Medicine

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Patterns of change of multisite pain over one year of follow-up and related risk factors
(Philadelphia : Saunders, London, 2022) Ntani, G.; Coggon, D.; Felli, V.E.; Harari, F.; Barrero, L.H.; Felknor, S.A.; Rojas, M.; Serra, C.; Bonzini, M.; Merisalu, E.; Habib, R.R.; Sadeghian, F.; Wickremasinghe, A.R.; Matsudaira, K.; Nyantumbu-Mkhize, B.; Kelsall, H.L.; Harcombe, H.; Walker-Bone, K.
Background: Multisite musculoskeletal pain is common and disabling. This study aimed to prospectively investigate distribution of musculoskeletal pain anatomically, and explore risk factors for increases/reductions in the number of painful sites. Methods: Using data from participants working in 45 occupational groups in 18 countries, we explored changes in reporting pain at 10 anatomical sites on two occasions 14 months apart. We used descriptive statistics to explore consistency over time in the number of painful sites, and their anatomical distribution. Baseline risk factors for increases/reductions by ≥3 painful sites were explored by random intercept logistic regression that adjusted for baseline number of painful sites. Results: Amongst 8,927 workers, only 20% reported no pain at either time point, and 16% reported ≥3 painful sites both times. After 14 months, the anatomical distribution of pain often changed but there was only an average increase of 0.17 painful sites. Some 14% workers reported a change in painful sites by ≥ 3. Risk factors for an increase of ≥ 3 painful sites included female sex, lower educational attainment, having a physically demanding job, and adverse beliefs about the work-relatedness of musculoskeletal pain. Also predictive were: older age, somatising tendency, and poorer mental health (each of which was also associated with lower odds of reductions of ≥ 3 painful sites). Conclusions: Longitudinally, the number of reported painful sites was relatively stable but the anatomical distribution varied considerably. These findings suggest an important role for central pain sensitisation mechanisms, rather than localised risk factors, among working adults.
The power of genetic diversity in genome-wide association studies of lipids
(Macmillan Journals Ltd, 2021) Graham, S.E.; Clarke, S.L.; Wu, K.H.; Kanoni, S.; Zajac, G.J.M.; Ramdas, S.; Surakka, I.; Ntalla, I.; Vedantam, S.; Winkler, T.W.; Locke, A.E.; Marouli, E.; Hwang, M.Y.; Han, S.; Narita, A.; Choudhury, A.; Bentley, A.R.; Ekoru, K.; Verma, A.; Trivedi, B.; Martin, H.C.; Hunt, K.A.; Hui, Q.; Klarin, D.; Zhu, X.; Thorleifsson, G.; Helgadottir, A.; Gudbjartsson, D.F.; Holm, H.; Olafsson, I.; Akiyama, M.; Sakaue, S.; Terao, C.; Kanai, M.; Zhou, W.; Brumpton, B.M.; Rasheed, H.; Ruotsalainen, S.E.; Havulinna, A.S.; Veturi, Y.; Feng, Q.; Rosenthal, E.A.; Lingren, T.; Pacheco, J.A.; Pendergrass, S.A.; Haessler, J.; Giulianini, F.; Bradford, Y.; Miller, J.E.; Campbell, A.; Lin, K.; Millwood, I.Y.; Hindy, G.; Rasheed, A.; Faul, J.D.; Zhao, W.; Weir, D.R.; Turman, C.; Huang, H.; Graff, M.; Mahajan, A.; Brown, M.R.; Zhang, W.; Yu, K.; Schmidt, E.M.; Pandit, A.; Gustafsson, S.; Yin, X.; Luan, J.; Zhao, J.H.; Matsuda, F.; Jang, H.M.; Yoon, K.; Medina-Gomez, C.; Pitsillides, A.; Hottenga, J.J.; Willemsen, G.; Wood, A.R.; Ji, Y.; Gao, Z.; Haworth, S.; Mitchell, R.E.; Chai, J.F.; Aadahl, M.; Yao, J.; Manichaikul, A.; Warren, H.R.; Ramirez, J.; Bork-Jensen, J.; Kårhus, L.L.; Goel, A.; Sabater-Lleal, M.; Noordam, R.; Sidore, C.; Fiorillo, E.; McDaid, A.F.; Marques-Vidal, P.; Wielscher, M.; Trompet, S.; Sattar, N.; Møllehave, L.T.; Thuesen, B.H.; Munz, M.; Zeng, L.; Huang, J.; Yang, B.; Poveda, A.; Kurbasic, A.; Lamina, C.; Forer, L.; Scholz, M.; Galesloot, T.E.; Bradfield, J.P.; Daw, E.W.; Zmuda, J.M.; Mitchell, J.S.; Fuchsberger, C.; Christensen, H.; Brody, J.A.; Feitosa, M.F.; Wojczynski, M.K.; Preuss, M.; Mangino, M.; Christofidou, P.; Verweij