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12. A saturated map of common genetic variants associated with human height

Author

Yengo, L., Vedantam, S., Marouli, E., Sidorenko, J., Bartell, E., Sakaue, S., Graff, M, Eliasen, A.U., Jiang, Y., Raghavan, S., Miao, J., Arias, J.D., Graham, S.E., Mukamel, R.E., Spracklen, C.N., Yin, X., Chen, Shiou-Shiou, Ferreira, T., Highland, H.H., Ji, Y., Karaderi, T., Lin, K., Lüll, K., Malden, D.E., Medina-Gomez, C., Machado, M., Moore, A., Rüeger, S., Sim, X., Vrieze, S., Ahluwalia, T.S., Akiyama, M., Allison, M.A., Alvarez, M., Andersen, M.K., Ani, A., Appadurai, V., Arbeeva, L., Bhaskar, S., Bielak, L.F., Bollepalli, S., Bonnycastle, L.L., Bork-Jensen, J., Bradfield, J.P., Bradford, Y., Braund, P.S., Brody, J.A., Burgdorf, K.S., Cade, B.E., Cai, H., Cai, Q., Campbell, A., Cañadas-Garre, M., Catamo, E., Chai, J.F., Chai, X., Chang, L.C., Chang, Y.C., Chen, Chen, Chesi, A., Choi, S.H., Chung, R.H., Cocca, M., Concas, M.P., Couture, C., Cuellar-Partida, G., Danning, R., Daw, E.W., Degenhard, F., Delgado, G.E., Delitala, A., Demirkan, A., Deng, X., Devineni, P., Dietl, A., Dimitriou, M., Dimitrov, L., Dorajoo, R., Ekici, A.B., Engmann, J.E., Fairhurst-Hunter, Z., Farmaki, A.E., Faul, J.D., Fernandez-Lopez, J.C., Forer, L., Francescatto, M., Freitag-Wolf, S., Fuchsberger, C., Galesloot, T.E., Gao, Y., Gao, Z., Geller, F., Giannakopoulou, O., Giulianini, F., Gjesing, A.P., Goel, A., Gordon, S.D.S., Gorski, M., Grove, J, Lores-Motta, Laura, Pauper, M., Hollander, A.I. den, Hoyng, C.B., Kiemeney, L.A.L.M., Visscher, P.M., Hirschhorn, J.N., Yengo, L., Vedantam, S., Marouli, E., Sidorenko, J., Bartell, E., Sakaue, S., Graff, M, Eliasen, A.U., Jiang, Y., Raghavan, S., Miao, J., Arias, J.D., Graham, S.E., Mukamel, R.E., Spracklen, C.N., Yin, X., Chen, Shiou-Shiou, Ferreira, T., Highland, H.H., Ji, Y., Karaderi, T., Lin, K., Lüll, K., Malden, D.E., Medina-Gomez, C., Machado, M., Moore, A., Rüeger, S., Sim, X., Vrieze, S., Ahluwalia, T.S., Akiyama, M., Allison, M.A., Alvarez, M., Andersen, M.K., Ani, A., Appadurai, V., Arbeeva, L., Bhaskar, S., Bielak, L.F., Bollepalli, S., Bonnycastle, L.L., Bork-Jensen, J., Bradfield, J.P., Bradford, Y., Braund, P.S., Brody, J.A., Burgdorf, K.S., Cade, B.E., Cai, H., Cai, Q., Campbell, A., Cañadas-Garre, M., Catamo, E., Chai, J.F., Chai, X., Chang, L.C., Chang, Y.C., Chen, Chen, Chesi, A., Choi, S.H., Chung, R.H., Cocca, M., Concas, M.P., Couture, C., Cuellar-Partida, G., Danning, R., Daw, E.W., Degenhard, F., Delgado, G.E., Delitala, A., Demirkan, A., Deng, X., Devineni, P., Dietl, A., Dimitriou, M., Dimitrov, L., Dorajoo, R., Ekici, A.B., Engmann, J.E., Fairhurst-Hunter, Z., Farmaki, A.E., Faul, J.D., Fernandez-Lopez, J.C., Forer, L., Francescatto, M., Freitag-Wolf, S., Fuchsberger, C., Galesloot, T.E., Gao, Y., Gao, Z., Geller, F., Giannakopoulou, O., Giulianini, F., Gjesing, A.P., Goel, A., Gordon, S.D.S., Gorski, M., Grove, J, Lores-Motta, Laura, Pauper, M., Hollander, A.I. den, Hoyng, C.B., Kiemeney, L.A.L.M., Visscher, P.M., and Hirschhorn, J.N.

Abstract

Item does not contain fulltext, Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Published
2022

13. A saturated map of common genetic variants associated with human height

Author

Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, Hirschhorn, JN, Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, and Hirschhorn, JN

Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Published
2022

16. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), Willer, C. J. (Cristen J.), Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), and Willer, C. J. (Cristen J.)

Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4‐23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Published
2021

21. The population-based prevalence of knee symptoms, radiographic, and symptomatic OA over 18 years: the Johnston county osteoarthritis project

Author

Nelson, A.E., primary, Hu, D., additional, Arbeeva, L., additional, Alvarez, C., additional, Cleveland, R.J., additional, Schwartz, T.A., additional, Murphy, L.B., additional, Helmick, C.G., additional, Callahan, L.F., additional, Renner, J.B., additional, Jordan, J.M., additional, and Golightly, Y.M., additional

Published
2020
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22. The population-based prevalence of hip symptoms, radiographic, and symptomatic hip OA over 26 years: the Johnston county osteoarthritis project

Author

Nelson, A.E., primary, Hu, D., additional, Arbeeva, L., additional, Alvarez, C., additional, Cleveland, R.J., additional, Schwartz, T.A., additional, Murphy, L.B., additional, Helmick, C.G., additional, Callahan, L.F., additional, Renner, J.B., additional, Jordan, J.M., additional, and Golightly, Y.M., additional

Published
2020
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23. Acceptability of telephone-based pain coping skills training among African Americans with osteoarthritis enrolled in a randomized controlled trial: A mixed methods analysis

Author

Griesemer, I., Arbeeva, L., Keefe, F.J., Somers, T.J., Dharmasri, C.J., Cené, C.W., Oddone, E.Z., Campbell, L.C., and Allen, K.D.

Abstract

Background: Osteoarthritis (OA) disproportionately impacts African Americans compared to Caucasians, including greater pain severity. The Pain Coping Skills Training for African Americans with Osteoarthritis (STAART) study examined a culturally enhanced Pain Coping Skills Training (CST) program among African Americans with OA. This mixed methods study evaluated the acceptability of the Pain CST program among STAART participants. Methods: STAART was a randomized controlled trial evaluating the effectiveness of an 11-session, telephone-based pain CST program, compared to a usual care control group. Participants were from the University of North Carolina and Durham Veterans Affairs Healthcare Systems. The present analyses included 93 participants in the CST group who completed a questionnaire about experiences with the program. Descriptive statistics of the questionnaire responses were calculated using SAS software. Thematic analysis was applied to open-response data using Dedoose software. Results: Participants' mean rating of overall helpfulness of the pain CST program for managing arthritis symptoms was 8.0 (SD = 2.2) on a scale of 0-10. A majority of participants reported the program made a positive difference in their experience with arthritis (83.1%). Mean ratings of helpfulness of the specific skills ranged from 7.7 to 8.8 (all scales 0-10). Qualitative analysis of the open-response data identified four prominent themes: Improved Pain Coping, Mood and Emotional Benefits, Improved Physical Functioning, and experiences related to Intervention Delivery. Conclusions: The high ratings of helpfulness demonstrate acceptability of this culturally enhanced pain CST program by African Americans with OA. Increasing access to cognitive-behavioral therapy-based programs may be a promising strategy to address racial disparities in OA-related pain and associated outcomes. Trial registration: NCT02560922, registered September 25, 2015.

Published
2020
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24. Pain coping skills training for African Americans with osteoarthritis: Results of a randomized controlled trial

Author

Keefe, F.J., Oddone, E.Z., Campbell, L.C., Arbeeva, L., Allen, K.D., Coffman, C.J., Cené, C.W., and Somers, T.J.

Abstract

African Americans bear a disproportionate burden of osteoarthritis (OA), but they have been underrepresented in trials of behavioral interventions for pain. This trial examined a culturally tailored pain coping skills training (CST) program, compared to a wait list control group, among 248 African Americans with knee or hip OA. The pain CST program involved 11 telephone-based sessions over 3 months. Outcomes were assessed at baseline, 3 months (primary), and 9 months, and included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (primary outcome), WOMAC total score and function subscale, PROMIS Pain Interference, Short-Form 12 Mental and Physical Composite Subscales, Coping Strategies Questionnaire - Total Coping Attempts, Pain Catastrophizing Scale, Patient Health Questionnaire-8, Arthritis Self-Efficacy Scale, and Patient Global Impression of Arthritis Symptom Change. Linear mixed models were fit for all outcomes. There were no significant between-group differences in WOMAC pain score at 3 months (-0.63 [95% confidence interval -1.45, 0.18]; P = 0.128) or 9 months (-0.84 [95% confidence interval -1.73, 0.06]; P = 0.068). Among secondary outcomes, at 3 months, there were significant differences, in favor of the CST group, for Coping Strategies Questionnaire Total Coping Attempts, Pain Catastrophizing Scale, Arthritis Self-Efficacy, and Patient Global Impression of Arthritis Symptom Change (P < 0.01). Coping Strategies Questionnaire Total Coping Attempts, Arthritis Self-Efficacy, and Patient Global Assessment Change were also significantly improved at 9 months in the CST group, compared with wait list (P < 0.01). The culturally tailored pain CST program did not significantly reduce pain severity but did improve key measures of pain coping and perceived ability to manage pain among African Americans with OA.

Published
2019
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30. Associations of number of physical therapy visits and frequency of use of an internet-based exercise training program with knee osteoarthritis outcomes

Author

Allen, K.D., primary, Pignato, M., additional, Arbeeva, L., additional, Schwartz, T., additional, Callahan, L., additional, Cooke, J., additional, Goode, A., additional, Golightly, Y., additional, Heiderscheit, B., additional, Hill, C., additional, Huffman, K., additional, and Seversen, H., additional

Published
2018
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35. Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

