講演情報
[O3-4]脊柱後縦靭帯骨化症の新規遺伝子領域の発見と肥満との因果関係
○小池 良直1,2,3,4, 高畑 雅彦3,4, 中島 正宏2, 寺尾 知可史2, 池川 志郎1,3,4 (1.理化学研究所 生命医科学研究センター 骨関節疾患研究チーム, 2.理化学研究所 生命医科学研究センター ゲノム解析応用研究チーム, 3.北海道大学大学院 整形外科学教室, 4.脊柱靱帯骨化症GWAS研究グループ)
Ossification of the posterior longitudinal ligament of the spine (OPLL) is a disease that causes spinal canal compromise and serious neurological sequelae in advanced cases. Its etiology and pathogenesis are mostly unknown. Lifestyle related diseases such as type 2 diabetes (T2D) and obesity have been implicated in the development of OPLL; however, no trait has been proven to have a causal relationship. To clarify the etiology and pathogenesis of OPLL, we conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, eight of which were previously unreported. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic and the other types. GWAS sub-analyses identified subtype-specific signals. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified five and three potential causal genes, respectively. These loci/genes contained bone metabolism-related genes. Genetic correlations with 99 complex traits showed positive correlation with T2D and body mass index (BMI) and negative correlation with cerebral aneurysm and osteoporosis. Mendelian randomization analyses demonstrated a significant causal effect of high BMI and high bone mineral density on OPLL, but not of T2D, indicating that high BMI confounded the T2D correlation. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insights into the etiology and pathogenesis of OPLL.