe C, Meyre D, Wheeler E, Ong K, Nohr EA, Vrijkotte TGM, Koppelman GH, Plomin R, Njølstad PR, Dedoussis GD, Froguel P, Sørensen TIA, Jacobsson B, Freathy RM, Zemel BS, Raitakari O, Vrijheid M, Feenstra B, Lyytikäinen LP, Snieder H, Kirsten H, Holt PG, Heinrich J, Widén E, Sunyer J, Boomsma DI, Järvelin MR, Körner A, Davey Smith G, Holm JC, Atalay M, Murray C, Bisgaard H, McCarthy MI, Jaddoe VWV, Grant SFA, and Felix JF

Subjects
Adolescent, Adult, Blood Pressure, Body Mass Index, Cardiometabolic Risk Factors, Cardiovascular Diseases pathology, Child, Child, Preschool, Diabetes Mellitus, Type 2 pathology, Female, Genome-Wide Association Study methods, Humans, Male, Menarche genetics, Mendelian Randomization Analysis, Waist-Hip Ratio, Cardiovascular Diseases genetics, Diabetes Mellitus, Type 2 genetics, Genetic Predisposition to Disease, Monosaccharide Transport Proteins genetics, Nedd4 Ubiquitin Protein Ligases genetics
Abstract

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MMcC: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. He serves on advisory panels for Pfizer, NovoNordisk, Zoe Global; has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly; has stock options in Zoe Global; has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier & Takeda. MS receives funding from Pfizer Inc. for a project not related to this research. IB and spouse own stock in GlaxoSmithKline and Incyte Corp. ZE and CDB currently serve on the editorial board of PLOS Genetics. AC reports personal fees from Novartis, personal fees from Thermo Fisher Scientific, personal fees from Philips, personal fees from Sanofi, personal fees from Stallergenes Greer, outside the submitted work. KC in involved in consultancy for Danone Research, LNC-therapeutic and Confo-therapeutic but no personal funding is received and this activity not linked to the present research.

Published
2020
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14. Effects of military training on plasma amino acid concentrations and their associations with overreaching.

Author

Ikonen JN, Joro R, Uusitalo AL, Kyröläinen H, Kovanen V, Atalay M, and Tanskanen-Tervo MM

Subjects
Education methods, Fatigue physiopathology, Humans, Male, Middle Aged, Military Personnel, Oxygen metabolism, Amino Acids blood, Amino Acids metabolism, Fatigue blood, Fatigue metabolism, Plasma metabolism
Abstract

Impact Statement: The diagnosis of overtraining syndrome and overreaching poses a great challenge. Military training aims at improving the physical performance of the conscripts, but an excessive training load could also lead to overreaching. This study of Finnish conscripts provides new insights into the pathophysiology of overreaching and overtraining through amino acids concentrations. In addition to confirming the possible use of plasma glutamine/glutamate concentration to indicate and predict overreaching, we made a novel finding, i.e. low alanine and arginine concentrations might have a role in performance decrement and fatigue related to overreaching. Moreover, this study is the first to show the possible association between amino acids with putative neuronal properties and overreaching. Thus, the present findings might help to detect and prevent overreaching and offer a reliable diagnostic approach. In order to avoid overreaching, military training should be planned more periodically and individually, especially during the first four weeks of military service.

Published
2020
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15. A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Author

Bradfield JP, Vogelezang S, Felix JF, Chesi A, Helgeland Ø, Horikoshi M, Karhunen V, Lowry E, Cousminer DL, Ahluwalia TS, Thiering E, Boh ET, Zafarmand MH, Vilor-Tejedor N, Wang CA, Joro R, Chen Z, Gauderman WJ, Pitkänen N, Parra EJ, Fernandez-Rhodes L, Alyass A, Monnereau C, Curtin JA, Have CT, McCormack SE, Hollensted M, Frithioff-Bøjsøe C, Valladares-Salgado A, Peralta-Romero J, Teo YY, Standl M, Leinonen JT, Holm JC, Peters T, Vioque J, Vrijheid M, Simpson A, Custovic A, Vaudel M, Canouil M, Lindi V, Atalay M, Kähönen M, Raitakari OT, van Schaik BDC, Berkowitz RI, Cole SA, Voruganti VS, Wang Y, Highland HM, Comuzzie AG, Butte NF, Justice AE, Gahagan S, Blanco E, Lehtimäki T, Lakka TA, Hebebrand J, Bonnefond A, Grarup N, Froguel P, Lyytikäinen LP, Cruz M, Kobes S, Hanson RL, Zemel BS, Hinney A, Teo KK, Meyre D, North KE, Gilliland FD, Bisgaard H, Bustamante M, Bonnelykke K, Pennell CE, Rivadeneira F, Uitterlinden AG, Baier LJ, Vrijkotte TGM, Heinrich J, Sørensen TIA, Saw SM, Pedersen O, Hansen T, Eriksson J, Widén E, McCarthy MI, Njølstad PR, Power C, Hyppönen E, Sebert S, Brown CD, Järvelin MR, Timpson NJ, Johansson S, Hakonarson H, Jaddoe VWV, and Grant SFA

Subjects
Bayes Theorem, Case-Control Studies, Child, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Male, Chromosome Mapping methods, Genome-Wide Association Study methods, Pediatric Obesity genetics, Polymorphism, Single Nucleotide, Wilms Tumor genetics
Abstract

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2019
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16. Consortium-based genome-wide meta-analysis for childhood dental caries traits.

