Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.
Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.
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DOI：
10.1371/journal.pgen.1000856
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发表时间：
2010-02-26
期刊：
影响因子：
4.5
通讯作者：
Jarvelin MR
中科院分区：
文献类型：
--
作者：
Pillas D;Hoggart CJ;Evans DM;O'Reilly PF;Sipilä K;Lähdesmäki R;Millwood IY;Kaakinen M;Netuveli G;Blane D;Charoen P;Sovio U;Pouta A;Freimer N;Hartikainen AL;Laitinen J;Vaara S;Glaser B;Crawford P;Timpson NJ;Ring SM;Deng G;Zhang W;McCarthy MI;Deloukas P;Peltonen L;Elliott P;Coin LJ;Smith GD;Jarvelin MR
牙齿发育是一个高度可遗传的过程，它与其他生长发育过程有关，并与整个头面部复合体的发育相互作用。牙齿发育异常很常见，其中牙齿发育不全是人类最常见的发育异常。我们对1966年芬兰北部出生队列(NFBC1966)的4564名个体和雅芳亲子纵向研究(ALSPAC)的1518名个体进行了一项关于首次牙齿萌发时间和一年内牙齿数量的全基因组关联研究。我们在P<；5×10−8处发现了5个基因座，其中5个与暗示性关联(P<；5×10−6)。这些基因座包括与牙齿和其他器官发育相关的几个基因(KCNJ2、EDA、HOXB2、RAD51L1、IGF2BP1、HMGA2、MSRB3)。已确定的四个基因座上的基因与癌症的发生有关。HOXB基因簇中的一个变异与31岁之前需要正畸治疗的咬合缺陷有关。全基因组关联研究已被用于识别与疾病易感性、中间表型和生理特征有关的遗传变异，如身高、头发颜色和月经初潮年龄。在这里，我们分析了NFBC1966和ALSPAC的出生队列，以调查一个关键的发育过程的遗传决定因素：乳牙发育。我们研究的前瞻性使我们能够准确测量第一次牙齿萌出时的年龄和一年的牙齿数量，并提供机会评估影响这些特征的基因变异是否与稍后生命过程中的牙齿问题有关。在我们发现的与乳牙发育相关的基因中，有几个已经确立了在牙齿发育和生长中的作用，几乎一半的基因提出了与癌症发生有关的建议。我们发现，其中一个变异还与咬合缺陷有关，需要在以后的生活中进行正畸治疗。我们的发现应该为研究牙齿发育的遗传结构提供坚实的基础，这一研究及其与医学和牙科的相关性可能会在进化生物学中产生影响，因为牙齿是进化的重要标志。
Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years. Genome-wide association studies have been used to identify genetic variants conferring susceptibility to diseases, intermediate phenotypes, and physiological traits such as height, hair color, and age at menarche. Here we analyze the NFBC1966 and ALSPAC birth cohorts to investigate the genetic determinants of a key developmental process: primary tooth development. The prospective nature of our studies allows us to exploit accurate measurements of age at first tooth eruption and number of teeth at one year, and also provides the opportunity to assess whether genetic variants affecting these traits are associated with dental problems later in the life course. Of the genes that we find to be associated with primary tooth development, several have established roles in tooth development and growth, and almost half have proposed links with the development of cancer. We find that one of the variants is also associated with occlusion defects requiring orthodontic treatment later in life. Our findings should provide a strong foundation for the study of the genetic architecture of tooth development, which as well as its relevance to medicine and dentistry, may have implications in evolutionary biology since teeth represent important markers of evolution.
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