Haller Gabe, Alvarado David, Mccall Kevin, Yang Ping, Cruchaga Carlos, Harms Matthew, Goate Alison, Willing Marcia, Morcuende Jose A, Baschal Erin, Miller Nancy H, Wise Carol, Dobbs Matthew B, Gurnett Christina A
Department of Orthopaedic Surgery.
Department of Psychiatry.
Hum Mol Genet. 2016 Jan 1;25(1):202-9. doi: 10.1093/hmg/ddv463. Epub 2015 Nov 12.
Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. While common genetic variants are associated with AIS, they explain only a small portion of disease risk. To explore the role of rare variants in AIS susceptibility, exome sequence data of 391 severe AIS cases and 843 controls of European ancestry were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level then by Gene Ontology terms. Novel non-synonymous/splice-site variants in extracellular matrix genes were significantly enriched in AIS cases compared with controls (P = 6 × 10(-9), OR = 1.7, CI = 1.4-2.0). Specifically, novel variants in musculoskeletal collagen genes were present in 32% (126/391) of AIS cases compared with 17% (146/843) of in-house controls and 18% (780/4300) of EVS controls (P = 1 × 10(-9), OR = 1.9, CI = 1.6-2.4). Targeted resequencing of six collagen genes replicated this association in combined 919 AIS cases (P = 3 × 10(-12), OR = 2.2, CI = 1.8-2.7) and revealed a highly significant single-gene association with COL11A2 (P = 6 × 10(-9), OR = 3.8, CI = 2.6-7.2). Importantly, AIS cases harbor mainly non-glycine missense mutations and lack the clinical features of monogenic musculoskeletal collagenopathies. Overall, our study reveals a complex genetic architecture of AIS in which a polygenic burden of rare variants across extracellular matrix genes contributes strongly to risk.
青少年特发性脊柱侧凸（AIS）是一种复杂的遗传性脊柱畸形，其病因一直难以捉摸。虽然常见的基因变异与AIS有关，但它们仅解释了疾病风险的一小部分。为了探索罕见变异在AIS易感性中的作用，我们使用通路负荷分析对391例严重AIS病例和843例欧洲血统对照的外显子序列数据进行了分析，该分析先在基因水平上对变异进行合并，然后按基因本体术语进行合并。与对照相比，细胞外基质基因中的新型非同义/剪接位点变异在AIS病例中显著富集（P = 6×10^(-9)，OR = 1.7，CI = 1.4 - 2.0）。具体而言，肌肉骨骼胶原基因中的新型变异在32%（126/391）的AIS病例中存在，而在内部对照中为17%（146/843），在EVS对照中为18%（780/4300）（P = 1×10^(-9)，OR = 1.9，CI = 1.6 - 2.4）。对六个胶原基因的靶向重测序在919例合并的AIS病例中重复了这种关联（P = 3×10^(-12)，OR = 2.2，CI = 1.8 - 2.7），并揭示了与COL11A2的高度显著单基因关联（P = 6×10^(-9)，OR = 3.8，CI = 2.6 - 7.2）。重要的是，AIS病例主要携带非甘氨酸错义突变，且缺乏单基因肌肉骨骼胶原病的临床特征。总体而言，我们的研究揭示了AIS复杂的遗传结构，其中细胞外基质基因中罕见变异的多基因负荷对风险有很大贡献。
