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

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

Hum.Mol.Genet., 2015, 24, 4, 1155, 68, IF: 7.692, PMID: 25281659

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 7 independent top SNPs (P<1x10-6) for birth length, of which 3 were novel and 4 were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The 3 novel SNPs were followed-up in 9 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; ss=0.046, S.E.=0.008, P=2.46x10-8, explained variance=0.05%). Rs905938 was also associated with infant length (N=28,228; P=5.54x10-4) and adult height (N=127,513; P=1.45x10-5). 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

BIOCHEMISTRY & MOLECULAR BIOLOGY, GENETICS & HEREDITY


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