Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 × 10-5 ). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 × 10-10 ). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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有明显骨折史的儿童常见风险等位基因的负担增加。

儿童常见病的极端表现通常被认为是孟德尔病因，但其多基因基础尚未得到充分探索。我们测试了有明显骨折史且没有成骨不全症 (OI) 的儿童是否会增加骨折的多基因风险。儿童时期的重大骨折史被定义为存在低创伤椎体骨折或多处长骨骨折。我们生成了足跟超声衍生的声速的多基因评分，称为“gSOS”，它可以预测骨质疏松性骨折的风险。我们测试了来自三个具有显着儿童骨折史的人群的 gSOS 是否较低。一个加拿大队列包括 94 名疑似孟德尔骨质疏松症的儿童，其中 68 名 OI 基因组为阴性。两个芬兰队列包括 59 名有明显骨折史的儿童和 22 名疑似孟德尔骨质疏松症的儿童，其中 18 名没有 OI。在排除了具有 OI 和祖先异常值的个体后，我们生成了 gSOS 估计值，并将它们的平均值与代表普通人群的英国生物银行子集的平均值进行了比较。所有三个队列 (n = 131) 的平均 gSOS 比 UK Biobank (n = 80,027, p = 1.1 × 10-5) 低 -0.47 SD。78 名疑似孟德尔骨质疏松症患者的 gSOS 甚至更低（-0.76 SD，p = 5.3 × 10-10）。在有明显骨折史的 131 人中，我们观察到 8 人的 gSOS 低于平均值 - 2 SD；他们的平均腰椎 DXA 衍生的骨矿物质密度 Z 评分为 -1.7 (SD 0.8)。总之，有严重骨折史但没有 OI 的儿童的常见风险等位基因负担增加。这表明，对于有极端骨折表现的儿童，应考虑多基因对疾病的贡献。© 2020 美国骨与矿物研究学会。