Patiño-Salazar J D, Ovejero D, Gabernet M, Martínez-Gil N, Alcaide-Consuegra E, Mellibovsky L, Nogués X, Grinberg D, Balcells S, Rabionet R, Garcia-Giralt N
Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, CIBERER, IBUB, IRSJD, Barcelona, Spain.
Musculoskeletal Research Group, Hospital del Mar Research Institute, Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Barcelona, Spain.
Osteoporos Int. 2025 Apr;36(4):637-644. doi: 10.1007/s00198-025-07413-4. Epub 2025 Feb 7.
Rare genetic variants in genes previously described to be involved in bone monogenic disorders were identified in postmenopausal women split into two groups according to extreme bone mineral density (BMD) values and lumbar spine Z-scores. A pathogenic variant in COL1A2 gene found in a woman with low BMD highlights the overlap between osteogenesis imperfecta and osteoporosis, which may share their genetic etiology. Other variants were not clearly associated with the extreme BMD, suggesting that there is little contribution of rare variants to postmenopausal osteoporosis.
We aimed to evaluate whether extreme values of bone mineral density (BMD) in a population-based cohort of postmenopausal women (BARCOS) could be determined by rare genetic variants in genes related to monogenic bone disorders.
A panel of 127 genes related to different skeletal phenotypes was designed. Massive sequencing by targeted capture of these genes was performed in 104 DNA samples from those women of the BARCOS cohort that exhibited the highest (HZ group) and lowest (LZ group) LS Z-scores, ranging from + 0.70 to + 3.80 and from - 2.35 to - 4.26, respectively. 5'UTR, 3'UTR, splice region, missense, nonsense, and short indel variants with MAF < 0.01 were annotated with CADD version 1.6 and considered in the analysis.
After filtering those variants with CADD > 25 and present only in one of the groups (either LZ or HZ), six variants were detected, most of which (5/6) were in the LZ group in TCIRG1, COL1A2, SEC24D, LRP4, and ANO5 genes, while only one, in the LMNA gene, was in the HZ group. According to the ClinVar database, the COL1A2 variant, causative of a recessive form of osteogenesis imperfecta, is described as pathogenic, while the other variants are considered of uncertain significance (VUS).
The variant identified in COL1A2 in a woman from the LZ group highlights the genetic overlap between monogenic diseases such as osteogenesis imperfecta and complex diseases like osteoporosis. However, the other variants were not clearly associated with the extreme BMD, suggesting that there is little contribution of rare variants to postmenopausal osteoporosis.
在根据极端骨矿物质密度（BMD）值和腰椎Z评分分为两组的绝经后女性中，鉴定出先前描述与骨单基因疾病相关基因中的罕见遗传变异。在一名低骨密度女性中发现的COL1A2基因中的致病变异突出了成骨不全症和骨质疏松症之间的重叠，它们可能共享遗传病因。其他变异与极端骨密度没有明显关联，这表明罕见变异对绝经后骨质疏松症的影响很小。
我们旨在评估在基于人群的绝经后女性队列（BARCOS）中，骨矿物质密度（BMD）的极端值是否可由与单基因骨疾病相关基因中的罕见遗传变异来确定。
设计了一组与不同骨骼表型相关的127个基因。对BARCOS队列中腰椎Z评分最高（HZ组）和最低（LZ组）的104名女性的DNA样本进行靶向捕获大规模测序，HZ组和LZ组的腰椎Z评分范围分别为+0.70至+3.80和-2.35至-4.26。使用CADD 1.6版本对MAF < 0.01的5'UTR、3'UTR、剪接区域、错义、无义及短插入缺失变异进行注释，并纳入分析。
在筛选出CADD > 25且仅存在于其中一组（LZ或HZ）的变异后，检测到6个变异，其中大部分（5/6）在LZ组的TCIRG1、COL1A2、SEC24D、LRP4和ANO5基因中，而仅1个在HZ组的LMNA基因中。根据ClinVar数据库，导致隐性成骨不全症的COL1A2变异被描述为致病的，而其他变异被认为意义不明确（VUS）。
在LZ组一名女性中鉴定出的COL1A2变异突出了成骨不全症等单基因疾病与骨质疏松症等复杂疾病之间的遗传重叠。然而，其他变异与极端骨密度没有明显关联，这表明罕见变异对绝经后骨质疏松症的影响很小。