Author

Haworth S, Shungin D, van der Tas JT, Vucic S, Medina-Gomez C, Yakimov V, Feenstra B, Shaffer JR, Lee MK, Standl M, Thiering E, Wang C, Bønnelykke K, Waage J, Jessen LE, Nørrisgaard PE, Joro R, Seppälä I, Raitakari O, Dudding T, Grgic O, Ongkosuwito E, Vierola A, Eloranta AM, West NX, Thomas SJ, McNeil DW, Levy SM, Slayton R, Nohr EA, Lehtimäki T, Lakka T, Bisgaard H, Pennell C, Kühnisch J, Marazita ML, Melbye M, Geller F, Rivadeneira F, Wolvius EB, Franks PW, Johansson I, and Timpson NJ

Subjects
Adolescent, Case-Control Studies, Child, Child, Preschool, Female, Humans, Male, Phenotype, Adaptor Proteins, Signal Transducing genetics, Biomarkers analysis, Dental Caries genetics, Dentition, Permanent, Genome-Wide Association Study methods, Phosphoproteins genetics, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

Published
2018
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17. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Author

Medina-Gomez C, Kemp JP, Trajanoska K, Luan J, Chesi A, Ahluwalia TS, Mook-Kanamori DO, Ham A, Hartwig FP, Evans DS, Joro R, Nedeljkovic I, Zheng HF, Zhu K, Atalay M, Liu CT, Nethander M, Broer L, Porleifsson G, Mullin BH, Handelman SK, Nalls MA, Jessen LE, Heppe DHM, Richards JB, Wang C, Chawes B, Schraut KE, Amin N, Wareham N, Karasik D, Van der Velde N, Ikram MA, Zemel BS, Zhou Y, Carlsson CJ, Liu Y, McGuigan FE, Boer CG, Bønnelykke K, Ralston SH, Robbins JA, Walsh JP, Zillikens MC, Langenberg C, Li-Gao R, Williams FMK, Harris TB, Akesson K, Jackson RD, Sigurdsson G, den Heijer M, van der Eerden BCJ, van de Peppel J, Spector TD, Pennell C, Horta BL, Felix JF, Zhao JH, Wilson SG, de Mutsert R, Bisgaard H, Styrkársdóttir U, Jaddoe VW, Orwoll E, Lakka TA, Scott R, Grant SFA, Lorentzon M, van Duijn CM, Wilson JF, Stefansson K, Psaty BM, Kiel DP, Ohlsson C, Ntzani E, van Wijnen AJ, Forgetta V, Ghanbari M, Logan JG, Williams GR, Bassett JHD, Croucher PI, Evangelou E, Uitterlinden AG, Ackert-Bicknell CL, Tobias JH, Evans DM, and Rivadeneira F

Subjects
Adolescent, Age Factors, Animals, Child, Child, Preschool, Genetic Loci, Humans, Infant, Infant, Newborn, Mice, Knockout, Polymorphism, Single Nucleotide genetics, Quantitative Trait, Heritable, Regression Analysis, Bone Density genetics, Genome-Wide Association Study
Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2018
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18. Genome-wide associations for birth weight and correlations with adult disease.

Author

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

Subjects
Adult, Anthropometry, Blood Pressure genetics, Chromatin Assembly and Disassembly, Cohort Studies, Datasets as Topic, Female, Genetic Loci genetics, Genetic Variation genetics, Genomic Imprinting genetics, Genotype, Glucose metabolism, Glycogen biosynthesis, Humans, Insulin metabolism, Male, Phenotype, Signal Transduction, Aging genetics, Birth Weight genetics, Coronary Artery Disease genetics, Diabetes Mellitus, Type 2 genetics, Fetus metabolism, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

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

Published
2016
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19. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

Author

Felix JF, Bradfield JP, Monnereau C, van der Valk RJ, Stergiakouli E, Chesi A, Gaillard R, Feenstra B, Thiering E, Kreiner-Møller E, Mahajan A, Pitkänen N, Joro R, Cavadino A, Huikari V, Franks S, Groen-Blokhuis MM, Cousminer DL, Marsh JA, Lehtimäki T, Curtin JA, Vioque J, Ahluwalia TS, Myhre R, Price TS, Vilor-Tejedor N, Yengo L, Grarup N, Ntalla I, Ang W, Atalay M, Bisgaard H, Blakemore AI, Bonnefond A, Carstensen L, Eriksson J, Flexeder C, Franke L, Geller F, Geserick M, Hartikainen AL, Haworth CM, Hirschhorn JN, Hofman A, Holm JC, Horikoshi M, Hottenga JJ, Huang J, Kadarmideen HN, Kähönen M, Kiess W, Lakka HM, Lakka TA, Lewin AM, Liang L, Lyytikäinen LP, Ma B, Magnus P, McCormack SE, McMahon G, Mentch FD, Middeldorp CM, Murray CS, Pahkala K, Pers TH, Pfäffle R, Postma DS, Power C, Simpson A, Sengpiel V, Tiesler CM, Torrent M, Uitterlinden AG, van Meurs JB, Vinding R, Waage J, Wardle J, Zeggini E, Zemel BS, Dedoussis GV, Pedersen O, Froguel P, Sunyer J, Plomin R, Jacobsson B, Hansen T, Gonzalez JR, Custovic A, Raitakari OT, Pennell CE, Widén E, Boomsma DI, Koppelman GH, Sebert S, Järvelin MR, Hyppönen E, McCarthy MI, Lindi V, Harri N, Körner A, Bønnelykke K, Heinrich J, Melbye M, Rivadeneira F, Hakonarson H, Ring SM, Smith GD, Sørensen TI, Timpson NJ, Grant SF, and Jaddoe VW

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Genetic Loci, Humans, Male, Risk, White People genetics, Young Adult, Body Mass Index, Genome-Wide Association Study, Obesity genetics, Polymorphism, Single Nucleotide
Abstract

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2016
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