Author

Suri, P. (Pradeep), Palmer, M.R. (Melody R.), Tsepilov, Y.A. (Yakov), Freidin, M.B. (Maxim B.), Boer, C.G. (Cindy), Yau, M.S. (Michelle S.), Evans, D.S. (Daniel), Gelemanovic, A. (Andrea), Bartz, T.M. (Traci M.), Nethander, M. (Maria), Arbeeva, L. (Liubov), Karssen, L.C. (Lennart), Neogi, T. (Tuhina), Campbell, A. (Archie), Mellström, D. (Dan), Ohlsson, C. (Claes), Marshall, L.M. (Lynn M.), Orwoll, E. (Eric), Uitterlinden, A. (Andre), Rotter, J.I. (Jerome I.), Lauc, G. (Gordan), Psaty, B.M. (Bruce M.), Karlsson, M. (Magnus), Lane, N.E., Jarvik, G.P. (Gail), Polasek, O. (Ozren), Hochberg, M.C. (Marc), Jordan, J.M. (Joanne), Meurs, J.B.J. (Joyce) van, Jackson, R.D. (Rebecca), Nielson, C. (Carrie), Mitchell, B.D. (Braxton), Smith, B.H. (Blair), Hayward, C. (Caroline), Smith, N.L. (Nicholas L.), Aulchenko, Y.S. (Yurii S.), Williams, F.M. (Frances), Suri, P. (Pradeep), Palmer, M.R. (Melody R.), Tsepilov, Y.A. (Yakov), Freidin, M.B. (Maxim B.), Boer, C.G. (Cindy), Yau, M.S. (Michelle S.), Evans, D.S. (Daniel), Gelemanovic, A. (Andrea), Bartz, T.M. (Traci M.), Nethander, M. (Maria), Arbeeva, L. (Liubov), Karssen, L.C. (Lennart), Neogi, T. (Tuhina), Campbell, A. (Archie), Mellström, D. (Dan), Ohlsson, C. (Claes), Marshall, L.M. (Lynn M.), Orwoll, E. (Eric), Uitterlinden, A. (Andre), Rotter, J.I. (Jerome I.), Lauc, G. (Gordan), Psaty, B.M. (Bruce M.), Karlsson, M. (Magnus), Lane, N.E., Jarvik, G.P. (Gail), Polasek, O. (Ozren), Hochberg, M.C. (Marc), Jordan, J.M. (Joanne), Meurs, J.B.J. (Joyce) van, Jackson, R.D. (Rebecca), Nielson, C. (Carrie), Mitchell, B.D. (Braxton), Smith, B.H. (Blair), Hayward, C. (Caroline), Smith, N.L. (Nicholas L.), Aulchenko, Y.S. (Yurii S.), and Williams, F.M. (Frances)

Abstract

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chr

Published
2018
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36. Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

Author

Suri, P, Palmer, MR, Tsepilov, YA, Freidin, MB, Boer, Cindy, Yau, MS, Evans, DS, Gelemanovic, A, Bartz, TM, Nethander, M, Arbeeva, L, Karssen, L, Neogi, T, Campbel, A, Mellstrom, D, Ohlsson, C, Marshall, LM, Orwoll, E, Uitterlinden, André, Rotter, JI, Lauc, G, Psaty, BM, Karlsson, MK, Lane, NE, Jarvik, GP, Polasek, O, Hochberg, M, Jordan, JM, van Meurs, Joyce, Jackson, R, Nielson, CM, Mitchell, BD, Smith, BH, Hayward, C, Smith, NL, Aulchenko, YS, Williams, FMK, Suri, P, Palmer, MR, Tsepilov, YA, Freidin, MB, Boer, Cindy, Yau, MS, Evans, DS, Gelemanovic, A, Bartz, TM, Nethander, M, Arbeeva, L, Karssen, L, Neogi, T, Campbel, A, Mellstrom, D, Ohlsson, C, Marshall, LM, Orwoll, E, Uitterlinden, André, Rotter, JI, Lauc, G, Psaty, BM, Karlsson, MK, Lane, NE, Jarvik, GP, Polasek, O, Hochberg, M, Jordan, JM, van Meurs, Joyce, Jackson, R, Nielson, CM, Mitchell, BD, Smith, BH, Hayward, C, Smith, NL, Aulchenko, YS, and Williams, FMK

