步速的复杂遗传学：全基因组荟萃分析方法
The complex genetics of gait speed: genome-wide meta-analysis approach.
作者信息
Ben-Avraham Dan, Karasik David, Verghese Joe, Lunetta Kathryn L, Smith Jennifer A, Eicher John D, Vered Rotem, Deelen Joris, Arnold Alice M, Buchman Aron S, Tanaka Toshiko, Faul Jessica D, Nethander Maria, Fornage Myriam, Adams Hieab H, Matteini Amy M, Callisaya Michele L, Smith Albert V, Yu Lei, De Jager Philip L, Evans Denis A, Gudnason Vilmundur, Hofman Albert, Pattie Alison, Corley Janie, Launer Lenore J, Knopman Davis S, Parimi Neeta, Turner Stephen T, Bandinelli Stefania, Beekman Marian, Gutman Danielle, Sharvit Lital, Mooijaart Simon P, Liewald David C, Houwing-Duistermaat Jeanine J, Ohlsson Claes, Moed Matthijs, Verlinden Vincent J, Mellström Dan, van der Geest Jos N, Karlsson Magnus, Hernandez Dena, McWhirter Rebekah, Liu Yongmei, Thomson Russell, Tranah Gregory J, Uitterlinden Andre G, Weir David R, Zhao Wei, Starr John M, Johnson Andrew D, Ikram M Arfan, Bennett David A, Cummings Steven R, Deary Ian J, Harris Tamara B, Kardia Sharon L R, Mosley Thomas H, Srikanth Velandai K, Windham Beverly G, Newman Ann B, Walston Jeremy D, Davies Gail, Evans Daniel S, Slagboom Eline P, Ferrucci Luigi, Kiel Douglas P, Murabito Joanne M, Atzmon Gil
机构信息
Department of Medicine and Genetics Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02131, USA.
出版信息
Aging (Albany NY). 2017 Jan 10;9(1):209-246. doi: 10.18632/aging.101151.
Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
新出现的证据表明，晚年活动能力差异的部分原因可归因于遗传因素，且随着年龄增长，遗传因素可能变得越发重要。我们的目标是系统评估老年个体中基因变异对步速的影响。我们对CHARGE联盟17个队列中的31478名老年人的步速全基因组关联研究（GWAS）进行了荟萃分析，并在来自4项独立研究的2588名老年人中验证了我们的结果。我们在组织中对候选信号进行网络分析和表达数量性状基因座（eQTL）分析，以跟进我们最初的发现。荟萃分析得出了一份包含69个基因内部或附近536个提示性全基因组显著单核苷酸多态性（SNP）的列表。通过通路分析进一步探究发现，步速是五个主要网络中的一个多基因复杂性状。随后的eQTL分析揭示了几个与丝氨酸蛋白酶16（PRSS16）、WD重复结构域蛋白1（WDSUB1）和蛋白酪氨酸磷酸酶受体T（PTPRT）表达显著相关的SNP，这除了荟萃分析和通路分析之外，还表明对步速的遗传影响可能通过突触功能和神经元发育途径发生。在这个规模适中的老年人群样本中，未发现步速的全基因组显著信号，这表明需要更精细的身体功能表型来确定衰老过程中步速的遗传基础。
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