Identification of PDXDC1 as a novel pleiotropic susceptibility locus shared between lumbar spine bone mineral density and birth weight.
Identification of PDXDC1 as a novel pleiotropic susceptibility locus shared between lumbar spine bone mineral density and birth weight.
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PDXDC1 被鉴定为腰椎骨矿物质密度和出生体重之间共有的新型多效性易感基因座
DOI：
10.1007/s00109-021-02165-0
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发表时间：
2022-05
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影响因子：
--
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中科院分区：
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--
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越来越多的流行病学研究表明，出生体重（BW）可能是日后骨骼健康的决定因素，尽管潜在的遗传机制仍不清楚。在这里，我们应用多效性条件错误发现率（cFDR）方法对腰椎骨密度（LS BMD）和BW的全基因组关联研究（GWAS）汇总统计量进行分析，旨在确定这两种特征之间共享的新的易感性变体。我们发现了5个新的潜在多效性基因座，它们位于7个不同的基因（NTAN 1，PDXDC 1，CACNA 1G，JAG 1，FAT 1 P1，CCDC 170，ESR 1）上或附近，其中PDXDC 1和FAT 1 P1以前没有与这些表型连锁。为了部分验证这一发现，我们证明，与假手术（SHAM）小鼠相比，卵巢切除（OVX）小鼠的生长板和小梁骨中PDXDC 1的表达显著降低。此外，免疫组化分析表明，破骨细胞和成骨细胞都表达PDXDC 1，支持其在骨代谢中的潜在作用。总之，我们的研究提供了一些共同的遗传机制，骨密度和体重的见解，以及一个新的潜在的治疗目标，预防OP的早期阶段的疾病发展。我们研究了LS BMD和BW之间的多效性信息富集。我们利用cFDR方法鉴定了与LS BMD和BW相关的遗传变异。PDXDC 1是一个新的多效性基因，可能与LS BMD和BW均相关。PDXDC 1的表达升高与较高的BMD和较低的n-6/n-3 PUFA比率相关，表明PDXDC 1具有骨保护作用。在线版本包含补充材料，可通过10.1007/s 00109 -021-02165-0获得。
An increasing number of epidemiological studies have suggested that birth weight (BW) may be a determinant of bone health later in life, although the underlying genetic mechanism remains unclear. Here, we applied a pleiotropic conditional false discovery rate (cFDR) approach to the genome-wide association study (GWAS) summary statistics for lumbar spine bone mineral density (LS BMD) and BW, aiming to identify novel susceptibility variants shared between these two traits. We detected 5 novel potential pleiotropic loci which are located at or near 7 different genes (NTAN1, PDXDC1, CACNA1G, JAG1, FAT1P1, CCDC170, ESR1), among which PDXDC1 and FAT1P1 have not previously been linked to these phenotypes. To partially validate the findings, we demonstrated that the expression of PDXDC1 was dramatically reduced in ovariectomized (OVX) mice in comparison with sham-operated (SHAM) mice in both the growth plate and trabecula bone. Furthermore, immunohistochemistry assay with serial sections showed that both osteoclasts and osteoblasts express PDXDC1, supporting its potential role in bone metabolism. In conclusion, our study provides insights into some shared genetic mechanisms for BMD and BW as well as a novel potential therapeutic target for the prevention of OP in the early stages of the disease development. We investigated pleiotropy-informed enrichment between LS BMD and BW. We identified genetic variants related to both LS BMD and BW by utilizing a cFDR approach. PDXDC1 is a novel pleiotropic gene which may be related to both LS BMD and BW. Elevated expression of PDXDC1 is related to higher BMD and lower ratio n-6/n-3 PUFA indicating a bone protective effect of PDXDC1. The online version contains supplementary material available at 10.1007/s00109-021-02165-0.
