RIKEN IMS AnnualReport 2020
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24Common bone and joint diseases are serious worldwide problems for health and the economy, as exemplified by the WHO initiative “Bone and Joint De-cade” (2000-2010) and the “Locomotive syndrome campaign” in Japan. We are searching for susceptibility genes for common (polygenic) bone and joint diseases, including osteoarthritis (OA), lumbar disc disease (LDD)/herniation (LDH), osteoporosis, avascular necrosis of the femoral head (ANF), scoliosis, and ossification of the posterior longitudinal ligament of the spine (OPLL).Through genome-wide association studies (GWASs) and next-generation sequencing approaches, we identify and characterize susceptibility genes and clarify their disease-causing mechanisms at the molecular level. Using the ge-nome information obtained from these studies, we will realize our final goal of “personalized medicine”. GWASs for OA, LDD/LDH, adolescent idiopathic scoliosis (AIS), OPLL, and ANF are in progress, and we have succeeded in the identification of several susceptibility genes. Functional studies of the genes in vitro and using animal models are underway.2) Genomic Study of Skeletal DysplasiaSkeletal dysplasia is a group of heritable (monogenic) disorders affecting the skeleton, and more than 450 diseases belong to this category. Skeletal dysplasia is an intractable disease, so many patients are waiting for an effective treatment. We are engaging in clinical and basic studies of these difficult diseases. By large-scale mutation screening, including exome sequencing, we are identifying the disease-causative genes (by now, we have identified 30 novel genes).Through the analyses of phenotypes and diseases genes, we consider the molecular mechanisms of bone and joint formation and the pathogenesis of common bone and joint diseases, as well as the diagnosis and treatment of rare intractable diseases. Using the disease genes for skeletal dysplasia as candidate genes, we perform association studies for common bone and joint diseases cor-responding to skeletal dysplasia, the so-called “rare to common” approach.Figure: GWAS meta-analysis results from SLE East Asians including 13,377 cases and 194,993 controls. Known and novel loci are represented in light blue and pink, respectively. The red dashed line: the genome-wide association significance threshold of p=5×10-8. The grey dashed line: p=10-30.Recent Major PublicationsYin X, Kim K, Suetsugu H, Bang SY, Wen L, Koido M, Ha E, Liu L, Sakamoto Y, Jo S, Leng RX, Otomo N, Laurynenka V, Kwon YC, Sheng Y, Sugano N, Hwang MY, Li W, Mukai M, Yoon K, Cai M, Ishigaki K, Chung WT, Huang H, Takahashi D, Lee SS, Wang M, Karino K, Shim SC, Zheng X, Miyamura T, Kang YM, Ye D, Nakamura J, …, Yamamoto K, Harley JB, Ohmura K, Kim TH, Yang S, Yamamoto T, Kim BJ, Shen N, Ikegawa S, Lee HS, Zhang X, Terao C, Cui Y, Bae SC. Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus. Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219209 (Epub 2020)Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Terao C, Amariuta T, Gazal S, Kochi Y, Horikoshi M, Suzuki K, Ito K, Koyama S, Ozaki K, Niida S, Sakata Y, Sakata Y, Kohno T, Shiraishi K, Momozawa Y, Hirata M, Matsuda K, Ikeda M, Iwata N, Ikegawa S, Kou I, Tanaka T, Nakagawa H, Suzuki A, …, Yamamoto K, Murakami Y, Nakamura Y, Raychaud-huri S, Inazawa J, Yamauchi T, Kadowaki T, Kubo M, Ka-matani Y. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet 52, 669-679 (2020)Matsuda M, Yamanaka Y, Uemura M, Osawa M, Megumu K, Saito MK, Nagahashi A, Nishio M, Guo L, Ikegawa S, Sakurai S, Kihara S, Maurissen TL, Nakamura M, Matsumoto T, Yoshitomi H, Ikeya M, Kawakami N, Yamamoto T, Woltjen K, Ebisuya M, Toguchida J, Alev C. Recapitulating the human segmentation clock with pluripotent stem cells. Nature 580, 124-129 (2020)Invited presentationsIkegawa S. “Identification of Novel Disease Genes and Re-classification of Dysosteosclerosis” The 65th Annual Meeting of the Japan Society of Human Genetics (English Symposium) (Nagoya, Japan/Online) November 2020Ikegawa S. “Genomic Study of Rare Diseases of Skeleton” India -Japan Webinar on "Rare Genetic Disorders" by Em-bassy of India (Tokyo, Japan/Online) October 2020Ikegawa S. “Genomic Study of Posterior Longitudinal Liga-ment of the Spine– Past, present and future” The 35th Annual Meeting of the Japan Orthopedic Society Basic Research Meeting) (Tokyo, Japan/Online) October 2020Ikegawa S. “Genomic Medicine in Orthopedics– Past, pres-ent and future)” The 135th Annual Meeting of the Middle Japan Orthopedic Society (Shimane, Japan/Online) October 2020Ikegawa S. “Differential Diagnosis of Skeletal Dysplasias and Genetic Skeletal Disorders” Virtual APAC MPS Summit 2020 (Taipei/Tokyo/Sydney/Seattle/Online) September 2020Laboratory for Bone and Joint DiseasesTeam Leader: Shiro Ikegawa1) Genomic Study of Common Diseases

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