, N.; Benjamins, J.W.; Engmann, J.; Kember, R.L.; Slieker, R.C.; Lo, K.S.; Zilhao, N.R.; Le, P.; Kleber, M.E.; Delgado, G.E.; Huo, S.; Ikeda, D.D.; Iha, H.; Yang, J.; Liu, J.; Leonard, H.L.; Marten, J.; Schmidt, B.; Arendt, M.; Smyth, L.J.; Cañadas-Garre, M.; Wang, C.; Nakatochi, M.; Wong, A.; Hutri-Kähönen, N.; Sim, X.; Xia, R.; Huerta-Chagoya, A.; Fernandez-Lopez, J.C.; Lyssenko, V.; Ahmed, M.; Jackson, A.U.; Irvin, M.R.; Oldmeadow, C.; Kim, H.N.; Ryu, S.; Timmers, P.R.H.J.; Arbeeva, L.; Dorajoo, R.; Lange, L.A.; Chai, X.; Prasad, G.; Lorés-Motta, L.; Pauper, M.; Long, J.; Li, X.; Theusch, E.; Takeuchi, F.; Spracklen, C.N.; Loukola, A.; Bollepalli, S.; Warner, S.C.; Wang, Y.X.; Wei, W.B.; Nutile, T.; Ruggiero, D.; Sung, Y.J.; Hung, Y.J.; Chen, S.; Liu, F.; Yang, J.; Kentistou, K.A.; Gorski, M.; Brumat, M.; Meidtner, K.; Bielak, L.F.; Smith, J.A.; Hebbar, P.; Farmaki, A.E.; Hofer, E.; Lin, M.; Xue, C.; Zhang, J.; Concas, M.P.; Vaccargiu, S.; van der Most, P.J.; Pitkänen, N.; Cade, B.E.; Lee, J.; van der Laan, S.W.; Chitrala, K.N.; Weiss, S.; Zimmermann, M.E.; Lee, J.Y.; Choi, H.S.; Nethander, M.; Freitag-Wolf, S.; Southam, L.; Rayner, N.W.; Wang, C.A.; Lin, S.Y.; Wang, J.S.; Couture, C.; Lyytikäinen, L.P.; Nikus, K.; Cuellar-Partida, G.; Vestergaard, H.; Hildalgo, B.; Giannakopoulou, O.; Cai, Q.; Obura, M.O.; van Setten, J.; Li, X.; Schwander, K.; Terzikhan, N.; Shin, J.H.; Jackson, R.D.; Reiner, A.P.; Martin, L.W.; Chen, Z.; Li, L.; Highland, H.M.; Young, K.L.; Kawaguchi, T.; Thiery, J.; Bis, J.C.; Nadkarni, G.N.; Launer, L.J.; Li, H.; Nalls, M.A.; Raitakari, O.T.; Ichihara, S.; Wild, S.H.; Nelson, C.P.; Campbell, H.; Jäger, S.; Nabika, T.; Al-Mulla, F.; Niinikoski, H.; Braund, P.S.; Kolcic, I.; Kovacs, P.; Giardoglou, T.; Katsuya, T.; Bhatti, K.F.; de Kleijn, D.; de Borst, G.J.; Kim, E.K.; Adams, H.H.H.; Ikram, M.A.; Zhu, X.; Asselbergs, F.W.; Kraaijeveld, A.O.; Beulens, J.W.J.; Shu, X.O.; Rallidis, L.S.; Pedersen, O.; Hansen, T.; Mitchell, P.; Hewitt, A.W.; Kähönen, M.; Pérusse, L.; Bouchard, C.; Tönjes, A.; Chen, Y.I.; Pennell, C.E.; Mori, T.A.; Lieb, W.; Franke, A.; Ohlsson, C.; Mellström, D.; Cho, Y.S.; Lee, H.; Yuan, J.M.; Koh, W.P.; Rhee, S.Y.; Woo, J.T.; Heid, I.M.; Stark, K.J.; Völzke, H.; Homuth, G.; Evans, M.K.; Zonderman, A.B.; Polasek, O.; Pasterkamp, G.; Hoefer, I.E.; Redline, S.; Pahkala, K.; Oldehinkel, A.J.; Snieder, H.; Biino, G.; Schmidt, R.; Schmidt, H.; Chen, Y.E.; Bandinelli, S.; Dedoussis, G.; Thanaraj, T.A.; Kardia, S.L.R.; Kato, N.; Schulze, M.B.; Girotto, G.; Jung, B.; Böger, C.A.; Joshi, P.K.; Bennett, D.A.; de Jager, P.L.; Lu, X.; Mamakou, V.; Brown, M.; Caulfield, M.J.; Munroe, P.B.; Guo, X.; Ciullo, M.; Jonas, J.B.; Samani, N.J.; Kaprio, J.; Pajukanta, P.; Adair, L.S.; Bechayda, S.A.; de Silva, H.J.; Wickremasinghe, A.R.; Krauss, R.M.; Wu, J.Y.; Zheng, W.; den Hollander, A.I.; Bharadwaj, D.; Correa, A.; Wilson, J.G.; Lind, L.; Heng, C.K.; Nelson, A.E.; Golightly, Y.M.; Wilson, J.F.; Penninx, B.; Kim, H.L.; Attia, J.; Scott, R.J.; Rao, D.C.; Arnett, D.K.; Walker, M.; Koistinen, H.A.; Chandak, G.R.; Yajnik, C.S.; Mercader, J.M.; Tusié-Luna, T.; Aguilar-Salinas, C.A.; Villalpando, C.G.; Orozco, L.; Fornage, M.; Tai, E.S.; van Dam, R.M.; Lehtimäki, T.; Chaturvedi, N.; Yokota, M.; Liu, J.; Reilly, D.F.; McKnight, A.J.; Kee, F.; Jöckel, 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.; März, 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.; Widén, 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.; Männikkö, 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.BJ.; Ghanbari, M.; Gordon-Larsen, P.; Huang, W.; Kim, Y.T.; 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.; Åsvold, 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.; VA Million Veteran Program; Global Lipids Genetics Consortium
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.

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