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影响因子：
64.8
作者：
Horikoshi, Momoko;Beaumont, Robin N.;Day, Felix R.;Warrington, Nicole M.;Kooijman, Marjolein N.;Fernandez-Tajes, Juan;Feenstra, Bjarke;van Zuydam, Natalie R.;Gaulton, Kyle J.;Grarup, Niels;Bradfield, Jonathan P.;Strachan, David P.;Li-Gao, Ruifang;Ahluwalia, Tarunveer S.;Kreiner, Eskil;Rueedi, Rico;Lyytikainen, Leo-Pekka;Cousminer, Diana L.;Wu, Ying;Thiering, Elisabeth;Wang, Carol A.;Have, Christian T.;Hottenga, Jouke-Jan;Vilor-Tejedor, Natalia;Joshi, Peter K.;Boh, Eileen Tai Hui;Ntalla, Ioanna;Pitkanen, Niina;Mahajan, Anubha;van Leeuwen, Elisabeth M.;Joro, Raimo;Lagou, Vasiliki;Nodzenski, Michael;Diver, Louise A.;Zondervan, Krina T.;Bustamante, Mariona;Marques-Vidal, Pedro;Mercader, Josep M.;Bennett, Amanda J.;Rahmioglu, Nilufer;Nyholt, Dale R.;Ma, Ronald C. W.;Tam, Claudia H. T.;Tam, Wing Hung;Ganesh, Santhi K.;van Rooij, Frank J. A.;Jones, Samuel E.;Loh, Po-Ru;Ruth, Katherine S.;Tuke, Marcus A.;Tyrrell, Jessica;Wood, Andrew R.;Yaghootkar, Hanieh;Scholtens, Denise M.;Paternoster, Lavinia;Prokopenko, Inga;Kovacs, Peter;Atalay, Mustafa;Willems, Sara M.;Panoutsopoulou, Kalliope;Wang, Xu;Carstensen, Lisbeth;Geller, Frank;Schraut, Katharina E.;Murcia, Mario;van Beijsterveldt, Catharina E. M.;Willemsen, Gonneke;Appel, Emil V. R.;Fonvig, Cilius E.;Trier, Caecilie;Tiesler, Carla M. T.;Standl, Marie;Kutalik, Zoltan;Bonas-Guarch, Silvia;Hougaard, David M.;Sanchez, Friman;Torrents, David;Waage, Johannes;Hollegaard, Mads V.;de Haan, Hugoline G.;Rosendaal, Frits R.;Medina-Gomez, Carolina;Ring, Susan M.;Hemani, Gibran;McMahon, George;Robertson, Neil R.;Groves, Christopher J.;Langenberg, Claudia;Luan, Jian'an;Scott, Robert A.;Zhao, Jing Hua;Mentch, Frank D.;MacKenzie, Scott M.;Reynolds, Rebecca M.;Lowe, William L.;Toenjes, Anke;Stumvoll, Michael;Lindi, Virpi;Lakka, Timo A.;van Duijn, Cornelia M.;Kiess, Wieland;Koerner, Antje;Sorensen, Thorkild I. A.;Niinikoski, Harri;Pahkala, Katja;Raitakari, Olli T.;Zeggini, Eleftheria;Dedoussis, George V.;Teo, Yik-Ying;Saw, Seang-Mei;Melbye, Mads;Campbell, Harry;Wilson, James F.;Vrijheid, Martine;de Geus, Eco J. C. N.;Boomsma, Dorret I.;Kadarmideen, Haja N.;Holm, Jens-Christian;Hansen, Torben;Sebert, Sylvain;Hattersley, Andrew T.;Beilin, Lawrence J.;Newnham, John P.;Pennell, Craig E.;Heinrich, Joachim;Adair, Linda S.;Borja, Judith B.;Mohlke, Karen L.;Eriksson, Johan G.;Widen, Elisabeth;Kahonen, Mika;Viikari, Jorma S.;Lehtimaki, Terho;Vollenweider, Peter;Bonnelykke, Klaus;Bisgaard, Hans;Mook-Kanamori, Dennis O.;Hofman, Albert;Rivadeneira, Fernando;Uitterlinden, Andre G.;Pisinger, Charlotta;Pedersen, Oluf;Power, Christine;Hyppoenen, Elina;Wareham, Nicholas J.;Hakonarson, Hakon;Davies, Eleanor;Walker, Brian R.;Jaddoe, Vincent W. V.;Jaervelin, Marjo-Riitta;Grant, Struan F. A.;Vaag, Allan A.;Lawlor, Debbie A.;Frayling, Timothy M.;Smith, George Davey;Morris, Andrew P.;Ong, Ken K.;Felix, Janine F.;Timpson, Nicholas J.;Perry, John R. B.;Evans, David M.;McCarthy, Mark I.;Freathy, Rachel M.
通讯作者：
Freathy, Rachel M.
影响因子：
4.1
作者：
Kuipers, Allison;Zhang, Yingze;Cauley, Jane A.;Nestlerode, Cara S.;Chu, Yanxia;Bunker, Clareann H.;Patrick, Alan L.;Wheeler, Victor W.;Hoffman, Andrew R.;Orwoll, Eric S.;Zmuda, Joseph M.
通讯作者：
Zmuda, Joseph M.
影响因子：
5.9
作者：
Cinelli G;Fabrizi M;Ravà L;Signore F;Vernocchi P;Semeraro M;Vallone C;Lanciotti R;Ciofi Degli Atti M;Manco M
通讯作者：
Manco M
DOI：
10.1073/pnas.1532175100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Charalambous, M;Smith, FM;Ward, A
通讯作者：
Ward, A
影响因子：
6.2
作者：
Burge, Russel;Dawson-Hughes, Bess;Tosteson, Anna
通讯作者：
Tosteson, Anna