Genetic insights into ossification of the posterior longitudinal ligament of the spine
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 (...
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2023-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/86514 |
| _version_ | 1797776553618178048 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yoshinao Koike |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T22:51:34Z |
| format | Article |
| id | doaj.art-eda7d0627866429283f54547e72b72f0 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T22:51:34Z |
| publishDate | 2023-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-eda7d0627866429283f54547e72b72f02023-07-20T10:53:36ZengeLife Sciences Publications LtdeLife2050-084X2023-07-011210.7554/eLife.86514Genetic insights into ossification of the posterior longitudinal ligament of the spineYoshinao Koike0https://orcid.org/0000-0002-5431-5572Masahiko Takahata1Masahiro Nakajima2Nao Otomo3Hiroyuki Suetsugu4Xiaoxi Liu5Tsutomu Endo6Shiro Imagama7Kazuyoshi Kobayashi8Takashi Kaito9Satoshi Kato10Yoshiharu Kawaguchi11Masahiro Kanayama12Hiroaki Sakai13Takashi Tsuji14Takeshi Miyamoto15Hiroyuki Inose16https://orcid.org/0000-0003-4195-2545Toshitaka Yoshii17Masafumi Kashii18Hiroaki Nakashima19Kei Ando20Yuki Taniguchi21https://orcid.org/0000-0002-2329-123XKazuhiro Takeuchi22Shuji Ito23Kohei Tomizuka24Keiko Hikino25Yusuke Iwasaki26Yoichiro Kamatani27Shingo Maeda28Hideaki Nakajima29Kanji Mori30Atsushi Seichi31Shunsuke Fujibayashi32Tsukasa Kanchiku33Kei Watanabe34Toshihiro Tanaka35Kazunobu Kida36Sho Kobayashi37https://orcid.org/0000-0002-8002-2001Masahito Takahashi38Kei Yamada39Hiroshi Takuwa40Hsing-Fang Lu41Shumpei Niida42https://orcid.org/0000-0002-6192-8035Kouichi Ozaki43Yukihide Momozawa44Genetic Study Group of Investigation Committee on Ossification of the Spinal LigamentsMasashi Yamazaki45Atsushi Okawa46Morio Matsumoto47Norimasa Iwasaki48Chikashi Terao49https://orcid.org/0000-0002-6452-4095Shiro Ikegawa50Laboratory 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, JapanDepartment of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, JapanLaboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, JapanLaboratory 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, JapanLaboratory 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, JapanLaboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, JapanDepartment of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, JapanDepartment of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, JapanDepartment of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, JapanDepartment of Orthopaedic Surgery, Toyama University, Toyama, JapanDepartment of Orthopedics, Hakodate Central General Hospital, Hakodate, JapanDepartment of Orthopaedic Surgery, Spinal Injuries Center, Iizuka, JapanDepartment of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan; Department of Spine and Spinal Cord Surgery, Fujita Health University, Toyoake, JapanDepartment of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan; Department of Orthopedic Surgery, Kumamoto University, Kumamoto, JapanDepartment of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, JapanDepartment of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Orthopaedic Surgery, National Okayama Medical Center, Okayama, JapanLaboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, JapanLaboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, JapanLaboratory for Pharmacogenomics, Center for Integrative Medical Sciences, RIKEN, Yokohama, JapanLaboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, JapanLaboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, JapanDepartment of Bone and Joint Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, JapanDepartment of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanDepartment of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, JapanDepartment of Orthopedics, Jichi Medical University, Shimotsuke, JapanDepartment of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Orthopedic Surgery, Yamaguchi University Graduate School of Medicine, Ube, JapanDepartment of Orthopaedic Surgery, Niigata University Medical and Dental General Hospital, Nankoku, JapanDepartment of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDepartment of Orthopaedic Surgery, Kochi Medical School, Nankoku, JapanDepartment of Orthopaedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanDepartment of Orthopaedic Surgery, Kyorin University School of Medicine, Tokyo, JapanDepartment of Orthopaedic Surgery, Kurume University School of Medicine, Obu, JapanLaboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, JapanLaboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, TaiwanCore Facility Administration, Research Institute, National Center for Geriatrics and Gerontology, Obu, JapanMedical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, JapanLaboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, JapanDepartment of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, JapanDepartment of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Orthopedic Surgery, Keio University School of Medicine, Nagoya, JapanDepartment of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, JapanLaboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, JapanLaboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, JapanOssification 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.https://elifesciences.org/articles/86514ossification of the posterior longitudinal ligament of the spinegenome-wide association studyMendelian randomizationpolygenic risk scoreobesitybone mineral density |
| spellingShingle | 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 Genetic insights into ossification of the posterior longitudinal ligament of the spine eLife ossification of the posterior longitudinal ligament of the spine genome-wide association study Mendelian randomization polygenic risk score obesity bone mineral density |
| title | Genetic insights into ossification of the posterior longitudinal ligament of the spine |
| title_full | Genetic insights into ossification of the posterior longitudinal ligament of the spine |
| title_fullStr | Genetic insights into ossification of the posterior longitudinal ligament of the spine |
| title_full_unstemmed | Genetic insights into ossification of the posterior longitudinal ligament of the spine |
| title_short | Genetic insights into ossification of the posterior longitudinal ligament of the spine |
| title_sort | genetic insights into ossification of the posterior longitudinal ligament of the spine |
| topic | ossification of the posterior longitudinal ligament of the spine genome-wide association study Mendelian randomization polygenic risk score obesity bone mineral density |
| url | https://elifesciences.org/articles/86514 |
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