Published
2018

40. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, Sarah E, Clarke, Shoa L, Wu, Kuan-Han H, Kanoni, Stavroula, Zajac, Greg JM, Ramdas, Shweta, Surakka, Ida, Ntalla, Ioanna, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Hwang, Mi Yeong, Han, Sohee, Narita, Akira, Choudhury, Ananyo, Bentley, Amy R, Ekoru, Kenneth, Verma, Anurag, Trivedi, Bhavi, Martin, Hilary C, Hunt, Karen A, Hui, Qin, Klarin, Derek, Zhu, Xiang, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Ruotsalainen, Sanni E, Havulinna, Aki S, Veturi, Yogasudha, Feng, QiPing, Rosenthal, Elisabeth A, Lingren, Todd, Pacheco, Jennifer Allen, Pendergrass, Sarah A, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Hindy, George, Rasheed, Asif, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Willemsen, Gonneke, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Yao, Jie, Manichaikul, Ani, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Sidore, Carlo, Fiorillo, Edoardo, McDaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Thuesen, Betina H, Munz, Matthias, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Lukas, Scholz, Markus, Galesloot, Tessel E., Bradfield, Jonathan P., Daw, E Warwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Feitosa, Mary F, Wojczynski, Mary K, Preuss, Michael, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Kember, Rachel L, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Leonard, Hampton L, Marten, Jonathan, Schmidt, Börge, Arendt, Marina, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlos, Lyssenko, Valeriya, Ahmed, Meraj, Jackson, Anne U, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul RHJ, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Chai, Xiaoran, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B., Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Hung, Yi-Jen, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Gorski, Mathias, Brumat, Marco, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Xue, Chao, Zhang, Jifeng, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, Lee, Jiwon, van der Laan, Sander W., Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Zimmermann, Martina E, Lee, Jong Young, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hildalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Schwander, Karen, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Highland, Heather M, Young, Kristin L, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Nadkarni, Girish N., Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, Bhatti, Konain Fatima, de Kleijn, Dominique, de Borst, Gert J., Kim, Eung Kweon, Adams, Hieab H.H., Ikram, M. 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Janaka, Wickremasinghe, Ananda R, Krauss, Ronald M, Wu, Jer-Yuarn, Zheng, Wei, den Hollander, Anneke I, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G, Lind, Lars, Heng, Chew-Kiat, Nelson, Amanda E, Golightly, Yvonne M, Wilson, James F, Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J, Rao, D C, Arnett, Donna K, Walker, Mark, Koistinen, Heikki A, Chandak, Giriraj R, Yajnik, Chittaranjan S, Mercader, Josep M, Tusie-Luna, Teresa, Aguilar-Salinas, Carlos, Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, E Shyong, van Dam, Rob M, Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F, McKnight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, McCarthy, Mark I, Palmer, Colin NA, Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M, Lu, Fan, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Parra, Esteban J, Cruz, Miguel, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M t, Elders, Petra JM, Rader, Daniel J, Damrauer, Scott M, Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D, Loos, Ruth J.F., Province, Michael A, Psaty, Bruce M, Brandslund, Ivan, Pramstaller, Peter P, Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F.A., Kiemeney, Lambertus ALM, de Graaf, Jacqueline, Loeffler, Markus, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W, Linneberg, Allan, Jukema, J. Wouter, Khera, Amit V, Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Cucca, Francesco, Mook-Kanamori, Dennis O, van Dijk, Ko Willems, Watkins, Hugh, Strachan, David P, Grarup, Niels, Sever, Peter, Poulter, Neil, Rotter, Jerome I, Dantoft, Thomas M, Karpe, Fredrik, Neville, Matt J, Timpson, Nicholas J, Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T, Pedersen, Nancy L, Magnusson, Patrik KE, Boomsma, Dorret I, de Geus, Eco JC, Cupples, L Adrienne, van Meurs, Joyce B.J., Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J, Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C, Kooner, Jaspal S, de Vries, Paul S, Morrison, Alanna C, North, Kari E., Daviglus, Martha, Kraft, Peter, Martin, Nicholas G, Whitfield, John B, Abbas, Shahid, Saleheen, Danish, Walters, Robin G, Holmes, Michael V, Black, Corri, Smith, Blair H, Justice, Anne E, Baras, Aris, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Kooperberg, Charles, Wei, Wei-Qi, Jarvik, Gail P, Namjou, Bahram, Hayes, M. 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K., Walker, M., Koistinen, H. A., Chandak, G. R., Yajnik, C. S., Mercader, J. M., Tusie-Luna, T., Aguilar-Salinas, C. A., Villalpando, C. G., Orozco, L., Fornage, M., Tai, E. S., van Dam, R. M., Lehtimaki, T., Chaturvedi, N., Yokota, M., Reilly, D. F., Mcknight, A. J., Kee, F., Jockel, K. -H., Mccarthy, M. I., Palmer, C. N. A., Vitart, V., Hayward, C., Simonsick, E., van Duijn, C. M., Lu, F., Qu, J., Hishigaki, H., Lin, X., Marz, W., Parra, E. J., Cruz, M., Gudnason, V., Tardif, J. -C., Lettre, G., 't Hart, L. M., Elders, P. J. M., Damrauer, S. M., Kumari, M., Kivimaki, M., van der Harst, P., Spector, T. D., Loos, R. J. F., Province, M. A., Psaty, B. M., Brandslund, I., Pramstaller, P. P., Christensen, K., Ripatti, S., Widen, E., Hakonarson, H., Grant, S. F. A., Kiemeney, L. A. L. M., de Graaf, J., Loeffler, M., Kronenberg, F., Gu, D., Erdmann, J., Schunkert, H., Franks, P. W., Linneberg, A., Jukema, J. W., Khera, A. V., Mannikko, M., Jarvelin, M. -R., Kutalik, Z., Cucca, F., Mook-Kanamori, D. O., van Dijk, K. W., Watkins, H., Strachan, D. P., Grarup, N., Sever, P., Poulter, N., Rotter, J. I., Dantoft, T. M., Karpe, F., Neville, M. J., Timpson, N. J., Cheng, C. -Y., Wong, T. -Y., Khor, C. C., Sabanayagam, C., Peters, A., Gieger, C., Hattersley, A. T., Pedersen, N. L., Magnusson, P. K. E., Boomsma, D. I., de Geus, E. J. C., Cupples, L. A., van Meurs, J. B. J., Ghanbari, M., Gordon-Larsen, P., Huang, W., Kim, Y. J., Tabara, Y., Wareham, N. J., Langenberg, C., Zeggini, E., Kuusisto, J., Laakso, M., Ingelsson, E., Abecasis, G., Chambers, J. C., Kooner, J. S., de Vries, P. S., Morrison, A. C., North, K. E., Daviglus, M., Kraft, P., Martin, N. G., Whitfield, J. B., Abbas, S., Saleheen, D., Walters, R. G., Holmes, M. V., Black, C., Smith, B. H., Justice, A. E., Baras, A., Buring, J. E., Ridker, P. M., Chasman, D. I., Kooperberg, C., Wei, W. -Q., Jarvik, G. P., Namjou, B., Hayes, M. G., Ritchie, M. D., Jousilahti, P., Salomaa, V., Hveem, K., Asvold, B. O., Kubo, M., Kamatani, Y., Okada, Y., Murakami, Y., Thorsteinsdottir, U., Stefansson, K., Ho, Y. -L., Lynch, J. A., Rader, D. J., Tsao, P. S., Chang, K. -M., Cho, K., O'Donnell, C. J., Gaziano, J. M., Wilson, P., Rotimi, C. N., Hazelhurst, S., Ramsay, M., Trembath, R. C., van Heel, D. A., Tamiya, G., Yamamoto, M., Kim, B. -J., Mohlke, K. L., Frayling, T. M., Hirschhorn, J. N., Kathiresan, S., Boehnke, M., Natarajan, P., Peloso, G. M., Brown, C. D., Morris, A. P., Assimes, T. L., Deloukas, P., Sun, Y. V., Willer, C. J., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, AMS - Ageing & Vitality, and AMS - Sports

