Chen Shan, Jain Mahim, Jhangiani Shalini, Akdemir Zeynep C, Campeau Philippe M, Klein Robert F, Nielson Carrie, Dai Hongzheng, Muzny Donna M, Boerwinkle Eric, Gibbs Richard A, Orwoll Eric S, Lupski James R, Posey Jennifer E, Lee Brendan
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA.
Osteogenesis Imperfecta Clinic, Kennedy Krieger Institute Baltimore MD USA.
JBMR Plus. 2020 Jan 22;4(3):e10335. doi: 10.1002/jbm4.10335. eCollection 2020 Mar.
Worldwide, one in five men aged over 50 years will experience osteoporosis or a clinical bone fracture, with a greater fracture-related mortality rate than women. However, the genetic etiology of osteoporosis in men is still poorly understood. We aimed to identify the genetic variants and candidate genes associated with extremely low or high BMD for a better understanding of the biology underlying low bone density that may point to potential therapeutic targets for increasing bone mass. Subjects from the Osteoporotic Fractures in Men Study (MrOS) cohort were evaluated by age and BMI-adjusted total hip BMD. Those with BMD values 3 SDs away from the mean were selected and the remaining individuals whose adjusted BMD ranked at the highest or lowest 100 were included. Men with the lowest adjusted BMD ( = 98) and highest adjusted BMD ( = 110) were chosen for exome sequencing. Controls ( = 82) were men of Northern and Western European descent from the US Utah population of the 1000 Genomes Project. Fisher's exact test was performed to compare low- or high-BMD subjects with controls for single-gene associations. Additionally, sets of candidate genes causative of heritable disorders of connective tissue, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), were grouped for multigene and mutation burden analyses. No single-gene associations with rare variants were found for either the low BMD group (33 genes) or high BMD group (18 genes). In the group of OI genes, we detected a significant threefold increased accumulation of rare variants in low-BMD subjects compared with controls ( = 0.009). Additionally, genes associated with EDS had a twofold increased frequency in low-BMD subjects compared with controls ( = 0.03). These findings reveal a rare variant burden in OI and EDS disease genes at low BMD, which suggests a potential gene-panel approach to screen for multivariant associations in larger cohorts. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
在全球范围内，每五名50岁以上的男性中就有一人会患骨质疏松症或发生临床骨折，其骨折相关死亡率高于女性。然而，男性骨质疏松症的遗传病因仍知之甚少。我们旨在识别与极低或极高骨密度相关的基因变异和候选基因，以便更好地理解低骨密度背后的生物学机制，这可能会为增加骨量指明潜在的治疗靶点。对男性骨质疏松性骨折研究（MrOS）队列中的受试者进行年龄和体重指数调整后的全髋骨密度评估。选择骨密度值与平均值相差3个标准差的受试者，并纳入其余调整后骨密度排名最高或最低的100名个体。选择调整后骨密度最低的男性（n = 98）和最高的男性（n = 110）进行外显子组测序。对照组（n = 82）是来自1000基因组计划美国犹他州人群的北欧和西欧血统男性。进行Fisher精确检验，以比较低骨密度或高骨密度受试者与对照组的单基因关联。此外，将包括成骨不全（OI）和埃勒斯-丹洛斯综合征（EDS）在内的结缔组织遗传性疾病的候选基因集进行分组，以进行多基因和突变负担分析。低骨密度组（33个基因）和高骨密度组（18个基因）均未发现与罕见变异的单基因关联。在OI基因组中，我们检测到低骨密度受试者中罕见变异的积累比对照组显著增加了三倍（P = 0.009）。此外，与EDS相关的基因在低骨密度受试者中的频率比对照组增加了两倍（P = 0.03）。这些发现揭示了低骨密度时OI和EDS疾病基因中的罕见变异负担，这表明在更大的队列中进行多变量关联筛查时，采用基因panel方法具有潜在可能性。© 2019作者。由Wiley Periodicals, Inc.代表美国骨与矿物质研究学会出版。
