Genetic insights into ossification of the posterior longitudinal ligament of the spine.

Autor:	Koike Y; 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., Takahata M; Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan., Nakajima M; Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan., Otomo N; 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., Suetsugu H; 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., Liu X; Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan., Endo T; Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan., Imagama S; Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan., Kobayashi K; Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan., Kaito T; Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan., Kato S; Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan., Kawaguchi Y; Department of Orthopaedic Surgery, Toyama University, Toyama, Japan., Kanayama M; Department of Orthopedics, Hakodate Central General Hospital, Hakodate, Japan., Sakai H; Department of Orthopaedic Surgery, Spinal Injuries Center, Iizuka, Japan., Tsuji T; Department of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan.; Department of Spine and Spinal Cord Surgery, Fujita Health University, Toyoake, Japan., Miyamoto T; Department of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan.; Department of Orthopedic Surgery, Kumamoto University, Kumamoto, Japan., Inose H; Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan., Yoshii T; Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan., Kashii M; Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan., Nakashima H; Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan., Ando K; Department of Orthopedics, Nagoya University Graduate School of Medicine, Nagoya, Japan., Taniguchi Y; Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan., Takeuchi K; Department of Orthopaedic Surgery, National Okayama Medical Center, Okayama, Japan., Ito S; 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., Tomizuka K; Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan., Hikino K; Laboratory for Pharmacogenomics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan., Iwasaki Y; Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan., Kamatani Y; Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan., Maeda S; Department of Bone and Joint Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Nakajima H; Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Mori K; Department of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, Japan., Seichi A; Department of Orthopedics, Jichi Medical University, Shimotsuke, Japan., Fujibayashi S; Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Kanchiku T; Department of Orthopedic Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan., Watanabe K; Department of Orthopaedic Surgery, Niigata University Medical and Dental General Hospital, Nankoku, Japan., Tanaka T; Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan., Kida K; Department of Orthopaedic Surgery, Kochi Medical School, Nankoku, Japan., Kobayashi S; Department of Orthopaedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan., Takahashi M; Department of Orthopaedic Surgery, Kyorin University School of Medicine, Tokyo, Japan., Yamada K; Department of Orthopaedic Surgery, Kurume University School of Medicine, Obu, Japan., Takuwa H; 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., Lu HF; 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., Niida S; Core Facility Administration, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan., Ozaki K; Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan., Momozawa Y; Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan., Yamazaki M; Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan., Okawa A; Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan., Matsumoto M; Department of Orthopedic Surgery, Keio University School of Medicine, Nagoya, Japan., Iwasaki N; Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan., Terao C; Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan., Ikegawa S; 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.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Jul 18; Vol. 12. Date of Electronic Publication: 2023 Jul 18.
DOI:	10.7554/eLife.86514
Abstrakt:	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. Competing Interests: YK, MT, MN, NO, HS, XL, TE, SI, KK, TK, SK, MK, HS, TT, TM, HI, TY, MK, HN, KA, YT, KT, SI, KT, KH, YI, YK, SM, HN, KM, AS, SF, TK, KW, TT, KK, SK, MT, KY, HT, HL, SN, KO, YM, AO, MM, NI, CT, SI No competing interests declared, YK Consulting fees from Medacta International, MY representatives of Japanese Organization of the Study for Ossification of Spinal Ligament (© 2023, Koike, Takahata, Nakajima et al.)
Databáze:	MEDLINE
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