Subjects
blood lipid level, Multifactorial Inheritance, GWAS, blood lipid levels, cardiovascular disease, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Medizin, LOCI, ANCESTRY, VARIANTS, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, Population Groups, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, METAANALYSIS, POLYMORPHISMS, RISK, Multidisciplinary, Cardiovascular Diseases, Genome-Wide Association Study, Cardiovascular Diseases/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Polymorphism, Single Nucleotide/genetics, CHOLESTEROL, Human Genetics, INDIVIDUALS, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], DISCOVERY, LOW-FREQUENCY, Delivery of Health Care
Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice.

Published
2021
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41. Gut Microbiome and Osteoarthritis: Insights From the Naturally Occurring Canine Model of Osteoarthritis.

Author

Stevens C, Norris S, Arbeeva L, Carter S, Enomoto M, Nelson AE, and Lascelles BDX

Subjects
Dogs, Animals, Male, Female, Firmicutes isolation & purification, Pain microbiology, Metagenomics, Gastrointestinal Microbiome, Osteoarthritis microbiology, Disease Models, Animal, Feces microbiology
Abstract

Objective: The purpose of this study was to enhance the current knowledge of the relationship between the gut microbiome and osteoarthritis (OA) and associated pain using pet dogs as a clinically relevant translational model., Methods: Fecal samples were collected from 93 owned pet dogs. Dogs were designated as either clinically healthy or OA pain using validated methods. Metagenomic profiling was performed through shotgun sequencing using the Illumina NovaSeq platform. MetaPhlAn2 and HUMAnN2 were used to evaluate bacterial taxonomic and pathway relative abundance. Comparisons between healthy and OA-pain groups were performed individually for each taxa using nonparametric tests following Benjamini and Hochberg adjustment for multiple comparisons. Permutation analysis of variance was performed using Bray-Curtis distance matrices. All downstream analyses were completed in R., Results: No significant differences between healthy and OA-pain dogs were observed for alpha and beta diversity. We found 13 taxa with nominally significant (P < 0.05) associations with OA case status, but none of the associations remained significant after adjustment for multiple comparisons. No differences in alpha or beta diversities or the Firmicutes to Bacteroidetes ratio were found regarding pain severity, mobility or activity level, age, or body composition score., Conclusion: Similar to recent studies in humans, the present study did not demonstrate a significant difference in the fecal microbial communities between dogs with OA pain and healthy control dogs. Future research in this naturally occurring model should expand on these data and relate the gut microbiome to gut permeability and circulating proinflammatory and anti-inflammatory molecules to better understand the influence of the gut microbiome on OA and OA pain., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Published
2024
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42. Prevalence and Factors Associated With High-Impact Chronic Pain in Knee Osteoarthritis: The Johnston County Health Study.

Author

George SZ, Allen KD, Alvarez C, Arbeeva L, Callahan LF, Nelson AE, Schwartz TA, and Golightly YM

Subjects
Humans, Male, Female, Middle Aged, Aged, Prevalence, Patient Reported Outcome Measures, Osteoarthritis, Knee epidemiology, Chronic Pain epidemiology
Abstract

Pain is a hallmark symptom of knee osteoarthritis (KOA), yet intensity and severity vary widely among individuals. There is a knowledge gap in understanding key characteristics of high-impact chronic pain (HICP) within the context of KOA. Therefore, our first purpose was to examine the prevalence of HICP in a cohort of individuals with radiographic evidence of KOA, and our second purpose was to assess patient-level factors associated with HICP. Data from the Johnston County Health Study were used to compare those with and without HICP. Variables included sociodemographic factors, clinical factors, health care use, and psychosocial distress. HICP status was classified with Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference and Physical Function measures. The results indicated that 15.5% (48/310) of participants were classified as having HICP when the PROMIS-Pain Interference cutoff score was used, while 21.2% (66/310) were classified as having HICP with a PROMIS-Physical Function cutoff score. Multivariable analyses indicated that HICP was consistently characterized by increased kinesiophobia and somatization, regardless of PROMIS measure used for HICP status. A secondary insight was that HICP was not consistently characterized by sociodemographic and clinical variables, as these findings were dependent on PROMIS measure used. These findings could be used to develop intervention approaches specific to individuals with KOA and to inform future investigations of sociodemographic and clinical factors associated with HICP. PERSPECTIVE: These findings provide additional information on the characterization of HICP for individuals with KOA. There was consistency in psychosocial factors associated with HICP, while sociodemographic and clinical factors varied based on how HICP status was defined., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Published
2024
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43. Physical activity and symmetry following total knee arthroplasty: Results of a pilot randomized trial.

