Abstract Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development. Research organism: Human
SHOW FULL ABSTRACT Yoshinao Koike, Masahiko Takahata, Masahiro Nakajima, Nao Otomo, Hiroyuki Suetsugu, Xiaoxi Liu, Tsutomu Endo, Shiro Imagama, Kazuyoshi Kobayashi, Takashi Kaito, Satoshi Kato, Yoshiharu Kawaguchi, Masahiro Kanayama, Hiroaki Sakai, Takashi Tsuji, Takeshi Miyamoto, Hiroyuki Inose, Toshitaka Yoshii, Masafumi Kashii, Hiroaki Nakashima, Kei Ando, Yuki Taniguchi, Kazuhiro Takeuchi, Shuji Ito, Kohei Tomizuka, Keiko Hikino, Yusuke Iwasaki, Yoichiro Kamatani, Shingo Maeda, Hideaki Nakajima, Kanji Mori, Atsushi Seichi, Shunsuke Fujibayashi, Tsukasa Kanchiku, Kei Watanabe, Toshihiro Tanaka, Kazunobu Kida, Sho Kobayashi, Masahito Takahashi, Kei Yamada, Hiroshi Takuwa, Hsing-Fang Lu, Shumpei Niida, Kouichi Ozaki, Yukihide Momozawa, Masashi Yamazaki, Atsushi Okawa, Morio Matsumoto, Norimasa Iwasaki, Chikashi Terao, Shiro Ikegawa, Cheryl Ackert-Bicknell
1Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan 2Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan 3Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan 4Department of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan 5Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 6Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan 7Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan 8Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan 9Department of Orthopaedic Surgery, Toyama University, Toyama, Japan 10Department of Orthopedics, Hakodate Central General Hospital, Hakodate, Japan 11Department of Orthopaedic Surgery, Spinal Injuries Center, Iizuka, Japan 12Department of Spine and Spinal Cord Surgery, Fujita Health University, Toyoake, Japan 13Department of Orthopedic Surgery, Kumamoto University, Kumamoto, Japan 14Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan 15Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan 16Department of Orthopaedic Surgery, National Okayama Medical Center, Okayama, Japan 17Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, Japan 18Laboratory for Pharmacogenomics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan 19Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan 20Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan 21Department of Bone and Joint Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan 22Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan 23Department of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, Japan 24Department of Orthopedics, Jichi Medical University, Shimotsuke, Japan 25Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan 26Department of Orthopedic Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan 27Department of Orthopaedic Surgery, Niigata University Medical and Dental General Hospital, Nankoku, Japan 28Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan 29Department of Orthopaedic Surgery, Kochi Medical School, Nankoku, Japan 30Department of Orthopaedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan 31Department of Orthopaedic Surgery, Kyorin University School of Medicine, Tokyo, Japan 32Department of Orthopaedic Surgery, Kurume University School of Medicine, Obu, Japan 33Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan 34Core Facility Administration, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan 35Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan 36Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan 37University of Colorado, United States 38Icahn School of Medicine at Mount Sinai, United States 1University of Colorado, United States 1University of Colorado, United States 