对儿童和成人全身体骨密度的全基因组扫描进行荟萃分析,揭示了 WNT16 基因座的等位基因异质性和年龄特异性效应。
Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus.
机构信息
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
出版信息
PLoS Genet. 2012 Jul;8(7):e1002718. doi: 10.1371/journal.pgen.1002718. Epub 2012 Jul 5.
To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1 × 10(-11) observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ± 500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6 × 10(-31) and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42 × 10(-10)) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9 × 10(-16)) and rs7801723 (P = 8.9 × 10(-28)), also mapping to C7orf58 (r(2) = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later in life.
为了确定影响骨骼积累的遗传基因座,我们对来自不同种族的 2660 名儿童的全身骨矿物质密度(TB-BMD)变异进行了全基因组关联扫描。我们发现了 7q31.31 处与 BMD 测量值相关的变体,最小等位基因频率为 0.37 的 rs917727 的 P 值最低,为 4.1×10(-11)。我们在包括儿童和成人在内的五个独立研究的 11052 名个体中,针对位于 rs917727 周围±500kb 的所有 SNP 进行了复制,在发现队列中的儿童的 1014 名母亲中,还对 rs3801387(与 rs917727 完全连锁不平衡(LD))进行了从头基因分型。在研究中,WNT16 周围的信号映射得到了复制,荟萃分析 P = 2.6×10(-31),并且能够解释 0.6%-1.8%的 TB-BMD 变异。对该信号进行条件分析显示,对于全身 BMD(P = 1.42×10(-10)),rs4609139 映射到 C7orf58 的二级信号。我们还检查了颅骨 BMD 关联的基因组区域,以测试关联是否独立于骨骼负荷。我们鉴定了两个影响颅骨 BMD 变化的信号,包括 rs917727(P = 1.9×10(-16))和 rs7801723(P = 8.9×10(-28)),它们也映射到 C7orf58(r(2) = 0.50 与 rs4609139)。在人类骨活检中具有降低的全身 BMD 和基因表达谱的 Wnt16 敲除(KO)小鼠支持 C7orf58 和 WNT16 在人类群体水平上观察到的 BMD 表型中的作用。总之,我们在儿童和成人中检测到两个独立的信号,影响全身和颅骨 BMD 变化,从而证明了 WNT16 基因座等位基因异质性的存在。一个颅骨 BMD 信号映射到 C7orf58 主要由儿童驱动,这表明在峰值骨量获取过程中存在时间决定因素。我们的生命历程方法假设,这些影响峰值骨量积累的遗传效应可能会影响以后生活中的骨质疏松症风险。