Author

Queen RM, Arbeeva L, Bracey DN, Hales D, Hill C, Huffman KF, Schwartz TA, and Allen KD

Abstract

Objective: This pilot trial examined a Physical Activity and Symmetry (PAS) intervention focused on common deficits of physical inactivity and joint loading asymmetry following total knee arthroplasty (TKA)., Design: Participants (n ​= ​60) were enrolled during routine physical therapy (PT) following TKA and randomized to the PAS intervention or an attention (ATT) control group. The PAS intervention included physical activity counseling and balance exercise to address joint loading symmetry; content was delivered during 2 sessions at the end of routine PT plus supplemental sessions 4-weeks and 8-weeks following PT. The ATT control condition included supplemental sessions at 4-weeks and 8-weeks focused on general evaluation of surgical recovery benchmarks. Primary outcomes were weekly minutes of moderate to vigorous physical activity (MVPA), measured with an accelerometer, and peak force loading symmetry (limb symmetry index; LSI) during a 10 ​m walk, measured with a 3-sensor in-shoe device. General linear mixed models compared changes in outcomes between randomized groups at 3-month and 6-month follow-up., Results: Both PAS and ATT groups increased MVPA, but there were no clinically meaningful between-group differences at 3- or 6-month follow-up (p ​> ​0.05). There were also no clinically meaningful between-group differences LSI at 3- or 6-month follow-up (p ​> ​0.05)., Conclusion: The PAS intervention did not yield improvements beyond ATT control. It is possible that PAS components were being delivered as part of routine PT, and a more intensive intervention (e.g., more visits, guidance for exercise progression) or targeted approach (e.g., those with deficits at end of routine care) may be needed to further improve outcomes., Competing Interests: The authors have no competing interests to declare.

Published
2024
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44. Investigating the relationship between radiographic joint space width loss and deep learning-derived magnetic resonance imaging-based cartilage thickness loss in the medial weight-bearing region of the tibiofemoral joint.

Author

Minnig MCC, Arbeeva L, Niethammer M, Nissman D, Lund JL, Marron JS, Golightly YM, and Nelson AE

Abstract

Objective: To investigate the relationship between measures of radiographic joint space width (JSW) loss and magnetic resonance imaging (MRI)-based cartilage thickness loss in the medial weight-bearing region of the tibiofemoral joint over 12-24 months. To stratify this relationship by clinically meaningful subgroups (sex and pain status)., Design: We analyzed a subset of knees (n ​= ​256) from the Osteoarthritis Initiative (OAI) likely in early stage OA based on joint space narrowing (JSN) measurements. Natural logarithm transformation was used to approximate near normal distributions for JSW loss. Pearson Correlation coefficients described the relationship between ln-transformed JSW loss and several versions of deep learning-derived MRI-based cartilage thickness loss parameters (minimum, maximum, and mean) in subregions of the femoral condyle, tibial plateau, and combined femoral and tibial regions. Linear mixed-effects models evaluated the associations between the ln-transformed radiographic and MRI-derived measures including potential confounders., Results: We found weak correlations between ln-transformed JSW loss and MRI-based cartilage thickness ranging from R ​= ​-0.13 (p ​= ​0.20) to R ​= ​0.26 (p ​< ​0.01). Correlations were higher (still poor) among females compared to males and painful compared to non-painful knees. Model results showed weak associations for nearly all MRI-based measures, ranging from no association to β (95% CI) ​= ​0.25 (0.11, 0.39). Associations were higher among females compared to males and minimal differences between painful and non-painful knees., Conclusions: Despite its recommended use in disease-modifying OA drug clinical trials, results suggest that JSW loss is an ineffective proxy measure of cartilage thickness loss over 12-24 months and within a localized region of the tibiofemoral joint., (© 2024 The Authors.)

Published
2024
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45. Machine Learning Approaches to the Prediction of Osteoarthritis Phenotypes and Outcomes.

Author

Arbeeva L, Minnig MC, Yates KA, and Nelson AE

Subjects
Humans, Disease Progression, Artificial Intelligence, Biomarkers, Prognosis, Machine Learning, Osteoarthritis diagnosis, Osteoarthritis physiopathology, Phenotype
Abstract

Purpose of Review: Osteoarthritis (OA) is a complex heterogeneous disease with no effective treatments. Artificial intelligence (AI) and its subfield machine learning (ML) can be applied to data from different sources to (1) assist clinicians and patients in decision making, based on machine-learned evidence, and (2) improve our understanding of pathophysiology and mechanisms underlying OA, providing new insights into disease management and prevention. The purpose of this review is to improve the ability of clinicians and OA researchers to understand the strengths and limitations of AI/ML methods in applications to OA research., Recent Findings: AI/ML can assist clinicians by prediction of OA incidence and progression and by providing tailored personalized treatment. These methods allow using multidimensional multi-source data to understand the nature of OA, to identify different OA phenotypes, and for biomarker discovery. We described the recent implementations of AI/ML in OA research and highlighted potential future directions and associated challenges., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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46. Precision Medicine-Based Machine Learning Analyses to Explore Optimal Exercise Therapies for Individuals With Knee Osteoarthritis: Random Forest-Informed Tree-Based Learning.

