eLife (Jul 2023)
Genetic insights into ossification of the posterior longitudinal ligament of the spine
- 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,
- Genetic Study Group of Investigation Committee on Ossification of the Spinal Ligaments,
- Masashi Yamazaki,
- Atsushi Okawa,
- Morio Matsumoto,
- Norimasa Iwasaki,
- Chikashi Terao,
- Shiro Ikegawa
Affiliations
- Yoshinao Koike
- ORCiD
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Masahiko Takahata
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Masahiro Nakajima
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan
- Nao Otomo
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; Department of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan
- Hiroyuki Suetsugu
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Xiaoxi Liu
- Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
- Tsutomu Endo
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Shiro Imagama
- Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Kazuyoshi Kobayashi
- Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Takashi Kaito
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan
- Satoshi Kato
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
- Yoshiharu Kawaguchi
- Department of Orthopaedic Surgery, Toyama University, Toyama, Japan
- Masahiro Kanayama
- Department of Orthopedics, Hakodate Central General Hospital, Hakodate, Japan
- Hiroaki Sakai
- Department of Orthopaedic Surgery, Spinal Injuries Center, Iizuka, Japan
- Takashi Tsuji
- Department of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan; Department of Spine and Spinal Cord Surgery, Fujita Health University, Toyoake, Japan
- Takeshi Miyamoto
- Department of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan; Department of Orthopedic Surgery, Kumamoto University, Kumamoto, Japan
- Hiroyuki Inose
- ORCiD
- Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
- Toshitaka Yoshii
- Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
- Masafumi Kashii
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan
- Hiroaki Nakashima
- Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Kei Ando
- Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Yuki Taniguchi
- ORCiD
- Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
- Kazuhiro Takeuchi
- Department of Orthopaedic Surgery, National Okayama Medical Center, Okayama, Japan
- Shuji Ito
- Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, Japan
- Kohei Tomizuka
- Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
- Keiko Hikino
- Laboratory for Pharmacogenomics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
- Yusuke Iwasaki
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
- Yoichiro Kamatani
- Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
- Shingo Maeda
- Department of Bone and Joint Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Hideaki Nakajima
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
- Kanji Mori
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, Japan
- Atsushi Seichi
- Department of Orthopedics, Jichi Medical University, Shimotsuke, Japan
- Shunsuke Fujibayashi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Tsukasa Kanchiku
- Department of Orthopedic Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
- Kei Watanabe
- Department of Orthopaedic Surgery, Niigata University Medical and Dental General Hospital, Nankoku, Japan
- Toshihiro Tanaka
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Kazunobu Kida
- Department of Orthopaedic Surgery, Kochi Medical School, Nankoku, Japan
- Sho Kobayashi
- ORCiD
- Department of Orthopaedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Masahito Takahashi
- Department of Orthopaedic Surgery, Kyorin University School of Medicine, Tokyo, Japan
- Kei Yamada
- Department of Orthopaedic Surgery, Kurume University School of Medicine, Obu, Japan
- Hiroshi Takuwa
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, Japan
- Hsing-Fang Lu
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan
- Shumpei Niida
- ORCiD
- Core Facility Administration, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan
- Kouichi Ozaki
- Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan
- Yukihide Momozawa
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
- Genetic Study Group of Investigation Committee on Ossification of the Spinal Ligaments
- Masashi Yamazaki
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
- Atsushi Okawa
- Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
- Morio Matsumoto
- Department of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan
- Norimasa Iwasaki
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Chikashi Terao
- ORCiD
- Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
- Shiro Ikegawa
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- DOI
- https://doi.org/10.7554/eLife.86514
- Journal volume & issue
-
Vol. 12
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.
Keywords
- ossification of the posterior longitudinal ligament of the spine
- genome-wide association study
- Mendelian randomization
- polygenic risk score
- obesity
- bone mineral density