Author

Kim S, Kosorok MR, Arbeeva L, Schwartz TA, Callahan LF, Golightly YM, Nelson AE, and Allen KD

Subjects
Humans, Precision Medicine, Random Forest, Exercise Therapy methods, Exercise, Treatment Outcome, Osteoarthritis, Knee therapy
Abstract

Objective: We applied a precision medicine-based machine learning approach to discover underlying patient characteristics associated with differential improvement in knee osteoarthritis symptoms following standard physical therapy (PT), internet-based exercise training (IBET), and a usual care/wait list control condition., Methods: Participants (n = 303) were from the Physical Therapy vs Internet-Based Training for Patients with Knee Osteoarthritis trial. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score at 12-month follow-up. Random forest-informed tree-based learning was applied to identify patient characteristics that were critical to improving outcomes, and patients with those features were grouped., Results: Age, BMI, and Brief Fear of Movement (BFOM) score, all at baseline, were identified as characteristics that effectively divided participants, creating 6 subgroups. Assigning treatments according to these models, compared to assigning a single best treatment to all patients, resulted in greater improvements of the average WOMAC at 12 months ( P = 0.01). Key patterns were that IBET was the optimal treatment for patients of younger age and low BFOM, whereas PT was the optimal treatment for patients of older age, high BFOM, and BMI (kg/m 2 ) between 26.3 and 37.2., Conclusion: These results suggest that easily assessed patient characteristics including age, fear of movement, and BMI could be used to guide patients toward either home-based exercise or PT, though additional studies are needed to confirm these findings. (ClinicalTrials.gov: NCT02312713)., (Copyright © 2023 by the Journal of Rheumatology.)

Published
2023
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47. Intestinal Helminth Infection Impairs Oral and Parenteral Vaccine Efficacy.

Author

Zhang Y, Hardy LC, Kapita CM, Hall JA, Arbeeva L, Campbell E, Urban JF, Belkaid Y, Nagler CR, and Iweala OI

Subjects
Mice, Animals, Vaccine Efficacy, CD4-Positive T-Lymphocytes, Vaccines, Synthetic, Ovalbumin, Mice, Inbred BALB C, Helminthiasis, Intestinal Diseases, Parasitic
Abstract

The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters Ag-specific Ab and cellular immune responses to oral and parenteral vaccination in mice. Oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine expressing chicken egg OVA (Salmonella-OVA) induced the accumulation of activated, OVA-specific T effector cells rather than OVA-specific regulatory T cells in the GALT. Intestinal helminth infection significantly reduced Th1-skewed Ab responses to oral vaccination with Salmonella-OVA. Activated, adoptively transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes of vaccinated mice, regardless of their helminth infection status. However, helminth infection increased the frequencies of adoptively transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the mesenteric lymph node. Ab responses to the oral Salmonella-OVA vaccine were reduced in helminth-free mice adoptively transferred with OVA-specific CD4+ T cells harvested from mice with intestinal helminth infection. Intestinal helminth infection also significantly reduced Th2-skewed Ab responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest that vaccine-specific CD4+ T cells induced in the context of helminth infection retain durable immunomodulatory properties and may promote blunted Ab responses to vaccination. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Published
2023
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48. Author Correction: The power of genetic diversity in genome-wide association studies of lipids.

Author

Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, Surakka I, Ntalla I, Vedantam S, Winkler TW, Locke AE, Marouli E, Hwang MY, Han S, Narita A, Choudhury A, Bentley AR, Ekoru K, Verma A, Trivedi B, Martin HC, Hunt KA, Hui Q, Klarin D, Zhu X, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Ruotsalainen SE, Havulinna AS, Veturi Y, Feng Q, Rosenthal EA, Lingren T, Pacheco JA, Pendergrass SA, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Hindy G, Rasheed A, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Willemsen G, Wood AR, Ji Y, Gao Z, Haworth S, Mitchell RE, Chai JF, Aadahl M, Yao J, Manichaikul A, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Sidore C, Fiorillo E, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Thuesen BH, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Daw EW, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Feitosa MF, Wojczynski MK, Preuss M, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Kember RL, Slieker RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Leonard HL, Marten J, Schmidt B, Arendt M, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Ahmed M, Jackson AU, Yousri NA, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Chai X, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Hung YJ, Chen S, Liu F, Yang J, Kentistou KA, Gorski M, Brumat M, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Xue C, Zhang J, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, Lee J, van der Laan SW, Chitrala KN, Weiss S, Zimmermann ME, Lee JY, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hildalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Schwander K, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Highland HM, Young KL, Kawaguchi T, Thiery J, Bis JC, Nadkarni GN, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, Bhatti KF, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Chen YE, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SLR, Kato N, Schulze MB, Girotto G, Jung B, Böger CA, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, den Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Hunt SC, Walker M, Koistinen HA, Chandak GR, Yajnik CS, Mercader JM, Tusié-Luna T, Aguilar-Salinas CA, Villalpando CG, Orozco L, Fornage M, Tai ES, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Lu F, Qu J, Hishigaki H, Lin X, März W, Parra EJ, Cruz M, Gudnason V, Tardif JC, Lettre G, 't Hart LM, Elders PJM, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Psaty BM, Brandslund I, Pramstaller PP, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney LALM, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Cucca F, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, de Geus EJC, Cupples LA, van Meurs JBJ, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Justice AE, Baras A, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Thorsteinsdottir U, Stefansson K, Ho YL, Lynch JA, Rader DJ, Tsao PS, Chang KM, Cho K, O'Donnell CJ, Gaziano JM, Wilson P, Rotimi CN, Hazelhurst S, Ramsay M, Trembath RC, van Heel DA, Tamiya G, Yamamoto M, Kim BJ, Mohlke KL, Frayling TM, Hirschhorn JN, Kathiresan S, Boehnke M, Natarajan P, Peloso GM, Brown CD, Morris AP, Assimes TL, Deloukas P, Sun YV, and Willer CJ

Published
2023
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49. CC-Chemokine Receptor-2 Expression in Osteoblasts Contributes to Cartilage and Bone Damage during Post-Traumatic Osteoarthritis.

Author

Willcockson H, Ozkan H, Valdés-Fernández J, Arbeeva L, Mucahit E, Musawwir L, Hooper LB, Granero-Moltó F, Prósper F, and Longobardi L

Subjects
Mice, Animals, Receptors, CCR2 genetics, Bone and Bones metabolism, Pain, Osteoblasts metabolism, Disease Progression, Osteophyte, Osteoarthritis metabolism, Cartilage, Articular metabolism
Abstract

In osteoarthritis (OA), bone changes are radiological hallmarks and are considered important for disease progression. The C-C chemokine receptor-2 (CCR2) has been shown to play an important role in bone physiology. In this study, we investigated whether Ccr2 osteoblast-specific inactivation at different times during post-traumatic OA (PTOA) progression improves joint structures, bone parameters, and pain. We used a tamoxifen-inducible Ccr2 inactivation in Collagen1α-expressing cells to obtain osteoblasts lacking Ccr2 ( CCR2 - Col1αKO ). We stimulated PTOA changes in CCR2 - Col1αKO and CCR2 +/+ mice using the destabilization of the meniscus model (DMM), inducing recombination before or after DMM (early- vs. late-inactivation). Joint damage was evaluated at two, four, eight, and twelve weeks post-DMM using multiple scores: articular-cartilage structure (ACS), Safranin-O, histomorphometry, osteophyte size/maturity, subchondral bone thickness and synovial hyperplasia. Spontaneous and evoked pain were assessed for up to 20 weeks. We found that early osteoblast- Ccr2 inactivation delayed articular cartilage damage and matrix degeneration compared to CCR2 +/+, as well as DMM-induced bone thickness. Osteophyte formation and maturation were only minimally affected. Late Collagen1α- Ccr2 deletion led to less evident improvements. Osteoblast- Ccr2 deletion also improved static measures of pain, while evoked pain did not change. Our study demonstrates that Ccr2 expression in osteoblasts contributes to PTOA disease progression and pain by affecting both cartilage and bone tissues.

Published
2023
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50. Patterns of variation among baseline femoral and tibial cartilage thickness and clinical features: Data from the osteoarthritis initiative.

Author

Keefe TH, Minnig MC, Arbeeva L, Niethammer M, Xu Z, Shen Z, Chen B, Nissman DB, Golightly YM, Marron JS, and Nelson AE

Abstract

Objective: To employ novel methodologies to identify phenotypes in knee OA based on variation among three baseline data blocks: 1) femoral cartilage thickness, 2) tibial cartilage thickness, and 3) participant characteristics and clinical features., Methods: Baseline data were from 3321 Osteoarthritis Initiative (OAI) participants with available cartilage thickness maps (6265 knees) and 77 clinical features. Cartilage maps were obtained from 3D DESS MR images using a deep-learning based segmentation approach and an atlas-based analysis developed by our group. Angle-based Joint and Individual Variation Explained (AJIVE) was used to capture and quantify variation, both shared among multiple data blocks and individual to each block, and to determine statistical significance., Results: Three major modes of variation were shared across the three data blocks. Mode 1 reflected overall thicker cartilage among men, those with higher education, and greater knee forces; Mode 2 showed associations between worsening Kellgren-Lawrence Grade, medial cartilage thinning, and worsening symptoms; and Mode 3 contrasted lateral and medial-predominant cartilage loss associated with BMI and malalignment. Each data block also demonstrated individual, independent modes of variation consistent with the known discordance between symptoms and structure in knee OA and reflecting the importance of features such as physical function, symptoms, and comorbid conditions independent of structural damage., Conclusions: This exploratory analysis, combining the rich OAI dataset with novel methods for determining and visualizing cartilage thickness, reinforces known associations in knee OA while providing insights into the potential for data integration in knee OA phenotyping., Competing Interests: Drs. Nelson and Golightly have received grant funding unrelated to this work from the 10.13039/100000030Centers for Disease Control and Prevention and 10.13039/100000002NIH/10.13039/100000069NIAMS and are Associate Editors of Osteoarthritis and Cartilage. Dr. Nelson is a Board Member of the Osteoarthritis Research Society International (OARSI)., (© 2023 The Author(s).)

Published
2023
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